Unrelated Donor Hematopoietic Stem Cell Research Articles

21: Unrelated Donor Hematopoietic Stem Cell Transplantation in Children with Acute Leukemia: Risks and Benefits of Umbilical Cord Blood versus Bone Marrow

21: Unrelated Donor Hematopoietic Stem Cell Transplantation in Children with Acute Leukemia: Risks and Benefits of Umbilical Cord Blood versus Bone Marrow

Severe Infections after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation in Adults: Comparison of Cord Blood Transplantation with Peripheral Blood and Bone Marrow Transplantation

We evaluated the occurrence of severe infections in 192 consecutive adult recipients of volunteer unrelated donor allogeneic hematopoietic stem cell transplants, with a detailed analysis of severe infections after receipt of cord blood transplants (CBTs; n = 48) or bone marrow transplants (BMTs)/peripheral blood stem cell transplants (PBSCTs; n = 144). At a 3-year median follow-up, CBT recipients had a higher risk of developing any severe infection (85% versus 69% in BMT/PBSCT recipients, P < .01). CBT recipients had a higher incidence of severe bacterial infections before day +100, but at 3 years the risks of these and other infections were similar in the CBT and BMT/PBSCT groups. In addition, the 100-day and 3-year incidences of infection-related mortality (IRM) did not differ between groups ( P = .2 and .5, respectively). In multivariate analysis, the most significant risk factor for IRM in all 192 patients was monocytopenia (.2 × 10 9/L). In CBT recipients, only neutropenia (.2 × 10 9/L) on day +30 and low nucleated cell dose infusion (<2 × 10 7/kg) showed a trend for increased IRM ( P = .05 in both cases). Stem cell source had no effect on day +100 or 3-year nonrelapse mortality (NRM), cytomegalovirus infection, cytomegalovirus disease (7% versus 6%), or overall survival (36% versus 39%, respectively). The number of mismatches in HLA (A, B, and DRB1) had no effect on any outcome in CBT recipients. In contrast, in the BMT/PBSCT group, the presence of any mismatch by low or high-resolution HLA typing (A, B, C, and DRB1) increased NRM and decreased overall survival ( P < .01). IRM was the primary or secondary cause of death in 61% and 59% of CBT and BMT/PBSCT recipients who died, respectively. Our results confirm the relevance of severe infectious complications as source of severe morbidity and NRM after volunteer unrelated donor hematopoietic stem cell transplantation in adults, but suggest that CBT recipients have a similar risk of dying from an infection if an accurate selection of a cord blood unit is done.

Topical issues in unrelated donor haematopoietic stem cell transplants: a report from a workshop convened by the Anthony Nolan Trust in London – 2005

Over more than three decades, The Anthony Nolan Trust (ANT) has provided an unrelated donor (UD) for over 4000 children and adults lacking a suitable family member donor, and has remained at the forefront of developments in haematopoietic stem cell transplantation (HSCT) and bone marrow register management. These three decades have seen major changes in clinical practice of UD-HSCT, including new indications, increased use of alternative haematopoietic cell sources, significant improvement of the outcome as a result of better support care, less-toxic conditioning regimens, and better donor selection, and expansion to older patients with higher comorbidities. In order to foster our goal of improving UD-HSCT availability and outcome in a progressively more complex clinical scenario, a new initiative from ANT was launched in 2005 to convene an experts workshop to address the topical issues in this field. Four consecutive panels addressed factors influencing donor selection and transplant outcome, the use of cord blood, regulatory and accreditation issues, and future developments in this field. This report summarizes the discussions held in this workshop, which will likely develop into a periodic event where transplant clinicians, scientists and registry members will meet to share their experience and vision in the field of UD-HSCT.

Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with nonpermissive HLA-DPB1 disparity in host-versus-graft direction

AbstractThe success of allogeneic hematopoietic stem cell transplantation (HSCT) from matched unrelated donors (UDs) for β-thalassemia may be hampered by the occurrence of graft rejection. Here, we show that the rate of this complication can be reduced by selecting 5-loci HLA-matched donors without nonpermissive mismatches at HLA-DPB1, defined according to an algorithm previously described and based on principles of central T-cell tolerance. Seventy-two consecutive patients and their UDs, prospectively selected for matching at the allelic level for HLA-A, -B, -C, -DRB, and -DQB1 loci, were enrolled in the analysis. These pairs were either DPB1 matched/permissively mismatched (n = 45, control group) or had at least one nonpermissive DPB1 mismatch in the host-versus-graft (HvG; n = 17) or in the graft-versus-host (GvH; n = 10) direction. In multivariate analysis, the risk of rejection was significantly increased in the group with HvG disparity (RR = 7.42; 95% CI = 1.29-42.68; P = .02) as compared to the control group. A lower, statistically significant, probability of thalassemia-free survival was found in patients belonging to the HvG group as compared to controls (RR = 5.15; 95% CI = 1.58-16.82; P = .01). These data suggest that in patients with thalassemia, the incidence of graft failure after HSCT may be reduced by appropriate selection of UDs, with such selection taking into account the functional rules of immunogenetics.

