Principles of HCT

The two major transplant approaches currently in use include autologous (using the patient's own hematopoietic stem cells) and allogeneic (using related or unrelated donor hematopoietic stem cells). Autologous transplant treats cancer by exposing patients to mega-dose (myeloablative) therapy with the intent of overcoming chemotherapy resistance in tumor cells, followed by infusion of the patient’s previously stored hematopoietic stem cells. In order for this approach to work, the following must apply:

• The higher chemotherapy/radiation therapy dose that can be used because of hematopoietic stem cell support achieves a significantly higher cell kill of the disease. This may include increased tumor kill in areas where standard-dose chemotherapy has less penetration (CNS).

• Meaningful percentages of cure or long-term remission from the disease must occur without significant nonhematopoietic toxicities limiting the therapeutic benefit achieved.

Allogeneic approaches to cancer may involve high-dose therapy as well, but because of immunologic differences between the donor and recipient, an additional graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) treatment effect can occur. Although autologous approaches are associated with less short-term mortality, many malignancies are resistant to mega-dose therapy alone and/or involve the bone marrow, thus requiring allogeneic approaches for optimal outcome.

Because the outcomes using chemotherapy and hematopoietic cell transplantation (HCT) treatments tend to improve with time, regular comparisons should be performed between these approaches to continually redefine optimal therapy for a given patient. For some diseases, randomized trials or intent-to-treat using a human leukocyte antigen (HLA)-matched sibling donor have established the benefit of HCT by direct comparison.[1,2] However, for very high-risk patients such as those with early relapse of ALL, randomized trials have not been feasible due to investigator bias.[3,4] In general, HCT approaches only offer benefit to children at high risk for relapse with standard chemotherapy approaches; therefore, treatment schemes that accurately identify high-risk patients and offer HCT if reasonably HLA-matched donors are available, saving higher risk approaches to HCT (HLA haploidentical or significantly mismatched donors) for only the very highest risk patients, has come to be the preferred approach for many diseases.[5]

When comparisons of similar patients treated with HCT or chemotherapy are made and randomized or intent-to-treat studies are not feasible, the following issues should be considered:

1. Remission status: Because patients failing to obtain remission do very poorly with any therapy, comparisons between HCT and chemotherapy should include only those who obtain remission, preferably after similar approaches to salvage therapy. In order to account for time-to-transplant bias, the chemotherapy comparator arm should only include patients who maintained remission until the median time to HCT. The HCT comparator arm should also only include patients who achieved the initial remission mentioned above and maintained that remission until the time of HCT.

2. Past or current therapy approaches used: Disease- and era-appropriate chemotherapy and HCT approaches should be compared.

3. HCT approach: HCT approaches that are very high risk or have documented lower rates of survival (i.e., haploidentical approaches) should not be combined for analysis with standard-risk HCT approaches (matched sibling and well-matched unrelated donors).

4. Criteria for relapse: Risk factors for relapse should be carefully defined and analysis based upon the most current knowledge of risk should be performed. One should avoid combining high- and intermediate-risk patient groups because a benefit for HCT in the high-risk group can be masked when outcomes are similar in the intermediate-risk group.[6]

5. Selection Bias: Attempts should be made to understand and eliminate or correct for selection bias. Examples include the following:
   • Higher risk patients preferentially undergoing HCT (i.e., patients who take several rounds to achieve remission or who relapse after obtaining remission and go back into a subsequent remission prior to HCT).
   • Sicker patients deferred from HCT because of comorbidities.
   • Patient/parent refusal.
   • Lack of or inability to obtain insurance approval for HCT.
   • Lack of access to HCT due to distance/inability to travel.

One source of bias difficult to control for or detect is physician bias for or against HCT. The effect of access to HCT and therapeutic bias on outcomes of pediatric malignancies where HCT may be indicated has been poorly studied to date.

Appropriate matching between donor and recipient HLA in the major histocompatibility complex located on chromosome 6 is essential to successful allogeneic HCT (see Table 1).

Enlarge

Figure 1. HLA Complex. Human chromosome 6 with amplification of the human leukocyte antigen (HLA) region. The locations of specific HLA loci for the class I B, C, and A alleles and the class II DP, DQ, and DR alleles are shown.

HLA class I (A, B, C, etc.) and class II (DRB1, DQB1, DPB1, etc.) alleles are highly polymorphic, therefore finding appropriately matched unrelated donors is a challenge for some patients, especially those of certain racial groups (e.g., African Americans and Hispanics).[7] Because full siblings of cancer patients have a 25% chance of being HLA matched, they have been the preferred source of allogeneic hematopoietic stem cells. Early serologic techniques of HLA assessment defined a number of HLA antigens, but more precise DNA methodologies have shown HLA allele-level mismatches in up to 40% of serologic HLA antigen matches. These differences are clinically relevant, as use of donors with allele-level mismatches affect survival and rates of graft-versus-host disease (GVHD) to a degree similar to patients with antigen-level mismatches.[8] Because of this, DNA-based allele-level HLA typing is standard when choosing unrelated donors.

The most commonly used related donor is a sibling from the same parents who is HLA matched for HLA A, HLA B, and HLA DRB1 at a minimum, at the antigen level. Given the distance on chromosome 6 between HLA A and HLA DRB1, there is approximately a 1% possibility of a crossover event occurring in a possible sibling match. Because a crossover event could involve the HLA C antigen and because parents may share HLA antigens that actually differ at the allele level, many centers perform allele-level typing of possible sibling donors at all of the key HLA antigens (HLA A, B, C, and DRB1). Any related donor that is a nonfull sibling should have full HLA typing because similar haplotypes from different parents could differ at the allele level. Although single-antigen mismatched related donors (5/6 antigen matched) have been used interchangeably with matched sibling donors in some studies in the past, a large Center for International Blood and Marrow Transplant Research (CIBMTR) study in pediatric HCT recipients showed that use of 5/6 antigen matched related donors who are not siblings results in rates of GVHD and overall survival equivalent to 8/8 allele level matched unrelated donors and slightly inferior survival compared to fully matched siblings.[9]

Optimal outcomes are achieved in unrelated allogeneic marrow transplantation when the pairs of antigens at HLA A, B, C, and DRB1 are matched between the donor and the recipient at the allele level (termed an 8/8 match).[10] A single antigen/allele mismatch at any of these antigens (7/8 match) lowers the probability of survival between 5% to 10% with a similar increase in the amount of significant (grades III–IV) acute GVHD.[10] Of these four antigen pairs, different reports have shown HLA A, C, and DRB1 mismatches to potentially be more highly associated with mortality than the other antigens,[8,10,11] but the differences in outcome are small and inconsistent, making it very difficult to conclude presently that one can pick a more favorable mismatch by choosing one type of antigen mismatch above another. Many groups are attempting to define specific antigens or pairs of antigens that are associated with poor outcome, but such studies require very large numbers of patients and exclusion of specific antigens or antigen pairs for donor choice is not widely practiced.

Although it is well understood that class II antigen DRB1 mismatches increase GVHD and worsen survival,[11] the need to match for two other important class II antigens, DQB1 and DPB1, is controversial. DQB1 mismatches have been associated with significant increases in acute GVHD,[12] but subsequent studies have not shown a difference in overall survival.[10] Many centers have adopted a policy to attempt to match patients at DQB1 in addition to the other four pairs of antigens; full matches using this approach are thus termed 10/10 HLA matches. Such matching is possible for a high percentage of patients because of strong linkage disequilibrium between DRB1 and DQB1, resulting in many 8/8 matched donors also being 10/10 matches. DPB1 mismatches have similarly been shown to lead to increased GVHD without a change in survival.[13,14] Although some centers attempt to match for DPB1 (12/12 match), it is challenging, because due to less linkage disequilibrium, only about 15% of 10/10 matches will also be 12/12 matches; studies showing whether it is better to mismatch at DQB1 compared with DPB1 have not been performed. A study grouping DPB1 antigens into permissive groups allowed up to 50% of patients with 10/10 matches to choose a favorable DPB1 match,[15] but this classification system is not yet generally accepted.

