Oncology

Haploidentical bone marrow transplant

Haploidentical bone marrow transplant

What every physician needs to know about haploidentical bone marrow transplant

History of haploidentical transplantation

Previous attempts of haploidentical transplantation using bone marrow (BM) and myeloablative conditioning regimen were associated with early and severe side effects, including hyperacute graft-versus-host disease (GVHD). In addition, high numbers of graft failures were observed. Attempts to partially deplete T-lymphocytes from the graft, brought some improvements in survival rates, but the transplant-related mortality was still unacceptably high.

More recently, newer and more efficient methods of in-vitro T-cell depletion techniques, and more effective drugs for in-vivo T-cell depletion and for pharmacological prophylaxis of GVHD became available, and haploidentical transplantation is now a reasonable alternative for patients without a suitable donor, and who can only be cured by an allogeneic transplantation.

When to perform a haploidentical transplantation

A human leukocyte antigen (HLA) matched sibling donor is the first choice, followed by an HLA-matched unrelated donor (MUD). The probability of identifying a MUD donor in the world-wide donor registry is dependent on the diversity of HLA antigens within a population, and on the patient's race. Moreover, a world-wide donor search is time-consuming and the time from initiation to actual transplant is in most cases 4 months or longer.

During the donor search, a significant proportion of patients will progress or even die, and an allogeneic hematopoietic stem cell transplantation (HSCT) will no longer be a therapeutic option. In order to avoid prolonged donor search time and the risk of disease progression, a tool to estimate the probability of identifying a "10 out of 10" HLA allele-matched unrelated donor has been described. This tool is helpful in guiding therapeutic strategies if the probability is found to be low.

An alternative and very rapid approach for patients without HLA-matched donors, or for patients at high risk of disease progression during the donor search, is the use of mismatched related family donors. In pediatric patients, these are mainly three out of six HLA-mismatched parental donors; in adult patients, mainly mismatched siblings or mismatched children of the patients. These donors are readily available within a few days and are also available during the post transplant course, for further adoptive immunotherapeutic strategies.

Conditioning regimens

The choice of the conditioning regimen depends on the clinical status of the patient, the underlying disease, the previous treatments, and patient age. The transplant-related mortality (TRM) is generally higher in older patients (greater than 50 years of age), after myeloablative regimens independent of the donor.

In haploidentical HSCT, various approaches have been used, such as myeloablative regimens with ex vivo T-cell depleted peripheral blood stem cells (PBSC), reduced intensity conditioning (RIC) regimens with ex vivo or in vivo T-cell depletion and post transplant pharmacoprophylaxis for GVHD, and myeloablative regimens with in vivo T-cell depletion, and post transplant GVHD pharmacoprophylaxis.

Most published series of haploidentical HSCT are small and involve diverse diseases and remission states; they therefore not allow final conclusions about which conditioning regimen should be used.

Total body irradiation (TBI) based myeloablative regimens, with partial T-cell depletion and post transplant immunosuppression are associated with a lower incidence of GVHD, but a higher rate of TRM. Nevertheless, encouraging results were observed in patients with advanced hematological malignancies. By using high numbers of mobilized peripheral blood stem cells (PBSC) and a more vigorous T-cell depletion technique, a very low incidence of GVHD was observed in patients with acute leukemias after conditioning with TBI, thiotepa, fludarabine, and anti-thymocyte globulin. However, the TRM is still in the range of 40% when using this approach.

Large numbers of CD34+ positively selected peripheral stem cells were transplanted after myeloablative conditioning in adults and children. While the incidence of GVHD was very low in the absence of any post transplant immunosuppression, the TRM was still high in the range of 36.5% and 37% for adults and children, respectively. Beside the organ toxicity from the conditioning regimen, the delayed immune reconstitution associated with severe and often lethal viral and fungal infections was the major contributor to the TRM in both adult and pediatric patients.

T-cell replete haploidentical transplants with granulocyte colony-stimulating factor (G-CSF) primed bone marrow, and unmanipulated PBSC with intensive in vivo T-cell depletion, using polyclonal anti-thymocyte globulin (ATG) or monoclonal antibodies following myeloablative regimens, are associated with a high engraftment rate and a higher incidence of GVHD.

RIC haploidentical transplantations are associated with a lower TRM rate and are increasingly used in adults and children, either in combination with CD3/19-depleted PBSC or in combination with T-replete BM and post transplant cyclophosphamide.

Patients considered at high risk for TRM prior to transplant and older patients, should be offered a RIC regimen. For younger patients, further studies are necessary to define the best preparative regimen for the different underlying diseases.