Impact of high-resolution matching in allogeneic unrelated donor stem cell transplantation in Switzerland

It is currently unknown what degree of human leukocyte antigen (HLA)-mismatching is acceptable in unrelated donor hematopoietic stem cell transplantation (UD-HSCT). Mismatches at some loci may be more permissive than others. We have analyzed the effect of high-resolution HLA-matching on outcome of all 214 consecutive recipients of UD-HSCT carried out in Switzerland. All typing was by the Swiss reference laboratory. Donor-recipient pairs were HLA-10/10 matched (n=130) or mismatched for either HLA-A/-B/-DRB1/multiple loci (n=33; (HLA-A/-B=10); (-DRB1=8); (multiple=15)); HLA-C (n=29) or HLA-DQ/-DRB3 (n=22; (DQ=16); (-DRB1=6)). The median follow-up was 32 months. Survival probabilities (+/-95% confidence interval) at 3 years were 57 (+/-10)% for recipients of HLA 10/10-matched transplants, 53 (+/-22)% for recipients of HLA-DQ/-DRB3-mismatched transplants, 44 (+/-20)% for recipients of HLA-C-mismatched transplants and 0% for recipients of transplants mismatched at HLA-A/-B/-DRB1/multiple loci (P<0.0001). In multivariate analyses, HLA compatibility was the variable most significantly associated with survival and treatment-related mortality. We found important differences in survival in recipients of UD-HSCT with best results for transplants from 10/10 matched donors. Single mismatches at HLA-DQ/-DRB3 were well tolerated, mismatches at HLA-C had intermediate results and mismatches at HLA-A/-B/-DRB1/multiple loci resulted in poor survival.

HLA-C mismatch is associated with inferior survival after unrelated donor non-myeloablative hematopoietic stem cell transplantation

HLA-C matching is an important determinant of outcome after myeloablative unrelated donor (URD) hematopoietic stem cell transplantation. However, its importance in non-myeloablative stem cell transplantation (NST) is not known. We report a retrospective analysis of 111 patients who underwent URD NST, of whom 78 were 10/10 matched at HLA-A, B, C, DRB1, DQB1 and 33 were mismatched at one or more HLA-C antigen/allele (24 HLA-C only; nine HLA-C+other locus mismatch). Patients were conditioned with busulfan (0.8 mg/kg/day i.v. x 4 days) and fludarabine (30 mg/m(2)/day i.v. x 4 days). Graft-versus-host disease prophylaxis included cyclosporine/prednisone- or tacrolimus/mini-methotrexate-based regimens. HLA-C disparity did not impair engraftment. Median marrow donor chimerisms were >or=90% donor at day+30 and +100 in both groups. Overall survival at 2 years was 30% in HLA-C-mismatched and 51% in 10/10-matched patients (P=0.008). In Cox regression, HLA-C mismatch was an independent predictor of death (hazard ratio 1.85, P=0.04). Treatment-related mortality was higher in the HLA-C-mismatched group: 48 versus 16% (P=0.0001). Cumulative relapse incidence was 35% in the HLA-C-mismatched and 55% in the 10/10-matched cohort, P=0.09. HLA-C mismatch is associated with inferior survival after URD NST.

Donor leukocyte infusions after unrelated donor hematopoietic stem cell transplantation

Donor leukocyte infusions provide direct and potent graft-versus-tumor activity to treat relapse after allogeneic stem cell transplantation. Extensive data are available on the use of donor leukocyte infusion after matched-sibling stem cell transplantation, but reports are remarkably few on the use of donor leukocyte infusion after unrelated-donor stem cell transplantation. But the role for unrelated-donor leukocyte infusion is not well established. The dramatic success of donor leukocyte infusion to treat relapse after matched-sibling stem cell transplantation has led to the use of unrelated-donor leukocyte infusion in many patients. Several case studies suggest that unrelated-donor leukocyte infusion effectively induces direct graft-versus-tumor reactions with toxicity comparable to that of matched-sibling donor leukocyte infusion. Important issues include the relationship between dose and response/toxicity appropriate timing, dose, and schedule; and identification of the best tumor targets. In particular nonmyeloablative transplant strategies using unrelated donors are expanding rapidly, but relapse rates are high. There is a paucity of data on unrelated-donor leukocyte infusion in this setting. This review summarizes recent data on the use of unrelated-donor leukocyte infusion. We discuss anticipated outcomes and identify areas under active investigation in both ablative and nonmyeloablative unrelated-donor stem cell transplantation.