Another commonly used hematopoietic stem cell source is that of unrelated umbilical cord blood, which is harvested from donor placentas moments after birth and cryopreserved, HLA typed, and banked. Unrelated cord blood transplantation has been successful with less stringent HLA matching requirements compared with standard related or unrelated donors, probably due to limited antigen exposure experienced in utero and different immunological composition. Cord blood matching is generally performed at an intermediate level for HLA A and B and at an allele level (high resolution) for DRB1. This means that matching of only 6 antigens is necessary to choose units for transplantation. Although better outcomes occur when 6/6 or 5/6 HLA matched units are used,[16] successful HCT has occurred even with 4/6 or less matched units in many patients. Better matching of units (matching for HLA-C, as well as A, B, and DRB1) has been shown to result in less transplant-related mortality, but has not been shown to have an impact on survival in children with malignancies.[17] Many centers will type up to 10 alleles and use the best match possible, but the impact of DQB1 mismatched has not been shown to affect outcome. Higher cell doses in cord blood units have been shown to improve outcomes, especially when the units have higher levels of HLA mismatch. One study showed that survival of recipients of 4/6 matched cords with cell doses greater than 5 × 10⁷ total nucleate cells/kg recipient weight is similar to 5/6 matched cord recipients receiving a cell dose of 2.5 to 5 × 10⁷ total nucleate cells/kg. Although no clear improvement in survival occurred for cell doses above 5 × 10⁷ total nucleate cells/kg, higher doses of cells improved outcomes for all levels of HLA mismatch.[18]

In addition to cell dose and matching level, the direction of mismatches between donor and recipient has been shown to be important in cord blood transplant outcomes. When cord blood units have paired identical antigens (for example, both HLA A antigens are HLA A 02), and if the recipient has one HLA A 02 antigen and a second antigen that is mismatched, T-cells from the recipient do not detect a mismatch in the cord and are less likely to reject this cord. T-cells from the cord blood unit in this case, however, would detect the other (non-HLA A 02) mismatched antigen in the A locus of the recipient, potentially stimulating a GVHD reaction (termed mismatch in the GVH direction only [GVH-O]). If the paired identical antigens are in the recipient and not in the cord blood unit, the mismatch is in the rejection direction only (R-O). It has been shown that mismatches that are only in the GVHD direction (GVH-O, paired antigens in the cord blood unit) lead to lower transplant-related mortality and overall mortality, compared with those with R-O mismatches. R-O mismatches have outcomes similar to patients who have bidirectional mismatches.[19] Current recommendations are for transplant centers to give priority to GVH-O mismatches above other mismatches and avoid selecting R-O mismatches.

Two aspects of umbilical cord blood HCT have made it more widely applicable. First, because a successful procedure can occur with multiple HLA mismatches, over 90% of patients from a wide variety of ethnicities are able to find a at least a 4/6 matched cord blood unit, allowing a method of performing HCT for populations that traditionally have not had HCT options because of having rare HLA haplotypes.[7,20] Second, as mentioned above, adequate cell dose (minimum 2–3 × 10⁷ total nucleate cells/kg and 1.7 × 10⁵ CD34+ cells/kg) has been shown to be associated with improved survival.[21,22] Total nucleate cells is generally used to judge units because techniques to measure CD34+ doses have not been standardized. Because even large single umbilical cord blood units are only able to supply these minimum doses to recipients weighing up to 40 kg to 50 kg, early umbilical cord blood HCT focused mainly on smaller children. Later studies showed that this size barrier could be overcome by using two umbilical cord blood units as long as each of the units is at least a 4/6 HLA match with the recipient; because two cords result in much higher cell doses, umbilical cord blood transplantation is now used widely for larger children and adults.[23] Single-center studies have suggested that the use of two umbilical cord blood units may decrease relapse in patients with malignancies; however, this has not been validated in multicenter studies.[24] It has been shown that grades II to IV acute GVHD is higher when two versus one umbilical cord blood unit is used; but transplant-related mortality has not been noted to be increased.[25] One study comparing adult and older pediatric patients transplanted with either double 4/6 to 6/6 matched umbilical cord blood or unrelated bone marrow/PBSCs showed survival to be equivalent.[26]

Currently, the three stem cell products used from both related and unrelated donors are bone marrow, peripheral blood stem cells (PBSCs), and cord blood. In addition, bone marrow or PBSCs can be T-cell depleted by several methods and the resultant stem cell product has very different properties. Finally, partially HLA-matched (half or more antigens [haploidentical]) related bone marrow or PBSCs can be used after in vitro or in vivo T-cell depletion and this product also behaves differently compared with other stem cell products. A comparison of stem cell products is presented in Table 3.

The main differences between the products are associated with the numbers of T-cells and CD34+ progenitor cells present; very high levels of T-cells are present in PBSCs, intermediate numbers in bone marrow, and low numbers in cord blood and T-cell depleted products. Patients receiving T-cell depleted products or cord blood generally have slower hematopoietic recovery, increased risk of infection, late immune reconstitution, higher risks of nonengraftment, and increased risk of Epstein-Barr virus (EBV)–associated lymphoproliferative disorder. This is countered by lower rates of GVHD and an ability to offer transplantation to patients where full HLA matching is not available. Higher doses of T-cells in PBSCs result in rapid neutrophil recovery and immune reconstitution, but suffer from increased rates of chronic GVHD.

There are only a few studies directly comparing outcomes of different stem cell sources/products in pediatric patients. A retrospective registry study of pediatric patients undergoing HCT for acute leukemia compared those receiving related donor bone marrow with related donor PBSCs. Although the bone marrow and PBSC recipient cohorts differed some in their risk profiles, after statistical correction, increased risk of GVHD and transplant-related mortality associated with PBSC led to poorer survival in the PBSC group.[27] This report, combined with lack of prospective studies comparing bone marrow and PBSCs, has led most pediatric transplant protocols to prefer bone marrow to PBSCs from related donors. For those requiring unrelated donors, a large Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial randomizing bone marrow and PBSCs that included pediatric patients has recently completed and analysis of the outcomes will be forthcoming.[28] In an attempt to determine whether unrelated bone marrow or cord blood is better, a retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) study of pediatric acute lymphoblastic leukemia patients undergoing HCT who received 8/8 HLA allele-matched unrelated donor bone marrow was compared with those receiving unrelated cord blood.[16] The analysis showed that the best survival occurred in recipients of 6/6 HLA-matched cord blood; survival after 8/8 HLA-matched unrelated bone marrow was slightly less and was statistically identical to patients receiving 5/6 and 4/6 HLA-matched cord blood units. Based upon these studies, most transplant centers consider matched sibling bone marrow to be the preferred stem cell source/product. If a sibling donor is not available, fully matched unrelated donor bone marrow or PBSCs or HLA matched (4/6 to 6/6) cord blood lead to similar survival. Although adult studies of T-cell depleted unrelated bone marrow or PBSC have shown outcomes similar to non-T-cell depleted approaches, large pediatric trials or retrospective studies comparing T-cell depleted matched or haploidentical bone marrow or PBSCs have not occurred.

Early HCT studies demonstrated progressively higher percentages of patients experiencing severe GVHD and lower survival as the number of donor/recipient HLA mismatches increased.[29] Studies have further demonstrated that even with very high numbers of donors in unrelated donor registries, patients with rare HLA haplotypes and patients with certain ethnic backgrounds (e.g., Hispanic, African American, Asian-Pacific Islander, etc.) have a low chance of achieving desired levels of HLA matching (7/8 or 8/8 match at the allele level).[7]

In order to allow access to HCT for patients without HLA matched donor options, investigators developed techniques allowing use of siblings, parents, or other relatives who share only a single haplotype of the HLA complex with the patient and are thus “half” matches. The majority of approaches developed to date rely on intense T-cell depletion of the product prior to infusion into the patient. The main challenge associated with this approach is intense immune suppression with delayed immune recovery. This can result in lethal infections,[30] increased risk of EBV-lymphoproliferative disorder, and high rates of relapse.[31] This has generally lead to inferior survival compared with matched HCT and has resulted in the procedure being generally practiced only at larger academic centers with a specific research focus aimed at studying and developing this approach.

