Matched Related Donor Group Research Articles

Biologically Randomized Comparison of Haploidentical Versus Human Leukocyte Antigen-Matched Related Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation

Using haploidentical donors for allogeneic hematopoietic cell transplantation (HCT) broadens transplant accessibility to a growing number of patients with hematologic disorders. Moreover, haploidentical HCT with post-transplant cyclophosphamide (PTCy) has become widespread practice due to accumulating evidence demonstrating favorable rates of survival and graft-versus-host disease (GvHD). Most studies comparing outcomes by donor sources have been confounded by variability in conditioning regimens, graft type (peripheral blood [PB] or bone marrow), and post-transplant GvHD prophylaxis (PTCy or non-PTCy), making it difficult to define the effect of donor source on outcomes. Levine Cancer Institute started a transplant and cellular therapy program in 2014, with both haploidentical and matched related donor (MRD) transplants initially performed using a uniform reduced-intensity conditioning (RIC) regimen, PB grafts, and PTCy-based GvHD prophylaxis. This retrospective observational study was conducted to compare the clinical outcomes associated with RIC haploidentical HCT and MRD HCT in patients receiving identical conditioning regimens, graft types, and supportive care. Our transplant database was queried to evaluate demographic characteristics, clinical features, and outcomes of RIC HCT for consecutive patients with hematologic malignancies who received haploidentical or MRD grafts between March 2014 and December 2017. An MRD was the preferred donor source; when unavailable, a haploidentical donor was used. Sixty-seven patients underwent haploidentical HCT and 25 MRD HCT. Overall, characteristics of transplant recipients were similar for the haploidentical and MRD groups; however, haploidentical donors were younger than MRDs (median 36 yr versus 57 yr, P < .0001). Results of univariable analysis showed similar overall survival (OS) for haploidentical and MRD HCT (hazard ratio [HR], 1.15; 95% CI, 0.61 to 2.15; P = .669). One-year, 1-yr, and 5-yr OS were 80.2%, 54.7%, and 41.2% for haploidentical HCT and 76.0%, 55.7%, and 51.1% for MRD HCT, respectively. With a median follow-up of 81.90 months, results of multivariable analysis revealed that donor source (haploidentical versus MRD) was not significantly associated with OS (HR, 0.97; 95% CI, 0.51 to 1.87; P = .933), relapse-free survival (HR, 0.75; 95% CI, 0.42 to 1.35; P = .337), cumulative incidence of relapse (HR, 0.81; 95% CI, 0.39 to 1.70; P = .579), or non-relapse mortality (HR, 1.12; 95% CI, 0.40 to 3.14; P = .827). Cumulative incidences of acute GvHD (aGvHD) and chronic GvHD (cGvHD) were not significantly different for haploidentical and MRD HCT (grades II to IV aGvHD: HR, 1.78; 95% CI, 0.72 to 4.37; P = .210; grades III to IV aGvHD: HR, 2.84; 95% CI, 0.34 to 23.63; P = .335; cGvHD: HR, 1.00; 95% CI 0.36 to 2.76; P = .995). With care that was homogenous in terms of conditioning regimens, graft type, GvHD prophylaxis, and supportive care, 92 patients who were biologically randomized to either haploidentical HCT or MRD HCT after RIC with PTCy had comparable outcomes.