Impact of high-resolution HLA matching on outcomes of unrelated donor hematopoietic stem cell transplantation

Impact of high-resolution HLA matching on outcomes of unrelated donor hematopoietic stem cell transplantation

Outcomes associated with a steroid-containing acute GVHD prophylaxis regimen for matched unrelated donor (MUD) hematopoietic stem cell transplantation

Background: Previously reported randomized trials have yielded differing conclusions about the addition of steroids to GVHD prophylaxis for patients undergoing sibling allogeneic transplant. Prophylaxis with cyclosporine plus methotrexate after MUD transplant has a reported grade 2–4 acute GVHD incidence of 74%. MUD transplantation was initiated at OHSU in 1996 using a 3-drug combination of cyclosporine, methotrexate, and steroids in a single-arm prospective protocol to examine the incidence and severity of GVHD and survival. Methods: The analysis included all patients undergoing MUD transplant who received GVHD prophylaxis with cyclosporine 2 mg/kg iv BID from day −2, methotrexate 15 mg/m2 iv on day +1 and 10 mg/m2 iv on days +3 and +6, and methylprednisolone 0.25 mg/kg iv BID beginning on day +7 and tapering at day +28. Patients were stratified by disease risk per CIBMTR classification. Patients with relapse and no GVHD were censored for GVHD outcomes at therapeutic withdrawal of immunosuppression. Results: 124 patients received the 3-drug regimen, including 50 with low-risk, 43 with intermediate-risk, and 31 with high-risk disease. One hundred sixteen (94%) of the MUD grafts were matched at 6 out of 6 HLA-antigens. Eight patients were not evaluable for GVHD due to death prior to engraftment. The maximum grade of acute GVHD is shown in Table 1. Sixty-four (55%) had grade 0–1 acute GVHD. Fifty-two (45%) developed grade 2–4 acute GVHD at a median onset of day +29. Twenty-eight (24%) developed grade 3–4 acute GVHD. Patients with low-risk disease had a median survival of 29 months and a 5-year OS of 42%, whereas those with intermediate/high-risk had a median survival of 10 months and a 5-year OS of 23%. The rate of disease relapse was 15% for both the low and intermediate/high-risk groups. Preliminary infection analysis among 64 patients demonstrated an incidence of all infections greater than 70%. Conclusions: The observed rate of grade 3–4 acute GVHD using a 3-drug prophylaxis strategy that includes steroids after MUD transplantation was low and delayed in onset when compared to previous trials of 2-drug combinations. The rate of disease relapse was low and the overall survival was comparable to other published strategies. Preliminary analysis suggests a high rate of infections. Additional analyses are planned to explore rates of chronic GVHD, as well as other potential steroid-related events such as hyperglycemia, musculoskeletal complications, alveolar hemorrhage or thrombotic microangiopathy (Table). Tabled 1Maximum Acute GVHD GradeNumberPercentGrade 04034%Grade 12421%Grade 22421%Grade 31513%Grade 41311% Open table in a new tab

HLA-DPB1 matching status has significant implications for recipients of unrelated donor stem cell transplants

AbstractStudies in unrelated donor (UD) hematopoietic stem cell transplantations (HSCT) show an effect of the matching status of HLA-DPB1 on complications. We analyzed 423 UD-HSCT pairs. Most protocols included T-cell depletion (TCD). All pairs had high-resolution tissue typing performed for 6 HLA loci. Two hundred eighty-two pairs were matched at 10 of 10 alleles (29% were DPB1 matched). In 141 HLA-mismatched pairs, 28% were matched for DPB1. In the 10 of 10 matched pairs (n = 282), the 3-year probability of relapse was 61%. This was significantly higher in DPB1-matched pairs (74%) as compared with DPB1-mismatched pairs (56%) (log rank, P = .001). This finding persisted in multivariate analysis. In the group overall (n = 423), relapse was also significantly increased if DPB1 was matched (log rank; P < .001). These results were similar in chronic myeloid leukemia (CML; P < .001) and acute lymphoblastic leukemia (ALL; P = .013). In ALL, DPB1-matched pairs had a significantly worse overall survival (log rank; P = .025). Thus, in recipients of TCD UD-HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status for the other HLA molecules. It is possible that this effect is especially apparent following TCD transplantations and invites speculation about the function of DPB1 within the immune system.

Comparable Long-Term Survival After Unrelated and HLA-Matched Sibling Donor Hematopoietic Stem Cell Transplantations for Acute Leukemia in Children Younger Than 18 Months

To describe outcomes after unrelated donor stem cell transplantation (HCT) in children (< 18 months at diagnosis) with acute leukemia and compare these with outcomes after human leukocyte antigen (HLA)-matched sibling donor HCT. We compared the results of unrelated donor HCT with bone marrow (n = 85) or cord blood grafts (n = 81) and HLA-matched sibling donor HCT with bone marrow grafts (n = 101) for acute myeloid or acute lymphoblastic leukemia using Cox proportional hazards models. Unrelated donor HCT recipients were younger, more likely to have MLL gene rearrangement, to have advanced leukemia, and to receive irradiation before HCT. Treatment-related mortality rates were 6%, 15%, and 31% after matched sibling, unrelated donor bone marrow, and cord blood HCT, respectively. Risks of relapse, overall and leukemia-free survival were significantly associated with disease status at transplantation. Though leukemia recurrence was lowest after unrelated donor HCT in first clinical remission (CR), overall survival, and leukemia-free survival rates were similar after matched sibling and unrelated donor HCT, after adjustment for disease status. Relapse, overall and leukemia-free survival did not differ by graft type (bone marrow v cord blood) or type of leukemia. Three-year probabilities of leukemia-free survival were 49% and 54% after HLA-matched sibling and unrelated donor transplantation in first CR, respectively. Corresponding rates for those with advanced leukemia were 20% and 30%. Unrelated donor HCT should be considered for infants with acute leukemia in first CR using the same eligibility criteria as are currently used for those with HLA matched sibling donors.