What features of the presentation will guide me toward possible causes and next treatment steps:

Ex vivo or in vivo T-cell depletion

Ex vivo T-cell depletion

Since graft-contaminating donor-derived T lymphocytes are the major cause of GVHD, various attempts were made to remove T-cells from the graft prior to infusion. Several methods have been used, among them the depletion of T-cells from BM using soybean agglutinin and rosette formation with sheep red blood cells. Later, partial in vitro T-cell depletion has been performed using anti-CD3 antibodies with a one to one and a half log reduction of T-cells, in combination with post transplant pharmacological GVHD prophylaxis.

The use of mobilized PBSC allows the collection of much larger numbers of stem cells, compared to BM. The transplantation of large doses of CD34+ positive stem cells is required according to the megadose concept described in animal models of haploidentical transplantation. According to this concept, the HLA barrier can be overcome due to the presence of "veto" cells within the CD34+ positively selected population. With the indirect removal of nearly all T-lymphocytes from the graft by positive selection of CD34+ stem cells (4 log), a high engraftment rate of 95% was seen after a preparative regimen consisting of total body irradiation (TBI), thiotepa, fludarabine and anti-thymocyte globulin (ATG), and no severe GVHD occurred in the absence of any pharmacologic GVHD prophylaxis.

A more recently introduced semiautomated device for CD34+ positive selection results in a high degree of T-cell depletion (4.5 to 5 log) and B-cell depletion and is successfully used in pediatric and adult patients. Due to indirect depletion of B-lymphocytes, post transplant Epstein-Barr virus (EBV) lymphoproliferative disorders are rarely seen after C34+ selection.

Another method is the negative depletion of CD3+ T-cells and CD19+ B-cells (CD3/19 depletion) using a semiautomated device. In addition to CD34+ stem cells, large numbers of other cells (NK cells, monocytes, dendritic cells) remain in the graft and are cotransplanted. Due to technical restraints, a lower T-cell depletion (3.4 - 4 log) is achieved compared to CD34+ positive selection. The additional cotransplanted cells, such as the NK cells, might support the engraftment and therefore, non-TBI and less intensive preparative regimens can be used, resulting in a lower TRM in children and adults as compared to CD34+ selection.

In patients receiving T-cell depleted grafts, post transplant pharmacological GVHD prophylaxis can be omitted if the infused T-cell number is less than 25.000/kg recipient body weight. If the T-cell number exceeds 25.000/kg body weight, post transplant pharmacological prophylaxis for GVHD should be given to avoid severe GVHD.

In vivo T-cell depletion (T cell-replete grafts)

Transplantation of T-cell replete haploidentical BM or mobilized PBSC in combination with in vivo T-cell depletion with ATG or monoclonal antibodies (alemtuzumab, basiliximab), and with post transplant pharmacological GVHD prophylaxis is gaining attention. The combined transplantation of G-CSF primed BM and PBSC following a myeloablative regimen, resulted in a high engraftment rate, but also in a much higher incidence of GVHD, compared to ex vivo T-cell depleted transplants. Unmanipulated G-CSF mobilized PBSC can also be transplanted, in combination with nonmyeloablative preparative regimens comprising fludarabine, cyclophosphamide and alemtuzumab.

A promising approach in T-cell replete transplantation is the post transplant use of cyclophosphamide (Cy) to induce tolerance, and thus avoid acute and chronic GVHD. In this setting, donor-derived lymphocytes proliferate in the host after exposure to host antigens. By timely application to post transplant Cy, proliferating lymphocytes are killed, whereas resting lymphocytes are spared. In these protocols, Cy (50mg/kg) is given on day 3 and 4, after non-myeloablative conditioning regimen and infusion of T-cell replete haploidentical BM, and the cumulative incidences of acute and chronic GVHD are in an acceptable range.

A lower incidence of GVHD might also be obtained by using non-inherited maternal antigen (NIMA) mismatched donors. The tolerance induction is the result of in utero exposure to maternal antigens and the development of long-lasting feto-maternal microchimerism, and NIMA mismatch in the GVHD direction is associated with a lower incidence of GVHD.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

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What conditions can underlie haploidentical bone marrow transplant:

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When do you need to get more aggressive tests:

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What imaging studies (if any) will be helpful?

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What therapies should initiate immediately and under what circumstances - even if root cause is unidentified?