Current approaches are rapidly evolving, resulting in improved outcome, with some pediatric groups reporting survival similar to standard approaches.[32,33] Newer techniques of T-cell depletion and add back (i.e., CD3/19 negative selection), have decreased transplant-related mortality.[34] Reduced toxicity regimens have led to improved survival, better supportive care has decreased the chance of morbidity from infection or EBV-lymphoproliferative disorder,[35] and some patient/donor combinations that have specific killer immunoglobulin-like receptor mismatches have shown decreased likelihood of relapse (refer to the Role of killer immunoglobulin-like receptor mismatching in HCT section of this summary for more information). Finally, techniques such as using combinations of granulocyte-colony stimulating factor (G-CSF) primed bone marrow and PBSCs with posttransplant antibody based T-cell depletion [36] or post-HCT cyclophosphamide (chemotherapeutic T-cell depletion) [37] have made these procedures more accessible to centers because expensive and complicated processing necessary for traditional T-cell depletion are not used. Reported survival using many different types of haploidentical approaches varies between 25% to 80% depending upon the technique used and the risk of the patient undergoing the procedure.[31,32,36,37] Whether haploidentical approaches are superior to cord blood or other stem cell sources for a given patient group has not been determined because comparative studies have yet to be performed.[31]

References

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2. Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001.  [PUBMED Abstract]
   
   
3. Lawson SE, Harrison G, Richards S, et al.: The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J Haematol 108 (3): 531-43, 2000.  [PUBMED Abstract]
   
   
4. Gaynon PS, Harris RE, Altman AJ, et al.: Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 24 (19): 3150-6, 2006.  [PUBMED Abstract]
   
   
5. Schrauder A, von Stackelberg A, Schrappe M, et al.: Allogeneic hematopoietic SCT in children with ALL: current concepts of ongoing prospective SCT trials. Bone Marrow Transplant 41 (Suppl 2): S71-4, 2008.  [PUBMED Abstract]
   
   
6. Pulsipher MA, Peters C, Pui CH: High-risk pediatric acute lymphoblastic leukemia: to transplant or not to transplant? Biol Blood Marrow Transplant 17 (1 Suppl): S137-48, 2011.  [PUBMED Abstract]
   
   
7. Barker JN, Byam CE, Kernan NA, et al.: Availability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities. Biol Blood Marrow Transplant 16 (11): 1541-8, 2010.  [PUBMED Abstract]
   
   
8. Woolfrey A, Klein JP, Haagenson M, et al.: HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 17 (6): 885-92, 2011.  [PUBMED Abstract]
   
   
9. Shaw PJ, Kan F, Woo Ahn K, et al.: Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood 116 (19): 4007-15, 2010.  [PUBMED Abstract]
   
   
10. Flomenberg N, Baxter-Lowe LA, Confer D, et al.: Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood 104 (7): 1923-30, 2004.  [PUBMED Abstract]
    
    
11. Petersdorf EW, Kollman C, Hurley CK, et al.: Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: the US National Marrow Donor Program Experience. Blood 98 (10): 2922-9, 2001.  [PUBMED Abstract]
    
    
12. Petersdorf EW, Longton GM, Anasetti C, et al.: Definition of HLA-DQ as a transplantation antigen. Proc Natl Acad Sci U S A 93 (26): 15358-63, 1996.  [PUBMED Abstract]
    
    
13. Shaw BE, Gooley TA, Malkki M, et al.: The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood 110 (13): 4560-6, 2007.  [PUBMED Abstract]
    
    
14. Varney MD, Lester S, McCluskey J, et al.: Matching for HLA DPA1 and DPB1 alleles in unrelated bone marrow transplantation. Hum Immunol 60 (6): 532-8, 1999.  [PUBMED Abstract]
    
    
15. Crocchiolo R, Zino E, Vago L, et al.: Nonpermissive HLA-DPB1 disparity is a significant independent risk factor for mortality after unrelated hematopoietic stem cell transplantation. Blood 114 (7): 1437-44, 2009.  [PUBMED Abstract]
    
    
16. Eapen M, Rubinstein P, Zhang MJ, et al.: Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 369 (9577): 1947-54, 2007.  [PUBMED Abstract]
    
    
17. Eapen M, Klein JP, Sanz GF, et al.: Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol 12 (13): 1214-21, 2011.  [PUBMED Abstract]
    
    
18. Barker JN, Scaradavou A, Stevens CE: Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood 115 (9): 1843-9, 2010.  [PUBMED Abstract]
    
    
19. Stevens CE, Carrier C, Carpenter C, et al.: HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection. Blood 118 (14): 3969-78, 2011.  [PUBMED Abstract]
    
    
20. Barker JN, Rocha V, Scaradavou A: Optimizing unrelated donor cord blood transplantation. Biol Blood Marrow Transplant 15 (1 Suppl): 154-61, 2009.  [PUBMED Abstract]
    
    
21. Wagner JE, Barker JN, DeFor TE, et al.: Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 100 (5): 1611-8, 2002.  [PUBMED Abstract]
    
    
22. Rubinstein P, Carrier C, Scaradavou A, et al.: Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 339 (22): 1565-77, 1998.  [PUBMED Abstract]
    
    
23. Barker JN, Weisdorf DJ, DeFor TE, et al.: Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 105 (3): 1343-7, 2005.  [PUBMED Abstract]
    
    
24. Verneris MR, Brunstein CG, Barker J, et al.: Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood 114 (19): 4293-9, 2009.  [PUBMED Abstract]
    
    
25. MacMillan ML, Weisdorf DJ, Brunstein CG, et al.: Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood 113 (11): 2410-5, 2009.  [PUBMED Abstract]
    
    
26. Brunstein CG, Gutman JA, Weisdorf DJ, et al.: Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 116 (22): 4693-9, 2010.  [PUBMED Abstract]
    
    
27. Eapen M, Horowitz MM, Klein JP, et al.: Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 22 (24): 4872-80, 2004.  [PUBMED Abstract]
    
    
28. Anasetti C, Logan BR, Lee SJ, et al.: Increased incidence of chronic graft-versus-host disease (GVHD) and no survival advantage with filgrastim-mobilized peripheral blood stem cells (PBSC) compared to bone marrow (BM) transplants from unrelated donors: results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0201, a phase III, prospective, randomized trial. [Abstract] Blood 118 (21): A-1, 2011. 
    