Quadruple Therapy with CsA, MTX, MMF and ATG and Triple Therapy with CsA, MTX and ATG for Preventing Graft-Versus-Host Disease in Unrelated Donor Hematopoietic Stem Cell Transplantation.

Objective To explore the effective protocol for graft-versus-host disease (GVHD) prophylaxis in unrelated donor hematopoietic stem cell transplantation (URD-HSCT).Methods 31 patients with leukemia received URD-HSCT, of whom 16 received quadruple therapy (quadruple group) with CsA, MTX, MMF and ATG for GVHD prophylaxis and 15 received triple therapy (triple group) with CsA, MTX and ATG. 22 patients were matched in all HLA genetic loci with donors, seven were mismatched in one HLA genetic locus, 1 in two HLA genetic loci, and 1 in three HLA genetic loci. Total body irradiation (TBI) plus cyclophosphamide (CTX) was adopted in 17 cases and modified BuCY conditioning regimen (hydroxyurea, busulfan, Ara-C, Cyclophosphamide) in the other 14 cases. Immune reconstitution of quadruple group and triple group at 1,3, 6, 9,12 month after transplantation were examined by flow cytometer, and the diference of the two group were estimated with Independent-Samples T test. The incidence of GVHD of the two group was esitimated with Mann-Whitney Test. Kaplan-Meier survival analysis model was used to estimate the overall survival and the disease-free survival (DFS).Results Immune reconstitution after transplantation of quadruple group and triple group have no significant difference (P>0.05). Acute GVHD (aGVHD) occurred in 9 patients (56.25%) of the quadruple group and in 11 (73.33%) of the triple group, respectively. The incidence of acute GVHD (aGVHD) differed little between the two group (P=0.238). The incidence ofIII~IV°aGVHD in the two group were 6.30% and 26.67%, respectively, and there was no significant difference (P=0.122). 6 patients had chronic GVHD (cGVHD), in the16 cases who could be followed up in quadruple group, 3 of the 11 patients who could be followed up in triple group developed cGVHD postoperatively (P=0.580). Four patients of quadruple group died of hemorrhagic cystitis, mycotic pneumonia, tuberculosis and relapse, respectively. 3 patients of triple group died of GVHD, and the other 3 died of GVHD associated interstitial pneumonia, cytomegalovirus (CMV) pneumonia and pneumocystis carinii infection. The lethality of GVHD of quadruple group and triple group were 0%,26.7%, respectively, and there was significant difference(P=0.027). The one-year disease-free survival rate was 75% and 60% in patients of the quadruple and the triple group, respectively, and significant difference was not noted (P= P=0.188).Conclusion Compared with triple therapy with CsA, MTX and ATG, CsA+MTX+MMF+ATG procedure dose not worsen the immune reconsititution after transplantation. It can't decrease the incidence and severity of aGVHD, but can lower the lethality of GVHD in URD-HSCT. The quadruple procedure may lead to higher relapse rate after URD-HSCT.

Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) in Children with Acute Leukemia: Risks and Benefits of Umbilical Cord Blood (CB) vs. Bone Marrow (BM).

Though CB is an accepted alternative to BM for HSCT, the selection of CB over BM remains controversial. Therefore, we compared the results of 492 unrelated donor BM and 508 CB transplants performed in children <16 years of age between 1995–2003. Median follow up was 45 and 59 months for CB and BM recipients, respectively. Compared to BM recipients, CB recipients were younger, less likely to be Caucasoid, more likely to have advanced disease, less likely to receive irradiation and more likely to receive cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Whereas, 7% of CB recipients were matched at HLA A, B (low resolution) and DRB1, 40%, 1-locus and 53%, 2 loci mismatched, respecively, 75% of BM recipients were matched and 25% mismatched at 1-locus. Neutrophil recovery at day 42 depended on graft type and cell dose: 97% with BM, 86% with matched CB, 79% with high cell dose (>0.3 x 108/kg) CB graft mismatched at 1 or 2 loci and 64% with low cell dose (≤ 0.3 x 108/kg) CB grafts. Rates of grades 2–4 acute GVHD were 70% with mismatched BM, 50% with matched BM, 40% with mismatched CB and 20% with matched CB. Corresponding rates of chronic GVHD were 35%, 33%, 17% and 27%. The relative efficacy of CB and BM transplantation depended on HLA disparity and CB cell dose as shown in the Table below. Children receiving matched CB had significanlty lower risks of treatment failure and overall mortality than those receiving matched BM; children receiving high cell dose CB mismatched at 1 locus had risks similar to those receiving matched BM. Children receiving low cell dose CB mismatched at 1 locus and CB mismatched at 2 loci (any cell dose) had higher risks of treatment failure and mortality than matched BM recipients during the first 3 months after transplantation; among children surviving the first 3 months, subsequent risks were similar to children receiving BM. The 3-year probability of leukemia-free survival was highest after matched CB transplants (60%); LFS probabilities were similar with matched BM and high cell dose CB mismatched at 1 locus (40% and 41%, respectively). Probabilities were lower after mismatched BM, low cell dose CB mismatched at 1 locus and CB mismatched at 2 loci (30%, 36% and 33%, respectively). These data support use of matched CB grafts or CB mismatched at 1 locus with a high cell dose for children needing HSCT, whether or not a matched BM donor is available; low cell dose or 2-loci mismatched CB grafts may provide a reasonable alternative when a matched BM donor is not available or for those whose disease requires immediate transplantation.Treatment failureOverall mortalityNRelative Risk (95% CI)P-valueRelative Risk (95% CI)P-valueBM Matched3681.001.00BM 1-Ag mismatched1231.26 (0.98–1.62)0.071.22 (0.93–1.59)0.15CB matched350.52 (0.30–0.92)0.020.54 (0.30–0.97)0.04CB 1-Ag mismatched, high dose1570.95 (0.75–1.22)0.710.96 (0.75–1.25)0.78CB 1-Ag mismatched, low dose44 ≤ 3 months1.85 (1.14–2.99)0.012.35 (1.44–3.83)0.001 >3 months0.69 (0.35–1.35)0.350.73 (0.37–1.42)0.35CB 2-Ag mismatched266 ≤ 3 months1.75 (1.36–2.60)<0.0012.06 (1.57–2.71)<0.001 >3 months0.87 (0.65–1.16)0.660.94 (0.70–1.25)0.66