Optimizing donor selection

One of the most important findings from the studies using highly purified haploidentical CD34+ stem cells, is the concept of natural killer (NK) alloreactivity. According to this concept, lysis of malignant cells by NK cells is influenced by mismatching of the killer immunoglobulin-like receptors (KIR) ligands between donor and recipient. It has been shown in this context, that mismatching of the inhibitory KIR ligands in GVHD direction can exert a powerful graft-versus-leukemia effect in the absence of GVHD. This anti-leukemic effect is especially pronounced in adult patients with acute myeloid leukemia (AML), but not with acute lymphoblastic leukemia (ALL). In a series of 61 adult patients with high-risk AML and in complete remission prior to transplant, transplantation from NK-alloreactive donors was associated with a significant lower relapse rate (3% versus 47%).

While these studies used KIR ligands of donors and recipients to predict NK alloreactivity (ligand-ligand model), other studies used a direct determination of the donors' KIR and the patients' corresponding ligands (receptor-ligand model). By employing the receptor-ligand model, pediatric patients with ALL, had a lower risk of relapse after KIR receptor-ligand mismatched haploidentical SCT with CD34+ stem cells. The gender of the haploidentical donor was also an independent prognostic factor for survival, and patients receiving stem cells from NK alloreactive maternal donors had a better event-free survival (EFS) than patients transplanted with stem cells from NK alloreactive fathers. NK non-alloreactive maternal donors also conferred a better outcome, compared to NK non-alloreactive paternal donors.

Less data on the role of alloreactive NK cells are available in CD3/19 depleted haploidentical SCT. In pediatric patients, a predominant expansion of KIR2DL2/3+ NK cells was seen early post transplant, and patients who were homozygous for the corresponding inhibitory KIR ligands (HLA C group 1 alleles) had a poorer outcome compared to patients who were heterozygous for HLA C group 1 alleles. Similar observations were also made after transplantation of CD34+ stem cells.

Further studies are required to determine the role of NK alloreactivity in T-cell replete haploidentical SCT. The anti-leukemic effects of alloreactive NK cells might be overridden by alloreactive T-Lymphocytes resulting in GVHD and its concomitant immunosuppressive treatment. In one study, a deleterious effect of KIR ligand mismatch was found to be an independent risk factor for acute and chronic GVHD and relapse. In another study, an improved survival with KIR gene mismatched donors and KIR haplotype B donors after non-myeloablative haploidentical BM transplantation, followed by high-dose Cy was reported. Recipients of inhibitory KIR gene mismatched BM of KIR haplotype AA recipients of BM from KIR Bx donors had a lower risk of relapse, and nonrelapse mortality.

Current knowledge suggests that for adult patients with AML and for children with ALL, an NK alloreactive donor might be chosen in the context of CD34+ positive selection. In the context of transplantation of T-replete BM and post transplant cyclophosphamide, a KIR gene mismatched donor or a donor with KIR haplotype B might predict a lower risk of relapse and nonrelapse mortality.

How to rebuild the immune system after haploidentical transplantation

Poor T-cell reconstitution is the major cause of infections, and contributes considerably to the TRM observed after haploidentical SCT. In order to fasten the immunoreconstitution, various strategies are investigated in clinical studies, among them, the adoptive transfer of donor-derived virus-specific T-cells, the adoptive immunotherapy with allodepleted donor-T-cells, the use of donor-derived T-cells selectively depleted of alloreactive lymphocytes by photodepletion and the use of donor-derived pathogen-specific T-cells of the post transplant infusion of CD8-depleted donor lymphocytes.

Another more recent approach is the adoptive transfer of CD4+CD25+ regulatory T-cells (T-reg) post transplant, followed by the infusion of large numbers of conventional T-cells (T-con) in the absence of any pharmacologic GVHD prophylaxis. The adoptive transfer of T-regs followed by T-cons prevented GVHD, promoted lymphoid reconstitution, improved immunity to opportunistic infections, and did not weaken the graft-versus-leukemia effect.

Conclusions

Advances in haploidentical SCT have raised interest in this approach. It is still an evolving field, and further improvements can be envisioned over the coming years. Due to the continuous availability of the donor, post transplant strategies to improve immunoreconstitution and to prevent disease recurrence can be designed. Given the current promising results in both pediatric and adult patients, haploidentical SCT, either with or without T-cell depletion, should no longer be regarded as a last resort for hopeless patients, but should be offered to patients with an indication for allogeneic transplantation, who do not have a matched sibling or a matched unrelated donor identified within a reasonable time frame.

What other therapies are helpful for reducing complications?

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What should you tell the patient and the family about prognosis?

Haploidentical transplantation offers a realistic chance of cure for those patients who do not have a HLA-matched donor. It can be performed in a timely manner and the availability of the donor after transplantation offers additional therapeutic strategies in case of expected and unexpected side effects.