Allogeneic Hematopoietic Stem-Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Background: GATA2 deficiency is an increasingly recognized bone marrow failure syndrome responsible for: MonoMAC, monocytopenia with atypical mycobacterial infection (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). GATA2 deficiency can be reversed by hematopoietic stem cell transplantation (HSCT). However, the intensity of conditioning required to ensure engraftment and reverse the myelodysplastic syndrome (MDS) characteristic of the disease remains controversial.Methods: We carried out a prospective study of allogeneic HSCT in 22 patients (mean age 26 years; range 17 to 45 years) with GATA2 deficiency, or the MonoMac syndrome, using a myeloablative, busulfan-based conditioning regimen. All 22 patients had MDS and two had AML. Eleven patients had clonal cytogenetic changes in the bone marrow. There were two matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor recipients. MRD and URD recipients received conditioning with 4 days of busulfan (days -6 to -3) to target an AUC between 3600 and 4800 min*microm/L and 4 days of fludarabine 40 mg/m2/day (days -6 to -3). Haploidentical related donor recipients received low-dose cyclophosphamide for two days (days -6 and -5), fludarabine 30 mg/m2/day for 5 days (days -6 to -2), 2-3 days of busulfan depending upon cytogenetics, along with 200 cGY total body irradiation (TBI) on day -1. MRD and URD recipients received tacrolimus and short course methotrexate for post-transplant graft-versus-host disease (GVHD) prophylaxis, whereas haploidentical recipients received high-dose post-transplant cyclophosphamide (PT/CY) followed by tacrolimus and mycophenolate mofetil for GVHD prophylaxis.Results: Nineteen of the 22 patients are alive with resolution of the clinical phenotype and correction of the bone marrow MDS with eradication of the cytogenetic changes at a median follow-up of 23 months (range, 6 to 48 months) giving an overall disease-free survival of 86 percent. The three deaths all occurred in the URD group. Of the three deaths, one resulted from refractory acute myelogenous leukemia (AML), and two from complications related to treatment for GVHD. There was a 26 percent incidence of grade III-IV acute GVHD (aGVHD) in the MRD and URD groups, and no grade III-IV aGVHD in the haploidentical related donor cohort. Similarly, there was a 46 percent incidence of chronic GVHD (cGVHD) in the MRD and URD cohort, whereas two of the 7 (28 percent) of the haploidentical related donor recipients had cGVHD.Conclusions: Despite overall disease-free survival of 86 percent with eradication of the clonal cytogenetic abnormalities in the bone marrow, GVHD remains a limitation in the MRD and URD cohorts treated with standard post-transplant tacrolimus/methotrexate prophylaxis for GVHD. We are currently de-escalating the busulfan dosing based on the AUC in all cohorts and incorporating PT/CY in the MRD and URD cohorts to decrease toxicity and reduce the incidence of aGVHD and cGVHD. Together with our previous studies using a nonmyeloablative regimen, it appears that when GATA2 deficiency patients are transplanted when they have a hypocellular bone marrow with MDS and without cytogenetic changes, a nonmyeloablative regimen results in reliable engraftment in GATA2 deficiency since the GATA2 deficient marrow has a proliferative disadvantage. However, with clonal progression and unfavorable cytogenetic changes and/or a hypercellular marrow, where the malignant clone has a proliferative advantage, a higher dose regimen results in more reliable engraftment and eradication of the clone. Studies to identify the precise level of conditioning for the stages of the disease are ongoing. DisclosuresNo relevant conflicts of interest to declare.

Matched Family versus Alternative Donor Hematopoietic Stem Cell Transplantation for Patients with Thalassemia Major: Experience from a Tertiary Referral Center in South India.

Hematopoietic stem cell transplantation (HSCT) is the only curative option available for patients with thalassemia major in India with increasing access to alternate donor transplantation for patients with no matched family donor. We aimed to analyze the impact of family and alternate donor HSCT on morbidity and mortality post-HSCT. We conducted a retrospective study in the department between July 2007 and December 2018 where all children who underwent HSCT for thalassemia major were included. A total of 264 children were included with a median age of 6 years (male/female, 1.4:1). The graft source was matched related donor (MRD) (76%; parent 15%, sibling 85%) and matched unrelated donor (MUD) (22%). All children received a myeloablative conditioning regimen with treosulfan/thiotepa/fludarabine in 93% and busulfan/cyclophosphamide in 7%. The source of stem cells was peripheral blood in 61%, bone marrow in 38%, and umbilical cord blood in 3%. The incidence of bacteremia was 14% versus 25% in MRD versus MUD groups. There was a higher incidence of posterior reversible encephalopathy syndrome (PRES) in the MUD group (10% versus 3%). Engraftment occurred in 97% with a higher trend toward mixed chimerism in the MRD group (12% versus 2%). When indicated, whole-blood donor lymphocyte infusion was used to ensure complete chimerism in children in the MRD group. A statistically significant difference was found in the incidence of graft versus host disease (GVHD), both acute and chronic between the MUD versus MRD groups, 60% versus 20% and 41% versus 17%, respectively (P=.001). Similarly, immune cytopenia and cytomegalovirus reactivation were also significantly higher in the MUD group, 27% versus 1.4% and 25% versus 2%, respectively (P=.001). Thalassemia-free survival in our cohort was 96%, 94%, and 84% with a median follow-up of 65 months in the matched sibling donor, matched family donor, and MUD groups, respectively. Overall survival of 95% and 90% with a median follow-up of 65 months was noted in those who underwent transplantation less than and greater than 7 years of age, respectively. MUD transplantation for patients with thalassemia major involves specific challenges such as PRES and unusual manifestations of GVHD such as immune cytopenia. Early interventions to optimize supportive care and measures to reduce GVHD are required to ensure survival rates of over 90%.