Impact of High-Resolution HLA Matching on Outcomes of Unrelated Donor Hematopoietic Stem Cell Transplantation.

Objective: We assessed the impact of high-resolution genotypic results of human leukocyte antigen (HLA) for all major class I and II loci between donors and recipients in the outcome of unrelated hematopoietic stem cell transplantation (HSCT).Method: Between 1999 and 2005, high-resolution genotyping for HLA-A, -B, -C and -DRB1 was performed for 23 unrelated HSCT. All the patients were typed as HLA identical by serologic technique and then they were also typed HLA identical by high resolution technique. Unrelated bone marrow transplantation using DNA-based high resolution HLA compatibilities were considered in the analyses of clinical outcomes such as hematopoietic engraftment, acute GVHD, and survival. And then, we compared with patients who received related HSCT (same institute, same duration) and also unrelated HSCT data from IBMTR.Results: Median follow up duration was 9 months (1–51). Fifteen patients were male and 8 were female. Median age was 22 years (range 6–52). Median time from diagnosis to transplantation was 7 months (range 4–63). Eight patients of acute myeloid leukemia (AML), 6 of chronic myeloid leukemia (CML, 2 of 6 were in blast crisis), 4 of acute lymphoid leukemia (ALL), 3 of severe aplastic anemia and each case of juvenile myelomonocytic leukemia and myelodysplastic syndrome were enrolled. Median value of total nucleated cell and CD34 positive cell count was 3.51 (1.06–20.7) x 108/kg and 4.88 (1.33–46.9) x 106/kg, respectively. The conditioning regimen and prophylaxis for graft versus host disease (GVHD) were not different from conventional HSCT except one case of non-myeloablative transplantation. Median value of granulocytic (absolute granulocyte count > 500/mm3) and platelet (> 20,000/mm3) engraftment were D + 16, D + 17, respectively. Grade II acute GVHD developed in 4 patients (2 patients subsequently proceded to chronic GVHD). Treatment related mortality was 2 out of 23 patients (8.7%). Median value of overall survival duration was 30 months. For AML patients, 3-year survival rate was 72.9 %.Conclusions: Our survival data for unrelated HSCT based on high resolution genotyped HLA matching was superior to unrelated HSCT. Although the sample size is small, the survival data of AML patients (CR1 at transplant) was superior to the survivals of related HSCT, as well as that of unrelated HSCT. The findings were that transplantation using unrelated donors selected by high-resolution genotype identity improves the transplantation outcomes similar degree to the result of the related HSCT.

Chronic Graft Versus Host Disease (cGVHD) Following Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT): Higher Response Rate in Recipients of Unrelated Donor (URD) Umbilical Cord Blood (UCB).