    
29. Beatty PG, Clift RA, Mickelson EM, et al.: Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med 313 (13): 765-71, 1985.  [PUBMED Abstract]
    
    
30. Aversa F, Tabilio A, Velardi A, et al.: 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 339 (17): 1186-93, 1998.  [PUBMED Abstract]
    
    
31. Barrett J, Gluckman E, Handgretinger R, et al.: Point-counterpoint: haploidentical family donors versus cord blood transplantation. Biol Blood Marrow Transplant 17 (1 Suppl): S89-93, 2011.  [PUBMED Abstract]
    
    
32. Leung W, Campana D, Yang J, et al.: High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 118 (2): 223-30, 2011.  [PUBMED Abstract]
    
    
33. González-Vicent M, Molina B, Andión M, et al.: Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study. Eur J Haematol 87 (1): 46-53, 2011.  [PUBMED Abstract]
    
    
34. Handgretinger R, Chen X, Pfeiffer M, et al.: Feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci 1106: 279-89, 2007.  [PUBMED Abstract]
    
    
35. Leen AM, Christin A, Myers GD, et al.: Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood 114 (19): 4283-92, 2009.  [PUBMED Abstract]
    
    
36. Huang XJ, Liu DH, Liu KY, et al.: Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38 (4): 291-7, 2006.  [PUBMED Abstract]
    
    
37. Luznik L, Fuchs EJ: High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 47 (1-3): 65-77, 2010.  [PUBMED Abstract]
    
    

Immunotherapeutic Effects of HCT

Early studies in hematopoietic cell transplantation (HCT) focused on delivery of intense myeloablative preparative regimens followed by “rescue” of the hematopoietic system with either an autologous or allogeneic bone marrow. Investigators quickly showed that allogeneic approaches led to a decreased risk of relapse caused by an immunotherapeutic reaction of the new bone marrow graft against tumor antigens. This phenomenon came to be termed the graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect, and has been shown to be associated with mismatches to both major and minor HLA antigens. The GVL effect is challenging to use therapeutically because of a strong association between GVL and clinical graft-versus-host disease (GVHD). For standard approaches to HCT, the highest survival rates have been associated with mild or moderate GVHD (overall grade I or II) compared with patients who have no GVHD and experience more relapse or patients with severe GVHD who experience more transplant-related mortality.

Understanding when GVL occurs and how to use GVL optimally is challenging. One method of study is comparing rates of relapse and survival between patients undergoing myeloablative HCT with autologous versus allogeneic donors for a given disease. In this setting, a clear advantage has been noted when allogeneic approaches are used for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). For ALL and AML specifically, autologous HCT approaches to most high-risk patient groups have shown results similar to chemotherapy, while allogeneic approaches have been superior.[1,2] Patients with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) generally fare better with autologous approaches, although there may be a role for allogeneic approaches in relapsed lymphoblastic lymphoma, lymphoma that is poorly responsive to chemotherapy, or lymphoma that has relapsed after autologous HCT.[3]

Further insights into the therapeutic benefit of GVL/GVT for given diseases have come from the use of reduced-intensity preparative regimens (refer to the Principles of HCT Preparative Regimens section of this summary for more information). This approach to transplantation relies on GVL, as the intensity of the preparative regimen is not sufficient for cure in most cases. Although studies have shown benefit for patients pursuing this approach if they are ineligible for standard transplantation,[4] because pediatric cancer patients can generally undergo myeloablative approaches safely, this approach has not been used for the majority of children with cancer who require HCT.

One can deliver GVL therapeutically through infusion of cells after transplant that either specifically or nonspecifically target tumor. The most common approach is the use of DLI. This approach relies on the persistence of donor T-cell engraftment after transplant to prevent rejection of donor lymphocytes infused to induce the GVL. Therapeutic DLI results in potent responses in patients with CML who relapse after transplant (60%–80% enter into long-term remission),[5] but responses in other diseases (AML and ALL) have been less potent, with only 20% to 30% long-term survival.[6] DLI works poorly in patients with acute leukemia who relapse early and who have high levels of active disease. Late relapse (>6 months after transplant) and treatment of patients into complete remission with chemotherapy prior to DLI have been associated with improved outcomes.[7] Infusions of DLI modified to enhance GVL or other donor cells (natural killer [NK] cells, etc.) have also been studied, but have yet to be generally adopted.

Another method of delivering GVL therapeutically is the rapid withdrawal of immune suppression after HCT. Some studies have scheduled more rapid immune suppression tapers based upon donor type (related donors more quickly than unrelated donors due to GVHD risk), and others have used sensitive measures of either low levels of persistent recipient cells (recipient “chimerism”) or minimal residual disease in order to assess risk of relapse and trigger rapid taper of immune suppression. A combination of early withdrawal of immune suppression after HCT with addition of DLI to prevent relapse in patients at high risk of relapse due to persistent/progressive recipient chimerism has been tested in patients transplanted for both ALL and AML. For patients with ALL, one study found increasing recipient chimerism in 46 of 101 patients. Thirty one of those patients had withdrawal of immune suppression and a portion went on to receive DLI if GVHD did not occur. This group had a 37% survival compared with 0% in the 15 patients who did not undergo this approach (P <.001).[8] For patients with AML after HCT, about 20% experienced mixed chimerism after HCT and were identified as high risk. Of these, 54% survived if they underwent withdrawal of immune suppression with or without DLI; there were no survivors among those who did not receive this therapy.[9]

Donor-derived NK cells in the post-HCT setting have been shown to promote engraftment, decrease GVHD, and lessen relapse of hematological malignancies.[10,11] NK cell function is modulated by interactions with a number of receptor families, including activating and inhibiting killer immunoglobulin-like receptors. The killer immunoglobulin-like receptor effect in the allogeneic HCT setting hinges upon expression of specific inhibitory killer immunoglobulin-like receptors on donor-derived NK cells and either the presence or absence of their matching HLA class I molecules (killer immunoglobulin-like receptor ligands) on recipient leukemic and normal cells. Normally the presence of specific killer immunoglobulin-like receptor ligands interacting with paired inhibitory killer immunoglobulin-like receptor molecules prevents NK cell attack of healthy cells. In the allogeneic transplant setting, recipient leukemia cells genetically differ from donor NK cells and they may not have the appropriate inhibitory killer immunoglobulin-like receptor ligand. This mismatch of ligand and receptor allows NK cell–based killing of recipient leukemia cells to proceed for certain donor-recipient genetic combinations.

The original observation of decreased relapse with certain killer immunoglobulin-like receptor-ligand combinations was made in the setting of T-cell depleted haploidentical transplantation and was strongest after HCT for AML.[11,12] Along with decreasing relapse, these studies have suggested a decrease in GVHD with appropriate killer immunoglobulin-like receptor-ligand combinations. Many subsequent studies did not detect survival effects for killer immunoglobulin-like receptor-incompatible HCT using standard transplantation methods,[13,14] which has led to the conclusion that T-cell depletion may be necessary to remove other forms of inhibitory cellular interactions. Decreased relapse and better survival has been noted with donor/recipient killer immunoglobulin-like receptor-ligand incompatibility after cord blood HCT, a relatively T-cell depleted procedure.[15,16] The role of killer immunoglobulin-like receptor incompatibility in sibling donor HCT and in diseases other than AML is controversial.[17,18]

A current challenge associated with the killer immunoglobulin-like receptor field is that several different approaches have been used to determine what is killer immunoglobulin-like receptor compatible and incompatible.[12,19] Standardization of classification and prospective studies should help clarify the utility and importance of this approach. Currently, because a limited number of centers perform haploidentical HCT and the data in cord blood HCT are early, most transplant programs do not use killer immunoglobulin-like receptor mismatching as part of their strategy for choosing a donor. Full HLA matching is considered most important for outcome, with considerations of killer immunoglobulin-like receptor incompatibility remaining secondary.

With low risk of GVHD and demonstrated efficacy in decreasing relapse in post-haploidentical HCT settings, NK cell infusions have been studied as a method of treating high-risk patients and consolidating patients in remission. The University of Minnesota group initially failed to demonstrate efficacy with autologous NK cells, but found that intense immunoablative therapy followed by purified haploidentical NK cells and IL-2 maintenance led to remission in 5 of 19 high-risk AML patients.[20] Researchers at St. Jude Children’s Research Hospital treated ten intermediate-risk AML patients who had completed chemotherapy and were in remission with lower-dose immunosuppression followed by haploidentical NK cell infusions and IL-2 for consolidation.[21] Expansion of NK cells was noted in all nine of the killer immunoglobulin-like receptor-incompatible donor/recipient pairs. All ten children remained in remission at 2 years. A follow-up phase II study is underway, as are many investigations into NK cell therapy for a number of cancer types.