The Effect of Donor Age on Outcome after Allogeneic Hematopoietic Stem Cell Transplantation

<h3>Background</h3> The age of patients admitted to HSCT is increasing. The median age of adult patients is close to 60 years at many centers. With a sibling donor this means that in most cases an older donor will be used. There are reports that donor age is important for the outcome. <h3>Hypothesis</h3> Our hypothesis is that it may be better to select a young well matched (10/10 match) unrelated donor (MUD), if available, instead of an older matched related donor (MRD). <h3>Material</h3> In a homogenous material consisting of patients with myeloid malignancies (AML, MDS, MPN, CML) receiving a PBSC graft and myeloablative conditioning, CsA+MTX as GVHD prophylaxis without <i>in vivo</i>T-cell depletion (no ATG), we studied the effect of the donor age. For this reason we selected patients with a MRD and an older donor (≥40y) and a 10/10 MUD with a younger donor (<40y) for analysis. There were 53 patients with a MRD and 60 with a MUD. Among patients with a MRD the donor age was grouped into three separate categories: 40-50y (n=18), 51-60y (n=23) and >60y (n=12). In the MUD group donor age groups were: 18-25y (n=22) and 26-39y (n=38) (table 1). <h3>Results</h3> The best OS, RFS, TRM and GRFS were seen in the "MUD age 18-25y" group (Figure 1). No effect was seen on incidence of relapse and acute and chronic GVHD. In multivariate analysis, corrected for differences between the groups, we found that OS, RFS, TRM and GRFS were better in the "MUD age 18-25y" group, compared to the MRD groups (figure 1). <h3>Conclusion</h3> In cases where an older sibling donor is available, it may be reasonable to search for a well-matched young (<25y) MUD. However, this is a limited small, single center study. Larger studies are warranted.

Results of a Multicentre, Randomized, Controlled Open-Label Study on the Use of Anti-T-Lymphocyte Globulin (ATLG) and Rituximab for Immunomodulation of Graft-Versus-Host Disease (GvHD) and Graft Failure (GF) in Patients with Non-Malignant Disorders

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is increasingly used to treat a wide range of non-malignant disorders. However, the optimal strategy to be employed for GvHD prevention remains a matter of debate. In particular, the use of ATLG for the prevention of immune-mediated complications in patients transplanted from a matched-related donor (MRD) is still controversial. In the matched unrelated donor (MUD) setting, there is retrospective evidence that Rituximab used as prophylaxis of EBV viremia may protect from acute GvHD (aGvHD) development, but the clinical benefit of pre-transplant Rituximab has never been assessed in prospective randomized studies. METHODS: We conducted a multicentre, randomized, open-label, trial (NCT01810926) in 5 Italian centres enrolling patients with non-malignant haematological and inherited metabolic disorders transplanted from either a MRD or a MUD, selected using high-resolution typing for HLA-class I/II loci and stringent criteria of HLA-compatibility (&gt;9/10). All patients received the same myeloablative regimen consisting of Treosulfan, Thiotepa and Fludarabine. Enrolled patients were randomized (1:1) to receive either standard or intensified GvHD prophylaxis. Cyclosporine-A plus short-term methotrexate was the standard GvHD prophylaxis in MRD HSCT recipients. In the experimental arm, patients were additionally given ATLG (Grafalon®, Neovii, 5 mg/kg/day on day -4,-3, and -2). In patients transplanted from a MUD, standard GvHD prophylaxis consisted of Cyclosporine-A plus short-term methotrexate and ATLG (10 mg/kg on day -4,-3 and-2). In the experimental arm, patients were additionally given Rituximab 200 mg/sq on day -1 (Mabthera®, Roche). In MRD group randomization was stratified by disease (hemoglobinopathies vs. other conditions) and in the MUD group by center. For patients given MRD HSCT, the primary end-point was the probability of survival (SUR) free from: a) primary and secondary GF, b) grade II-IV aGvHD, c) chronic GvHD (cGvHD), d) death, whichever occurred first. For patients transplanted from a MUD, the primary end-point was the SUR probability free from: a) grade II-IV aGvHD, b) EBV viremia (&gt;1,000 copies of viral DNA/ml whole blood), whichever occurred first. Secondary endpoint was overall SUR (OS). Statistical analyses were conducted according to intention-to-treat. FINDINGS: Between August 2011 and February 2018, 126 patients were enrolled. Patient and disease characteristics by randomized treatment are shown in Table 1. Median age at HSCT was 6.1 years in the MRD group (range 0.8-38) and 4.9 years in the MUD group (range 0.9-20.7). Median follow-up was 3.6 years. Among the 51 MRD-HSCT recipients, 25 were randomly assigned to the ATLG group and 26 to the NO-ATLG group. No death and no cases of grade II-IV aGvHD were observed in either of the two randomization arms. Two GF occurred in each of the two arms, while 1 and 2 cases of cGvHD occurred in the ATLG and NO-ATLG groups, respectively. Consequently, no statistically significant difference in the probability of SUR without events was observed (p=0.75) and the 3-years estimates (±SE) were 86.9%±7.1% vs. 83.8%±7.5%, respectively. In the MUD setting, 38 patients were allocated in the Rituximab group and 37 in the NO-Rituximab group. Although no statistically significant difference in OS (p=0.21) was observed between the two arms (3-years estimates: 94.1%±4.1% for Rituximab, 85.7%±5.9% for No-Rituximab), patients receiving Rituximab had a better probability of SUR without events (73.0%±7.3% vs 26.5%±7.3%, respectively; p=0.0002), entirely due to a lower incidence of EBV viremia. One case of fatal post-transplant lymphoproliferative disorder was observed in the No-Rituximab arm. Eight patients developed grade II-IV aGvHD in each of the two arms. No patient has persistent dependence on ivIG replacement therapy. CONCLUSIONS Our data indicate that, in patients with non-malignant disorders given a MRD HSCT, the addition of ATLG does not confer any advantage in the prevention of both acute and chronic GvHD, as well as of GF. In MUD-HSCT recipients, the administration of a fixed dose of pre-transplant Rituximab as part of the conditioning regimen does not affect the risk of aGvHD and transplant-related mortality, while it significantly reduces the incidence of episodes of EBV-viremia, without impairing B-cell recovery. Disclosures Algeri: Bluebird bio: Consultancy, Honoraria; Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria. Merli:Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