The nature of chronic graft versus host disease (cGVHD) after umbilical cord blood (UCB) transplant has not been well characterized. We analyzed clinical presentation and response to treatment in 170 patients with cGVHD (123 following transplant from an unrelated donor (URD) and 47 following transplant from UCB). URD transplant recipients were significantly younger (median age 25 (0.5–57) versus 39 (0.2–61) years, p = 0.002; and were less likely to receive a transplant from an HLA mismatched donor (33% versus 90%, p<0.0001). Seven% and 43% of patients underwent a transplant using a non myeloablative conditioning in the URD and UCB groups, respectively (p< 0.001). Progressive onset of cGVHD was seen in 27% and 19% of patients in URD and UCB cohorts (p =0.15) and platelet count of < 100,000/μl was seen in 36% and 15% of patients (p =0.014), respectively. The median follow up was 5 (0.14–10.8) and 1.5 (0.02–8.8) years in the 2 groups, respectively. A higher rate of response (CR+PR) to treatment was seen in UCB group across all time periods. Rates of response were 48% versus 74% at 2 months (p =0.005); 49% versus 78% at 6 months (p =0.001) and 51% versus 72% at 1 year (p =0.03) in the URD and UCB groups, respectively. Overall survival at 2 years was 59% (50–67%) versus 71% (53–83%) at 2 years and at 5 years was 54% (44–63%) versus 64% (42–79%) (p=0.17). In multivariate analysis, progressive onset of CGVHD (RR=2.3, 95% CI 1.4–3.8−2.3,p=0.002), platelet count of <100,000/μl (RR=3.5, 95% CI 1.7–7.3,p=0.0009), liver involvement (RR=2.5, 95% CI 1.4–4.6,p=0.002), and no CR or PR at 2 months (RR=3.5, 95% CI 2.1–5.9,p<0.0001) were associated with significantly increased mortality. These data suggests that among patients undergoing transplant from unrelated donor or cord blood, despite similar clinical presentation, higher rates of response to treatment were seen in UCB recipients. Early identification of high risk groups (progressive onset, less than PR at 2 months, platelet count < 100,000/μl and liver involvement should facilitate timely assignment of intensified therapy.Response to TreatmentResponse2 mo2 mo6 mo6 mo1 year1yearURDUCBURDUCBURDUCBCR+PR49 (48)29 (74)54 (49)32 (78)53 (51)23 (72)SD+Prog53 (52)10 (26)56 (51)9 (22)52 (49)9 (28)

Allogeneic and Matched Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies Using a Modified Reduced Intensity Conditioning Regimen.

INTRODUCTION:Use of a reduced intensity conditioning regimen (RICR) in hematopoietic stem cell transplant may result in lower treatment related mortality (TRM), less acute graft versus host disease (aGVHD) and better survivability, utilizing the graft versus tumor effect from HSCT.METHODS: Our institution's original RICR protocol conditioning regimen (Trial A) consists of fludarabine 30 mg/m2 (Day-5 to D-2), melphalan 140–180 mg/m2 (Day -3) and ethyol 910 mg/m2 (Day-3) in addition to mycophenolate mofetil 1 g q12H and tacrolimus(serum level 5–15 ng/ml) beginning Day -3 as immunosuppressive therapy. Transplantation was done using peripheral blood stem cells from the best HLA-antigen match sibling (allo) or matched unrelated donor (MUD). We retrospectively compared transplant data from this original protocol to a modified RICR protocol (Trial B) using a lower dose of melphalan 100mg/m2 and addition of thymoglobulin 2mg/kg/d (D-2 to D0).RESULTS: 46 patients were transplanted in Trial A with median age of 46 years. 25 patients had allogeneic and 21 had MUD transplant. 30 patients were transplanted in Trial B with median age of 44 years. 22 patients had an allogeneic and 8 had a MUD transplant. All patients were heavily pretreated with 13 patients in Trial A and 9 patients in Trial B have undergone at least one previous stem cell transplant. At D30, all patients in Trial B were alive while 11% of patients in Trial A died of treatment related cause. At D100, 51% of patients in Trial A and 70% of patients in Trial B were alive. D100 TRM was 40% in Trial A and 20% in Trial B.Table 1Treatment OutcomeOS(%)TRM (%)RM (%)Trial ATrial BTrial ATrial BTrial ATrial B30 DaysMUD8110019000Allo961004000Total8910011000100 daysMUD4063603800Allo607324141614Total51704020910OS:overall survival TRM:treatment related mortality RM: relapse mortality1 year overall survival was 30% in trial A and 20% in Trial B. 1 year disease free survival (DFS) was 18% in trial A and 13% in Trial B.Table 21 year treatment outcome*Overall Survival(%)Disease Free Survival (DFS) %Trial ATrial BTrial ATrial BMUD2113140Allo37232118Total30201813*for Trial B, 5 living patients have not yet reached 1 year follow-upIncidence of aGVHD≥2 in patients not receiving DLI and alive for more than 30 days post transplant was 56% in Trial A (MUD 67%, Allo50%) and 25% in Trial B (MUD63%, Allo 6%). At D100, aGVHD was the most common cause of death in Trial A while overwhelming sepsis was leading cause of death in Trial B. WBC engraftment with ANC>500 was achieved in 98% of patients in Trial A and 93% of patients in Trial B. Average day of engraftment was 13 days in Trial A and 15 days in Trial B. Platelet engraftment with platelet count at least 20,000 was achieved in 80% of patients in both protocols with average day of engraftment at 18 days in Trial A and 21 days in Trial B. 95% of patients in Trial A had achieved at least 80% donor marrow cells at D100 while only 81% achieved this level of chimerism in Trial B.CONCLUSION: The modified RICR protocol for HSCT is a tolerable regimen which results in a lower incidence of D100 TRM and aGVHD but overall and disease free survival are not improved. Marrow engraftment is achieved although slightly delayed compared to the original protocol.

Use of Peripheral Blood Grafts Is Associated with Increased Acute and Chronic Graft-Versus-Host Disease without Improved Survival after Unrelated Donor Transplantation.