References

1. Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001.  [PUBMED Abstract]
   
   
2. Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007.  [PUBMED Abstract]
   
   
3. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010.  [PUBMED Abstract]
   
   
4. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009.  [PUBMED Abstract]
   
   
5. Porter DL, Collins RH Jr, Shpilberg O, et al.: Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions. Biol Blood Marrow Transplant 5 (4): 253-61, 1999.  [PUBMED Abstract]
   
   
6. Levine JE, Barrett AJ, Zhang MJ, et al.: Donor leukocyte infusions to treat hematologic malignancy relapse following allo-SCT in a pediatric population. Bone Marrow Transplant 42 (3): 201-5, 2008.  [PUBMED Abstract]
   
   
7. Warlick ED, DeFor T, Blazar BR, et al.: Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies postallogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 18 (3): 480-6, 2012.  [PUBMED Abstract]
   
   
8. Bader P, Kreyenberg H, Hoelle W, et al.: Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22 (9): 1696-705, 2004.  [PUBMED Abstract]
   
   
9. Rettinger E, Willasch AM, Kreyenberg H, et al.: Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood 118 (20): 5681-8, 2011.  [PUBMED Abstract]
   
   
10. Ruggeri L, Capanni M, Urbani E, et al.: Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295 (5562): 2097-100, 2002.  [PUBMED Abstract]
    
    
11. Giebel S, Locatelli F, Lamparelli T, et al.: Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 102 (3): 814-9, 2003.  [PUBMED Abstract]
    
    
12. Ruggeri L, Mancusi A, Capanni M, et al.: Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 110 (1): 433-40, 2007.  [PUBMED Abstract]
    
    
13. Davies SM, Ruggieri L, DeFor T, et al.: Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 100 (10): 3825-7, 2002.  [PUBMED Abstract]
    
    
14. Farag SS, Bacigalupo A, Eapen M, et al.: The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant 12 (8): 876-84, 2006.  [PUBMED Abstract]
    
    
15. Cooley S, Trachtenberg E, Bergemann TL, et al.: Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood 113 (3): 726-32, 2009.  [PUBMED Abstract]
    
    
16. Willemze R, Rodrigues CA, Labopin M, et al.: KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia 23 (3): 492-500, 2009.  [PUBMED Abstract]
    
    
17. Leung W: Use of NK cell activity in cure by transplant. Br J Haematol 155 (1): 14-29, 2011.  [PUBMED Abstract]
    
    
18. Leung W, Campana D, Yang J, et al.: High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 118 (2): 223-30, 2011.  [PUBMED Abstract]
    
    
19. Leung W, Iyengar R, Triplett B, et al.: Comparison of killer Ig-like receptor genotyping and phenotyping for selection of allogeneic blood stem cell donors. J Immunol 174 (10): 6540-5, 2005.  [PUBMED Abstract]
    
    
20. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al.: Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105 (8): 3051-7, 2005.  [PUBMED Abstract]
    
    
21. Rubnitz JE, Inaba H, Ribeiro RC, et al.: NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 28 (6): 955-9, 2010.  [PUBMED Abstract]
    
    

Principles of HCT Preparative Regimens

In the days just prior to infusion of the stem cell product (bone marrow, peripheral blood stem cell, or cord blood), hematopoietic cell transplantation (HCT) recipients receive chemotherapy/immunotherapy sometimes combined with radiation therapy. This is called a preparative regimen and the original intent of this treatment was to:

• Create bone marrow space in the recipient for the donor cells to engraft.
• Suppress the immune system or eliminate the recipient T-cells to minimize risks of rejection.
• Intensely treat cancer (if present) with mega-dose therapy of active agents with the intent to overcome therapy resistance.

With the recognition that donor T-cells can facilitate engraftment and kill tumors through graft-versus-leukemia effects (obviating the need to create bone marrow space and intensely treat cancer), reduced-intensity or minimal-intensity HCT approaches focusing on immune suppression rather than myeloablation have been developed. The resultant lower toxicity associated with these regimens has led to lower rates of transplant-related mortality and an expansion eligibility for allogeneic HCT to older individuals and younger patients with pre-HCT comorbidities that put them at risk for severe toxicity after standard HCT approaches.[1] The many preparative regimens available now vary tremendously in the amount of immunosuppression and myelosuppression that they cause, with the lowest intensity regimens relying heavily on a strong graft-versus-tumor effect.

Enlarge

Figure 2. Selected preparative regimens frequently used in pediatric HCT categorized by current definitions as non-myeloablative, reduced-intensity, or myeloablative. Although FLU plus Treosulfan and FLU plus Busulfan (full-dose) are considered myeloablative approaches, some refer to them as reduced toxicity regimens.

Although these regimens represent a spectrum of varying degrees of myelosuppression and immune suppression, they have been categorized clinically in the following three major categories:[2]

• Myeloablative: Intense approaches that cause irreversible pancytopenia requiring stem cell rescue for restoration of hematopoiesis.
• Nonmyeloablative: Regimens that cause minimal cytopenias and do not require stem cell support.
• Reduced-intensity conditioning: Regimens that are of intermediate intensity and do not meet the definitions of nonmyeloablative or myeloablative regimens.

Enlarge

Figure 3. Classification of conditioning regimens in 3 categories, based on duration of pancytopenia and requirement for stem cell support. Myeloablative regimens (MA) produce irreversible pancytopenia and require stem cell support. Nonmyeloablative regimens (NMA) produce minimal cytopenia and would not require stem cell support. Reduced-intensity regimens (RIC) are regimens which cannot be classified as MA nor NMA.[2] Reprinted from Biology of Blood and Marrow Transplantation, 15 (12), Andrea Bacigalupo, Karen Ballen, Doug Rizzo, Sergio Giralt, Hillard Lazarus, Vincent Ho, Jane Apperley, Shimon Slavin, Marcelo Pasquini, Brenda M. Sandmaier, John Barrett, Didier Blaise, Robert Lowski, Mary Horowitz, Defining the Intensity of Conditioning Regimens: Working Definitions, Pages 1628-1633, Copyright 2009, with permission from Elsevier.

The use of reduced-intensity conditioning and nonmyeloablative regimens is well-established in older adults who cannot tolerate more intense myeloablative approaches,[3-5] but only a handful of younger patients with malignancies have been studied using these approaches.[6-10] A large Pediatric Blood and Marrow Transplant Consortium study identified patients at high risk for transplant-related mortality with myeloablative regimens (e.g., history of previous myeloablative transplant, severe organ system dysfunction, or active invasive fungal infection) and successfully treated them with a reduced-intensity regimen.[11] Transplant-related mortality was low in this high-risk group, and long-term survival occurred in most patients with minimal or no detectable disease present at the time of transplantation. Because the risks of relapse are higher with these approaches, their use in pediatric cancer is currently limited to patients ineligible for myeloablative regimens.

Intense myeloablative approaches almost invariably result in rapid establishment of hematopoiesis derived completely from donor cells upon count recovery within weeks of the transplant. The introduction of reduced-intensity conditioning and nonmyeloablative approaches into HCT practice has resulted in a slower pace of transition to donor hematopoiesis (gradually increasing from partial to full donor hematopoiesis over months) that is sometimes only partial. DNA-based techniques have been established to differentiate donor and recipient hematopoiesis, applying the word chimerism (from the Greek chimera, a mythical animal with parts taken from various animals) to describe whether all or part of hematopoiesis after HCT is from the donor or recipient.