In children with hematological malignancies, the outcome is comparable to HLA-matched transplantations. In adult patients, the outcome is yet inferior compared to HLA-matched transplants, but might be similar for certain subgroups of patients.

"What if" scenarios.

Prevention and treatment of infections

Common to all approaches of allogeneic HSCT in pediatric and adult patients is a slow immunoreconstitution. With the intensive ex vivo or in vivo depletion of T-cells, poor T-cell reconstitution is the major cause for infectious complications and contributes considerably to the TRM observed in unmanipulated or in vitro T-cell depleted haplotype mismatched transplants. Viral reactivation, especially of cytomegalovirus (CMV) and adenovirus (ADV) are quite common, especially after ex vivo T-cell depleted haploidentical stem cell transplantation (SCT), or after T-replete transplants, and can lead to severe, and often lethal diseases. In addition, fungal diseases such as Aspergillus and other bacterial infections contribute to the TRM.

To prevent diseases from viral reactivation, an intensive screening should be employed using weekly qualitative polymerase-chain reaction (PCR) for CMV and ADV in serum and treatment with anti-CMV reagents (gancyclovir, Foscavir) should be immediately started. For ADV, cidofovir has been shown to be effective. In addition to screening of the serum, weekly screening of stool for ADV antigen or by PCR might allow very early identification of patients at risk for developing systemic ADV disease. If ADV is detected in stool, treatment with cidofovir might be considered to prevent systemic spreading of the virus.

In order to determine the response to the antiviral treatment, viral copy numbers should be followed weekly by quantitative PCR during antiviral therapy. If the viral load in serum increases despite appropriate treatment, donor-derived virus-specific T-cells directed against CMV, ADV and EBV can be adoptively transferred. Several methods for the generation of donor-derived virus-specific T-cells are available, and virus-specific T-cells have successfully been used in patients with therapy-refractory CMV and ADV infection after haploidentical SCT.

Fungal infections are also seen more often after haploidentical transplantation, and antifungal prophylaxis is recommended until some recovery of the immune system is seen. A recovery of CD4+ T-cells seems to herald the recovery of the immune system and it might be prudent to continue the post transplant antifungal and antiviral prophylaxis until a CD4 count of at least 100/µl or better, greater than 200/µl has been reached.

Pathophysiology

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What other clinical manifestations may help me to diagnose haploidentical bone marrow transplant?

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What other additional laboratory studies may be ordered?

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What's the evidence?

Aversa, F, Tabilio, A, Velardi, A. "Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype". N Engl J Med. vol. 339. 1998. pp. 1186-1193.

[The authors performed for the first time haploidentical transplantations in patients with high-risk leukemia, using highly enriched CD34+ mobilized peripheral stem cells, using a two-step method (T-cell depletion, followed by CD34+ positive selection). With this study, they showed that the HLA barrier can be overcome successfully, and that haploidentical transplantation is possible in the absence of any post transplant pharmacologic GVHD prophylaxis, and without significant GVHD.]

Aversa, F, Terenzi, A, Tabilio, A. "Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse". J Clin Oncol. vol. 23. 2005. pp. 3447-3454.

[In this study, large numbers of CD34+ stem cells were obtained using single step positive selection. A high engraftment rate, and a low incidence of GVHD was observed after a myeloablative preparative regimen. The event-free survival was 48% and 46% for adult patients with AML and ALL, respectively.]

Klingebiel, T, Cornish, J, Labopin, M. "Pediatric Diseases and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group". Blood. vol. 115. 2010. pp. 3437-3446.

[The authors analyzed the outcome of 127 children with ALL who underwent haploidentical transplantation of highly purified CD34+ stem cells in first, second, third complete remission, or in relapse. The 5 year leukemia -free survival (LFS) was 30%, 34%, 22% and 0%, respectively. In multivariate analysis, haploidentical SCT performed at larger centers was associated with improved LFS, and decreased risk of relapse. A trend for better LFS was seen in patients receiving higher numbers of CD34+ stem cells. The experience of the transplant center with haploidentical transplantation has an impact on the outcome and centers initiating haploidentical transplant programs may collaborate with experienced centers.]

Luznik, L, O'Donnell, PV, Symons, HJ. "HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide". Biol Blood Marrow Transplant. vol. 14. 2008. pp. 641-650.