Data from the CIBMTR indicate that approximately 70% of unrelated donor hematopoietic stem cell transplants (HCT) in the U.S. utilize peripheral blood (PB) rather than bone marrow (BM) as a graft source. Comparative studies verifying its benefit, however, are lacking. We, therefore, performed a retrospective analysis comparing the results of 275 unrelated PB and 620 unrelated BM transplants in adults 18–60 years of age with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myeloid leukemia (CML), transplanted in 2000–2002. 73% of PB grafts were matched at HLA A, B, C (low resolution) and DRB1, 21% were mismatched at a single locus and 6% were mismatched at ≥ 2 loci. 69% of BM grafts were matched, 26% were mismatched at a single locus and 5% were mismatched at ≥ 2 loci. Median follow-up was 24 (range, 6–48) and 34 (range, 6–54) months for PB and BM recipients, respectively. Groups were similar except PB recipients were less likely to have CML, were more likely to have MDS and were transplanted more recently. Incidences of neutrophil recovery (95% vs. 90% at day 100, p=0.01) and platelets ≥20,000/ul (81% vs. 66%, at 1-year, p <0.0001) were significantly higher after PB than BM transplants. Incidences of grades 2–4 but not grades 3–4 acute graft-versus-host disease (GVHD) were significantly higher after PB than BM transplants (56% vs.45%, at day 100, p=0.003). Chronic GVHD was also significantly higher after PB transplants (54% vs. 39%, at 3 years, p<0.0001). Despite higher rates of grade 2–4 acute and chronic GVHD after PB transplantation, incidence of relapse was similar in the two groups for both early and advanced leukemia. In multivariate analysis, risks of treatment-related mortality (TRM), treatment failure (relapse or death) and overall mortality during the first 9 months after transplantation were similar. However, among patients surviving the first 9 months, subsequent risks of TRM (relative risk [RR] 1.90, 95% confidence interval [CI], 1.14–3.17, p=0.01) and treatment failure (RR 1.60, 95% CI 1.06–2.44, p=0.03) were significantly higher in the PB cohort. Three-year adjusted (from multivariate models) probabilities of leukemia-free survival were 29% and 31%, p=0.5, after PB and BM transplantation, respectively; corresponding probabilities of overall survival were 31% and 32%, p=0.8. While these data do not indicate a survival advantage with either stem cell source by disease or risk group, PB is associated with earlier engraftment. This advantage is offset by higher rates of grades 2–4 acute and chronic GVHD, leading to a higher risk of late adverse events. Randomized clinical trials are necessary to better define the relative risks and benefits of PB in the setting of unrelated donor HCT.

Influence of HLA-C Matching on aGvHD of Unrelated and Family Donor Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies.

With a continuous decrease in family size, identification of an HLA identical sibling donor for allogeneic hematopoietic stem cell transplantation (HSCT) is often unsuccessful. High resolution HLA-Typing of HLA class I and II loci has opened new avenues for identification of the optimal unrelated donor. Yet, the role of HLA-C matching in HSCT remains controversial. This is particularly true for pediatric transplantation recipients in whom currently little data are available. Here we report on the role of HLA-C matching in a single center cohort of children aged 0–18 years (median: 9,6 years; n=32) who underwent HSCT from an unrelated (n=28) or non-sibling family (n=4) donor for hematopoietic malignancies with a typical disease distribution for pediatric transplant recipients (11 ALL, 6 AML, 8 MDS, 3 JMML, 3 CML, 1 NHL). Patients (pts) with acute leukemia not in remission were excluded from the study. Donor selection was performed prospectively on the basis of HLA A, B low resolution and DR, DQ high resolution-typing with 4 donors exhibiting an isolated HLA-A or -B MM. Donors mismatched for HLA-DRB1 and -DQB1 (n=2) were excluded from the evaluation. In retrospective analysis, the number of donors with additional 1–2 HLA-C antigen MM was high (12/32 pts, 38%). Upon evaluation of the influence of HLA-C MM on critical transplantation parameters, significant correlation between HLA-C MM and severe acute GvHD (aGvHD III–IV; p=0,012) was documented. Of 31 pts evaluable for aGvHD, 7/12 (58%) pts in the HLA-C-MM group suffered from severe aGvHD vs. 2/19 (10%) pts without an HLA-C MM. There was no correlation with severe aGvHD and patient age, sex, underlying disease, stem cell source nor HLA-C KIR epitope or HLA-A/B MM. While none of the 4 pts with isolated HLA-A/B MM showed severe aGVHD, 3/5 pts with combined HLA-A/B plus -C MM exhibited grade III–IV aGvHD. In those pts evaluable for chronic GvHD there was no difference between pts transplanted from an HLA-C MM vs. -matched donor. As in other studies, in our transplantation cohort, aGvHDIII–IV is significantly correlated with transplant-related mortality (TRM) with 6/9 (66%) pts with aGvHDIII–IV dead of complications vs. 3/23 (13%) with no or low grade aGvHD (p=0,007). Accordingly TRM is also increased in HLA-C MM pts with 5/12 (42%) pts vs 5/20 (25%) pts in the HLA-C matched group. High TRM is counterbalanced by a complete absence of relapses in the HLA-C MM group compared to 4/20 relapses in the HLA-C matched group resulting in comparable overall survival with 53+/−16% vs. 69+/−11% after a median observation time of 3.5 vs. 2.9 years, respectively (p=0.59). The high risk of GvHDIII–IV in pts. with HLA-C MM documents the necessity for HLA-C typing for optimal donor selection in T-cell replete transplants. Our data demonstrate that in a T cell-replete transplant setting, increased risk for severe aGvHD may neutralize the beneficial effect that an HLA-C-based KIR MM might have on the graft-versus-leukemia effect. In the absence of an ideally matched donor, awareness of the HLA-C constellation will assist with optimization of immunsuppressive prophylaxis.