There are several implications to the pace and extent of donor-chimerism eventually achieved by an HCT recipient. For patients receiving reduced-intensity conditioning or nonmyeloablative regimens, rapid progression to full donor chimerism is associated with less relapse, but more graft-versus-host disease (GVHD).[12] The delayed pace of obtaining full-donor chimerism after these regimens has led to late-onset acute GVHD, occurring as much as 6 months to 7 months after HCT (generally within 100 days after myeloablative approaches).[13] A portion of patients achieve stable mixed chimerism of both donor and recipient. Mixed chimerism is associated with more relapse after HCT for malignancies and less GVHD; however, this condition is often advantageous for nonmalignant HCT, where usually only a percentage of normal hematopoiesis is needed to correct the underlying disorder and GVHD is not beneficial.[14] Finally, serially measured decreasing donor chimerism, especially T-cell specific chimerism, has been associated with increased risk of rejection.[15]

Because of the implications of persistent recipient chimerism, most transplant programs test for chimerism shortly after engraftment and continue testing regularly until stable full donor hematopoiesis has been achieved. Investigators have defined two approaches to treat the increased risks of relapse and rejection associated with increasing recipient chimerism: rapid withdrawal of immune suppression and donor lymphocyte infusions (DLI). These approaches are frequently used to address this issue, and have been shown in some cases to decrease relapse risk and stop rejection.[16,17] Timing of tapers of immune suppression and doses and approaches to the administration of DLI to increase or stabilize donor chimerism vary tremendously between transplant regimens and institutions.

References

1. Deeg HJ, Sandmaier BM: Who is fit for allogeneic transplantation? Blood 116 (23): 4762-70, 2010.  [PUBMED Abstract]
   
   
2. Bacigalupo A, Ballen K, Rizzo D, et al.: Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 15 (12): 1628-33, 2009.  [PUBMED Abstract]
   
   
3. Giralt S, Estey E, Albitar M, et al.: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 89 (12): 4531-6, 1997.  [PUBMED Abstract]
   
   
4. Slavin S, Nagler A, Naparstek E, et al.: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91 (3): 756-63, 1998.  [PUBMED Abstract]
   
   
5. Storb R, Yu C, Sandmaier BM, et al.: Mixed hematopoietic chimerism after marrow allografts. Transplantation in the ambulatory care setting. Ann N Y Acad Sci 872: 372-5; discussion 375-6, 1999.  [PUBMED Abstract]
   
   
6. Bradley MB, Satwani P, Baldinger L, et al.: Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases. Bone Marrow Transplant 40 (7): 621-31, 2007.  [PUBMED Abstract]
   
   
7. Del Toro G, Satwani P, Harrison L, et al.: A pilot study of reduced intensity conditioning and allogeneic stem cell transplantation from unrelated cord blood and matched family donors in children and adolescent recipients. Bone Marrow Transplant 33 (6): 613-22, 2004.  [PUBMED Abstract]
   
   
8. Gómez-Almaguer D, Ruiz-Argüelles GJ, Tarín-Arzaga Ldel C, et al.: Reduced-intensity stem cell transplantation in children and adolescents: the Mexican experience. Biol Blood Marrow Transplant 9 (3): 157-61, 2003.  [PUBMED Abstract]
   
   
9. Pulsipher MA, Woolfrey A: Nonmyeloablative transplantation in children. Current status and future prospects. Hematol Oncol Clin North Am 15 (5): 809-34, vii-viii, 2001.  [PUBMED Abstract]
   
   
10. Roman E, Cooney E, Harrison L, et al.: Preliminary results of the safety of immunotherapy with gemtuzumab ozogamicin following reduced intensity allogeneic stem cell transplant in children with CD33+ acute myeloid leukemia. Clin Cancer Res 11 (19 Pt 2): 7164s-7170s, 2005.  [PUBMED Abstract]
    
    
11. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009.  [PUBMED Abstract]
    
    
12. Baron F, Baker JE, Storb R, et al.: Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 104 (8): 2254-62, 2004.  [PUBMED Abstract]
    
    
13. Vigorito AC, Campregher PV, Storer BE, et al.: Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD. Blood 114 (3): 702-8, 2009.  [PUBMED Abstract]
    
    
14. Marsh RA, Vaughn G, Kim MO, et al.: Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood 116 (26): 5824-31, 2010.  [PUBMED Abstract]
    
    
15. McSweeney PA, Niederwieser D, Shizuru JA, et al.: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97 (11): 3390-400, 2001.  [PUBMED Abstract]
    
    
16. Bader P, Kreyenberg H, Hoelle W, et al.: Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22 (9): 1696-705, 2004.  [PUBMED Abstract]
    
    
17. Horn B, Soni S, Khan S, et al.: Feasibility study of preemptive withdrawal of immunosuppression based on chimerism testing in children undergoing myeloablative allogeneic transplantation for hematologic malignancies. Bone Marrow Transplant 43 (6): 469-76, 2009.  [PUBMED Abstract]
    
    

Complications After HCT

Because of the intensity of therapy associated with the transplant process, the pretransplant clinical status of recipients (e.g., age, presence of infections or organ dysfunction, functional status, etc.) is associated with risk of transplant-related mortality. The best tool to assess the impact of pretransplant comorbidities on outcomes after transplant was developed by adapting an existing comorbidity scale, the Charlson Comorbidity Index. Investigators at the Fred Hutchinson Cancer Research Center systematically defined which of the Charlson Comorbidity Index elements were correlated with transplant-related mortality in adult and pediatric patients. They also determined several additional comorbidities that have predictive power specific to transplant patients. Successful validation defined what is now termed the HCT-Charlson Comorbidity Index.[1] Transplant-related mortality increases with cardiac, hepatic, pulmonary, gastrointestinal, infectious, and autoimmune comorbidities, or a history of previous solid tumors (see Table 4).

The predictive power of this index for both transplant-related mortality and overall survival (OS) is strong, with a hazard ratio of 3.54 (95% confidence interval [CI], 2.0–6.3) for nonrelapse mortality (NRM) and 2.69 (95% CI, 1.8–4.1) for survival for patients with a score of 3 or more compared with those who have a score of 0. Although the original studies were performed with patients receiving intense, myeloablative approaches, the HCT-Charlson Comorbidity Index has been shown to be predictive of outcome for patients receiving reduced-intensity and nonmyeloablative regimens as well.[2] It has also been combined with disease status [3] and Karnofsky score,[4] leading to even better prediction of survival outcomes.

The large majority of patients assessed in the HCT-Charlson Comorbidity Index studies have been adults, and the comorbidities listed are skewed toward adult diseases. The relevance of this scale for pediatric and young adult recipients of HCT has been explored in two studies. A retrospective cohort study was conducted at four large centers of pediatric patients with a median age of 6 years and a wide variety of both malignant and nonmalignant disorders.[5] The HCT-Charlson Comorbidity Index was predictive of both NRM and survival, with 1-year NRM of 10%, 14%, and 28% and 1-year OS of 88%, 67%, and 62% for patients with scores of 0, 1–2, and 3+, respectively. A second study included young adults (aged 16–39 years) and demonstrated similar increases in mortality with higher HCT-Charlson Comorbidity Index scores (NRM 24% and 38% and OS 46% and 28% for patients with scores of 0–2 and 3+, respectively).[6] In both studies, more than three-quarters of the reported comorbidities were associated with respiratory or hepatic conditions and infection.[5,6] Patients with pre-HCT pulmonary dysfunction were at particularly high risk for comorbidity, with a 2-year OS of 29% compared with 61% in those with normal lung function before HCT.[6]

Sinusoidal obstructive syndrome/veno-occlusive disease of the liver (SOS/VOD) is defined clinically by right upper quadrant pain with hepatomegaly, fluid retention (weight gain and ascites), and hyperbilirubinemia. Pathologically, inciting agents cause damage to the hepatic sinusoids, resulting in biliary obstruction. This syndrome has been estimated to occur in 15% to 40% of myeloablative transplantations in children, and risk factors include the use of busulfan (especially before therapeutic pharmacokinetic monitoring), total-body irradiation, serious infection, graft-versus-host disease (GVHD), and pre-existing liver dysfunction due to hepatitis or iron overload.[7,8] Life-threatening SOS/VOD generally occurs early after transplantation and is characterized by multiorgan system failure.[9] Milder, reversible forms can occur with full recovery expected. Approaches to both prevention and treatment with agents such as heparin, protein C, and antithrombin III have been studied with mixed results, but recent studies have suggested prophylactic ursodiol may have an effect on SOS/VOD.[10] Another agent with demonstrated activity is defibrotide, a mixture of oligonucleotides with antithrombotic and fibrinolytic effects on microvascular endothelium. Defibrotide has been shown to decrease mortality in the treatment of severe VOD,[11] and has also demonstrated efficacy in decreasing VOD incidence when used prophylactically.[12] Defibrotide is not FDA approved, but is routinely used by U.S. centers through a pre-approval protocol.