[In this paper, the authors describe the safety and efficacy of high-dose post transplantation cyclophosphamide to prevent GVHD and graft rejection after nonmyeloablative conditioning regimen and Tcell-replete bone marrow transplantation from haploidentical donors. The cumulative incidences of grades II-IV and grades III-IV acute GVHD at day 200 were 34% and 6%, respectively. The cumulative incidences of nonrelapse mortality and relapse at 1 year was 15% and 51%, respectively. Patients with lymphoid malignancies had a better event-free survival, compared to patients with myelogenous malignancies.]

Rizzieri, DA, Koh, LP, Long, GD. "Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution". J Clin Oncol.. vol. 25. 2007. pp. 690-697.

[In this paper, the authors describe their experience of haploidentical transplantation in adult patients with hematological malignancies using a nonmyeloablative conditioning regimen in conjunction with T-replete peripheral stem cells and post transplant pharmacologic GVHD prophylaxis. The TRM was low (10.2%) and only 8% had severe GVHD. The 1 year survival rate was 31%, and a standard risk group of patients with aplasia or in remission at transplantation demonstrated a 1year survival rate of 63%.]

Ruggeri, L, Capanni, M, Urbani, E. "Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants". Science.. vol. 295. 2002. pp. 2097-2100.

[The authors of this article were the first to describe the concept of Natural Killer (NK) alloreactivity in haploidentical transplantation, and demonstrate that donor-versus-recipient NK alloreactivity can eliminate leukemia relapse and graft rejection, and also be protective against GVHD in a mouse model of haploidentical transplantation, using highly enriched stem cells.]

Ruggeri, L, Mancusi, A, Capanni, M. "Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value". Blood. vol. 110. 2007. pp. 433-440.

[In this paper, the role of NK cell alloreactivity was analyzed in adult patients with AML, who received haploidentical transplants from NK alloreactive or non-NK alloreactive donors. The NK alloreactivity was determined using the ligand-ligand model, that is, the presence of KIR ligands (certain HLA alleles) which were missing in the recipients (KIR ligand disparity in GVHD direction). Transplantation from NK alloreactive donors was associated with a significantly lower relapse rate in patients transplanted in complete remission (3% versus 47%), better event-free survival in patients transplanted in relapse (34% versus 6%), and in remission (67% versus 18%).]

Leung, W, Iyengar, R, Turner, V. "Determinants of antileukemia effects of allogeneic NK cells". J Immunol.. vol. 172. 2004. pp. 644-650.

[The authors demonstrate for the first time the role of NK alloreactivity in pediatric patients who received haploidentical transplants after myeloablative conditioning regimens, followed by infusion of highly purified CD34+ stem cells. To determine the NK alloreactivity, the receptor-ligand model was employed, that is, the presence of inhibitory receptors in the donors and the absence of KIR ligands in the recipients. Patients transplanted from a NK-alloreactive donor had a much lower risk of relapse, compared to patients who received their graft from a non NK- alloreactive donor. In contrast to the studies in adults, where the NK-alloreactivity had only an influence on the outcome in patients with AML, but not ALL, a significant influence of the NK alloreactivity was found in pediatric ALL.]

Symons, HJ, Leffell, MS, Rossiter, ND, Zahurak, M, Jones, RJ, Fuchs, EJ. "Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation". Biol Blood Marrow Transplant.. vol. 16. 2010. pp. 533-542.

[In this paper, the authors demonstrate the role of KIR gene mismatches and the role of KIR haplotype B donors after nonmyeloablative haploidentical T cell-replete bone marrow transplantation with high-dose post transplant cyclophosphamide. Compared to recipients of bone marrow from KIR gene matched donors, recipients of inhibitory KIR gene mismatched bone marrow had an improved overall survival, event-free survival and lower rate of relapse. Donors who had at least one KIR B haplotype conferred, also a better outcome.]

Leung, W, Campana, D, Yang, J. "High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia". Blood.. vol. 118. 2011. pp. 223-230.

[In this study, the outcome of children with very high-risk leukemia after allogeneic transplantation from matched sibling, HLA-matched unrelated and haploidentical donors was analyzed. The 5 year overall survival rates were 70% after matched sibling, 61% after matched unrelated, and 88% after haploidentical donor transplantation.]

Di Ianni, M, Falzetti, F, Carotti, A. "Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation". Blood. vol. 117. 2011. pp. 3921-3928.

[This is the first clinical study applying donor-derived T-regulatory (Treg) cells in conjunction with conventional T cells in haploidentical transplantation. The adoptive transfer of Treg cells prevented GVHD in the absence of pharmacologic GVHD prophylaxis, promoted lymphoid reconstitution, improved immunity to opportunistic pathogens, and did not weaken the graft-versus-leukemia effect.]
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