HLA-C Mismatch Is Associated with Inferior Outcome after Unrelated Donor Non-Myeloablative Hematopoietic Stem Cell Transplantation.

Donor-recipient disparity at HLA-C is an important determinant of clinical outcome after myeloablative unrelated donor (URD) hematopoietic stem cell transplantation, but its importance in URD non-myeloablative stem cell transplantation (NST) is less clear.Methods: We performed a retrospective analysis of 111 patients who underwent unrelated donor NST for hematologic malignancies from 2000–2004. Of these, 78 were 10/10 matched at HLA-A, B, C, DRB1, DQB1, and 33 were mismatched at one or more HLA-C antigen/allele (21 single C, 3 double C, 9 single C + other HLA locus mismatch). A majority (78%) of the mismatches at HLA-C were detectable at the antigen level. Diseases included AML (24), ALL (3), MDS (17), CML (10), CLL (23), NHL (22), and HD (12). All patients received non-myeloablative conditioning with intravenous busulfan (0.8mg/kg/d x 4 days) and fludarabine (30mg/m2/d x 4 days). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine plus prednisone or tacrolimus plus low-dose methotrexate based regimens. Stem cell source was primarily G-CSF mobilized PBSC.Results: Median time to neutrophil engraftment (ANC > 500/ul) among patients who nadired was 12 days (range 8–21 days) in both groups. Median unfractionated marrow donor chimerism were ≥ 90% donor at day+30 and day +100 in both groups. There was one late graft failure in the C-mismatched cohort, and one early graft rejection in the 10/10 matched cohort. HLA-C disparity was associated with an increased risk for grade III-IV acute GVHD (33% vs. 12%, p = 0.01) in univariate and multivariate logistic regression analyses (odds ratio 3.6, p = 0.03). This finding remained significant even when baseline differences in GVHD prophylaxis between the 2 cohorts were taken into consideration. Cumulative relapse incidence was not statistically different: 35% in the C-mismatched group, versus 55% in the 10/10 matched cohort, p = 0.09. There was a higher incidence of treatment related mortality in the C-mismatched group: 48% versus 16% (p = 0.001). Overall survival at 2 years was 27% in C-mismatched, vs. 47% in 10/10 matched patients (p = 0.009). In Cox regression model, HLA-C disparity was an independent factor for poor survival (hazard ratio 1.85, p = 0.04).Conclusions: Donor recipient disparity at HLA-C does not influence engraftment or donor chimerism after URD NST, but is associated with increased acute GVHD and inferior survival. HLA-C is an important transplantation antigen and should be considered in the selection of unrelated donors for NST.

Impact of Activating Killer Immunoglobulin-Receptor Genotype of the Donor on Outcome of Unrelated Donor - Hematopoietic Stem Cell Transplantation.

Function of NK cells is regulated by a balance between inhibitory and activating signals transmitted through killer immunoglobulin-like receptors (KIR). The goal of the present analysis was to evaluate the impact of donor activating KIR genotype (KIR2DS1 and KIR2DS2 loci) on outcome of unrelated donor-hematopoietic stem cell transplantation (URD-HSCT). Fourty-two URD-HSCT recipients with haematological malignancies, aged 28 (14–48) years (male/female - 26/16) were included in the analysis. The conditioning regimen was myeloablative and based on chemotherapy alone (n=33) or total body irradiation (n=9). Graft-vs-host disease (GVHD) prophylaxis consisted of cyclosporin, methotrexate, and pre-transplant anti-thymocyte globulin. Patients were grouped according to their donors' activating KIR genotype including two loci: KIR2DS1 and KIR2DS2.The overall survival at 2.5 years with respect of the donors' activating KIR genotype was as follows: KIR2DS1(−)DS2(−) (n=15) − 82% (+/−12%), KIR2DS1(+)DS2(−) (n=9) − 78% (+/−14%), KIR2DS1(−)DS2(+)− (n=7) 86% (+/−13%), KIR2DS1(+)DS2(+) (n=11) − 0%. The OS rate differed significantly between KIR2DS1(+)DS2(+) group and the remaining patients: 0% vs. 82% (+/−7%), p=0.03. The difference resulted mainly from higher cumulative incidence of non-relapse mortality in the KIR2DS1(+)DS2(+) group: 100% vs. 18% (+/−8%), p=0.098. The reasons of death in patients with KIR2DS1(+)DS2(+) donors were chronic GVHD (n=4) and acute GVHD (n=1). We conclude that the concomitance of both KIR2DS1 and KIR2DS2 in the donor is associated with high risk of mortality following URD-HSCT, resulting mainly from the incidence of severe GVHD. Whether this effect is associated with the activity of NK cells or KIR-bearing T lymphocytes requires further investigation.