Although transplant-associated microangiopathy clinically mirrors hemolytic uremic syndrome, its causes and clinical course are different from other hemolytic uremic syndrome–like syndromes. Transplant-associated microangiopathy has most frequently been associated with the use of the calcineurin inhibitors, tacrolimus and cyclosporine, and has been noted to occur more frequently when either of these two medications are used in combination with sirolimus.[13] Diagnostic criteria for this syndrome have been standardized and include the presence of schistocytes on a peripheral smear and increased lactic dehydrogenase, decreased haptoglobin, and thrombocytopenia with or without anemia.[14] Suggestive symptoms consistent but not necessary for the diagnosis include a sudden worsening of renal function and neurologic symptoms. Treatment for transplant-associated microangiopathy includes cessation of the calcineurin inhibitor and substitution with other immune suppressants if necessary. In addition, careful management of hypertension and renal damage by dialysis, if necessary, is vital. Prognosis for normalization of kidney function when disease is caused by calcineurin inhibitors alone is generally poor; however, most transplant-associated microangiopathy associated with the combination of a calcineurin inhibitor and sirolimus has been reversed after stopping sirolimus, and in some cases, both medications.[13]

Idiopathic pneumonia syndrome is characterized by diffuse, noninfectious lung injury that occurs within the first few months after transplantation. Diagnostic criteria include signs and symptoms of pneumonia, evidence of nonlobar radiographic infiltrates, and abnormal pulmonary function, all in the absence of documented infectious organisms.[15] With this in mind, early assessment by bronchioalveolar lavage to rule out infection is important. Time of onset ranges from 14 days to 90 days after the infusion of donor cells. Mortality rates of 50% to 70% have been reported,[16] although these estimates are from the mid-1990s and outcomes may have improved. Possible etiologies include direct toxic effects of the conditioning regimens and occult infection leading to secretion of high levels of inflammatory cytokines into the alveoli. Traditional therapy has been high-dose methylprednisolone and pulmonary support. The addition of etanercept, a soluble interleukin-2 receptor, to steroid therapies has shown promising short-term outcomes (extubation, improved short-term survival) in single-center studies,[17] but multicenter studies showing improved long-term survival are lacking. In recent years, the incidence of this complication appears to be decreasing, possibly due to less-intensive preparative regimens, better HLA matching, and better definition of occult infections through polymerase chain reaction (PCR) testing of blood and bronchioalveolar specimens.

Epstein-Barr virus (EBV) infection increases through childhood from approximately 40% in 4-year olds to more than 80% in teenagers. Patients with a history of previous EBV infection are at risk for reactivation of EBV when undergoing HCT procedures that result in intense, prolonged lymphopenia (T-cell–depleted procedures, use of antithymocyte globulin or alemtuzumab, and to a lesser degree, use of cord blood).[18-20] Patients experiencing EBV reactivation can vary from isolated increase in EBV titers in the bloodstream as measured by PCR to an aggressive monoclonal disease with marked lymphadenopathy presenting as lymphoma (lymphoproliferative disorder). Isolated bloodstream reactivation can improve in some cases without therapy as immune function improves; however, lymphoproliferative disorder may require more aggressive therapy. Treatment of EBV-lymphoproliferative disorder in the past has relied on decreasing immune suppression and treatment with chemotherapy such as cyclophosphamide. Recently, CD20-positive EBV-lymphoproliferative disorder and EBV reactivation have been shown to respond to therapy with the CD20 monoclonal antibody therapy, rituximab.[21,22] In addition, some centers have found efficacy in treating or preventing this complication with therapeutic or prophylactic EBV-specific cytotoxic T cells.[23] Improved understanding of the risk of EBV reactivation, early monitoring, and aggressive therapy have significantly decreased the risk of mortality from this challenging complication.

GVHD is the result of immunologic activation of donor lymphocytes targeting major or minor HLA disparities present in the tissues of a recipient. Acute GVHD usually occurs within the first 3 months of transplantation, although delayed acute GVHD has been noted in reduced-intensity conditioning and nonmyeloablative approaches, where achieving a high level of full donor chimerism is sometimes delayed. Typically, acute GVHD presents with at least one of three manifestations: skin rash, hyperbilirubinemia, and secretory diarrhea. Acute GVHD is classified by grading the severity of skin, gastrointestinal, and liver involvement and further combining the individual grading of these three areas into an overall stage that is prognostically significant (see Tables 5 and 6).[24] Patients with grade III or IV acute GVHD are at higher risk for mortality, generally due to organ system damage caused by infections or progressive acute GVHD that is sometimes resistant to therapy.

Morbidity and mortality from acute GVHD can be reduced through immune suppressive medications given prophylactically or T-cell depletion of grafts, either ex vivo by actual removal of cells from a graft or in vivo with anti-lymphocyte antibodies (antithymocyte globulin or anti-CD52 [alemtuzumab]). Approaches to GVHD prevention in non-T-cell–depleted grafts have included intermittent methotrexate, a calcineurin inhibitor (i.e., cyclosporine or tacrolimus), a combination of a calcineurin inhibitor with methotrexate (currently the most commonly used approach in pediatrics), or various combinations of a calcineurin inhibitor with steroids or mycophenolate mofetil. When significant acute GVHD occurs, first-line therapy is generally methylprednisolone. Patients with acute GVHD resistant to this therapy have a poor prognosis but a good percentage of cases respond to second-line agents (e.g., mycophenolate mofetil, infliximab, pentostatin, sirolimus, or extracorporeal photopheresis). Complete elimination of acute GVHD with intense T-cell depletion approaches has generally resulted in increased relapse, more infectious morbidity, and increased EBV-lymphoproliferative disorder. Because of this, most HCT GVHD prophylaxis is given in an attempt to balance risk by giving sufficient immune suppression to prevent most severe acute GVHD but not completely removing GVHD risk.

Chronic GVHD is a syndrome that may involve a single or several organ systems, with clinical features resembling autoimmune diseases.[25,26] Chronic GVHD is usually first noted 2 to 12 months after HCT. It may occur distinctly:

• After a history of acute GVHD (classic chronic GVHD).
• As part of an ongoing GVHD process when manifestations diagnostic of chronic GVHD occur while symptoms of acute GVHD persist (overlap syndrome).
• As new-onset chronic GVHD when no acute GVHD has occurred (de novo chronic GVHD).

Chronic GVHD occurs in approximately 15% to 30% of children after sibling donor HCT [27] and in 20% to 45% of children after unrelated donor HCT, with higher risk associated with peripheral blood stem cells (PBSCs) and a lower risk with cord blood.[28,29] The tissues that are commonly involved include skin, eyes, mouth, hair, joints, liver, and gastrointestinal tract. Other tissues such as lungs, nails, muscles, urogenital system, and nervous system may be involved.

Risk factors for the development of chronic GVHD include the following:[27,30,31]

• Patient’s age.
• Type of donor.
• Use of PBSCs.
• History of acute GVHD.
• Conditioning regimen.

The diagnosis of chronic GVHD is based on clinical features (at least one diagnostic clinical sign, e.g., poikiloderma) or distinctive manifestations complemented by relevant tests (e.g., dry eye with positive Schirmer test).[32] Tables 7 to 11 list organ manifestations of chronic GVHD with a specific listing of findings that are sufficient to establish the diagnosis of chronic GVHD. Biopsy of affected sites may be needed to confirm the diagnosis.[33]

Common skin manifestations include alterations in pigmentation, texture, elasticity, and thickness, with papules, plaques, or follicular changes. Patient-reported symptoms include dry skin, itching, limited mobility, rash, sores, or changes in coloring or texture. Generalized scleroderma may lead to severe joint contractures and debility. Associated hair loss and nail changes are common. Other important symptoms that should be assessed include dry eyes and oral changes such as atrophy, ulcers, and lichen planus. In addition, joint stiffness along with restricted range of motion, weight loss, nausea, difficulty swallowing, and diarrhea should be noted.

Several factors have been associated with increased risk of nonrelapse mortality (NRM) in children who develop significant chronic GVHD. Children who received HLA mismatched grafts, PBSCs, who were older than 10 years, or who had platelet counts of less than 100,000/µL at diagnosis of chronic GVHD have an increased risk of NRM. NRM was 17%, 22%, and 24% at 1, 3, and 5 years after diagnosis with chronic GVHD. Many of these children require long-term immune suppression. By 3 years after diagnosis of chronic GVHD, about a third of children had died either of relapse or NRM, a third were off immune suppression, and a third still required some form of immune suppressive therapy.[34]

Older literature describes chronic GVHD as either limited or extensive. A National Institutes of Health (NIH) Consensus Workshop in 2006 expanded the definition to better predict long-term outcomes and to define how future studies can judge response.[35] According to the NIH grading system:[32]

• Mild disease involves only one or two sites with no significant functional impairment (maximum severity score of 1 in a 0-to-3–point scale).
• Moderate disease involves either more sites (>2) or is associated with higher severity score (maximum score of 2 in any site).
• Severe disease indicates major disability (a score of 3 in any site) or a lung score of 2.

Thus, high-risk patients include those with severe disease of any site or extensive involvement of multiple sites, especially those with symptomatic lung involvement, greater than 50% skin involvement, platelet count of less than 100,000/µl, poor performance score (<60%), weight loss greater than 15%, chronic diarrhea, progressive onset chronic GVHD, or a history of steroid treatment with greater than 0.5 mg/kg/day of prednisone for acute GVHD.

Steroids remain the cornerstone of chronic GVHD therapy; however, many approaches have been developed to minimize steroid dosing, including use of calcineurin inhibitors.[36] Topical therapy to affected areas is preferred for patients with limited disease.[37] A number of agents such as mycophenolate mofetil,[38] pentostatin,[39] sirolimus,[40] and rituximab,[41] have been tested with some success. Other approaches including extracorporeal photopheresis have been evaluated and show some efficacy in a percentage of patients.[42]

Besides significantly affecting organ function, quality of life, and functional status, infection is the major cause of chronic GVHD-related death. Therefore, all patients with chronic GVHD should receive prophylaxis against Pneumocystis jirovecii pneumonia, common encapsulated organisms, and varicella by using agents such as trimethoprim/sulfamethoxazole, penicillin, and acyclovir. While disease progression is the primary cause of death in long-term follow-up of hematopoietic stem cell transplantation patients with no chronic GVHD, transplant-related complications account for 70% of the deaths in patients with chronic GVHD.[27] Guidelines concerning ancillary therapy and supportive care of patients with chronic GVHD have been published.[37]

References

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9. Bearman SI: The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 85 (11): 3005-20, 1995.  [PUBMED Abstract]
   
   
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14. Ho VT, Cutler C, Carter S, et al.: Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11 (8): 571-5, 2005.  [PUBMED Abstract]
    
    
15. Clark JG, Hansen JA, Hertz MI, et al.: NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 147 (6 Pt 1): 1601-6, 1993.  [PUBMED Abstract]
    
    
16. Kantrow SP, Hackman RC, Boeckh M, et al.: Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 63 (8): 1079-86, 1997.  [PUBMED Abstract]
    
    
17. Yanik GA, Ho VT, Levine JE, et al.: The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood 112 (8): 3073-81, 2008.  [PUBMED Abstract]
    
    
18. Gerritsen EJ, Stam ED, Hermans J, et al.: Risk factors for developing EBV-related B cell lymphoproliferative disorders (BLPD) after non-HLA-identical BMT in children. Bone Marrow Transplant 18 (2): 377-82, 1996.  [PUBMED Abstract]
    
    
19. Shapiro RS, McClain K, Frizzera G, et al.: Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 71 (5): 1234-43, 1988.  [PUBMED Abstract]
    
    
20. Brunstein CG, Weisdorf DJ, DeFor T, et al.: Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood 108 (8): 2874-80, 2006.  [PUBMED Abstract]
    
    
21. Blaes AH, Cao Q, Wagner JE, et al.: Monitoring and preemptive rituximab therapy for Epstein-Barr virus reactivation after antithymocyte globulin containing nonmyeloablative conditioning for umbilical cord blood transplantation. Biol Blood Marrow Transplant 16 (2): 287-91, 2010.  [PUBMED Abstract]
    
    
22. Kuehnle I, Huls MH, Liu Z, et al.: CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95 (4): 1502-5, 2000.  [PUBMED Abstract]
    
    
23. Liu Z, Savoldo B, Huls H, et al.: Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the prevention and treatment of EBV-associated post-transplant lymphomas. Recent Results Cancer Res 159: 123-33, 2002.  [PUBMED Abstract]
    
    
24. Glucksberg H, Storb R, Fefer A, et al.: Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18 (4): 295-304, 1974.  [PUBMED Abstract]
    
    
25. Shlomchik WD, Lee SJ, Couriel D, et al.: Transplantation's greatest challenges: advances in chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (1 Suppl 1): 2-10, 2007.  [PUBMED Abstract]
    
    
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30. Leung W, Ahn H, Rose SR, et al.: A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86 (4): 215-24, 2007.  [PUBMED Abstract]
    
    
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36. Koc S, Leisenring W, Flowers ME, et al.: Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 100 (1): 48-51, 2002.  [PUBMED Abstract]
    
    
37. Couriel D, Carpenter PA, Cutler C, et al.: Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 12 (4): 375-96, 2006.  [PUBMED Abstract]
    
    
38. Martin PJ, Storer BE, Rowley SD, et al.: Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood 113 (21): 5074-82, 2009.  [PUBMED Abstract]
    
    
39. Jacobsohn DA, Gilman AL, Rademaker A, et al.: Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a Pediatric Blood and Marrow Transplant Consortium study. Blood 114 (20): 4354-60, 2009.  [PUBMED Abstract]
    
    
40. Jurado M, Vallejo C, Pérez-Simón JA, et al.: Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (6): 701-6, 2007.  [PUBMED Abstract]
    
    
41. Cutler C, Miklos D, Kim HT, et al.: Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108 (2): 756-62, 2006.  [PUBMED Abstract]
    
    
42. González Vicent M, Ramirez M, Sevilla J, et al.: Analysis of clinical outcome and survival in pediatric patients undergoing extracorporeal photopheresis for the treatment of steroid-refractory GVHD. J Pediatr Hematol Oncol 32 (8): 589-93, 2010.  [PUBMED Abstract]
    
    

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with hematopoietic stem cell transplantation. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Changes to This Summary (10/05/2012)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Principles of Hematopoietic Cell Transplantation (HCT)

Added text to state that better matching of units has been shown to result in less transplant-related mortality, but has not been shown to have an impact on survival in children with malignancies (cited Eapen et al. as reference 17). Also revised text to state that many centers will type up to 10 alleles and use the best match possible, but the impact of DQB1 mismatched has not been shown to affect outcome.

Added text about how the direction of mismatches between donor and recipient has been shown to be important in cord blood transplant outcomes (cited Stevens et al. as reference 19).

Revised Table 3 to update the risk of chronic graft-versus-host-disease with bone marrow and cord blood transplants.

Complications After HCT

Added this new section.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of hematopoietic cell transplantation in treating childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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