PB2361 INCIDENCE, RISK FACTORS AND OUTCOMES OF SINUSOIDAL OBSTRUCTION SYNDROME AFTER HAPLOIDENTICAL ALLOGENEIC STEM CELL TRANSPLANTATION

Background:Recent studies have reported that the outcomes after haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) are comparable to those after matched related donor (MRD) HSCT in hematological disease patients. Hepatic sinusoidal obstruction syndrome (SOS) is a rare but lethal complication with a reported incidence of 8%∼14% and a mortality rate higher than 80% for the severe type of SOS after MRD HSCT. Although sufficient information is available on SOS after MRD HSCT, few studies have systematically investigated SOS after HID HSCT. Here, we conducted a retrospective multicenter study in China to assess the incidence, clinical characteristics, risk factors and transplant outcomes of SOS following HID HSCT.Aims:The aim of this study is to compare the incidence, clinical characteristics, risk factors and transplant outcomes of SOS after HID HSCT and MRD HSCT.Methods:We retrospectively evaluated 36 consecutive patients with a confirmed diagnosis of SOS after allogeneic HSCT (allo‐HSCT) (HID: 23 patients, MRD: 13 patients) at four large HSCT centers in China between January 2003 and July 2018. The diagnosis of SOS was based on clinical criteria that required the occurrence of two of the following events: hyperbilirubinemia (≥ 2 mg/dL), hepatomegaly or right upper quadrant pain of hepatic origin, or unexplained weight gain (&gt; 2% of baseline body weight) due to fluid accumulation. The SOS severity was defined as mild, moderate, severe or very severe. Kaplan‐Meier survival analysis was used to estimate the cumulative incidence of relapse, overall survival (OS) and transplant‐related mortality (TRM), and a log‐rank test was performed to assess the statistical significance. Cox regression analysis was used to identify potential risk factors affecting the occurrence of SOS.Results:SOS developed in 0.4% of the patients (HIDs: 0.4%, MRDs: 0.5%, p = 0.952) at a median time of 21.50 days (range, 1‐55) after allo‐HSCT. No significant difference was found between the two groups in gender, disease distribution, interval from diagnosis to HSCT, disease status at the time of HSCT, donor‐patient sex match, donor‐patient ABO match, stem cell source, follow‐up time, engraftment time and cumulative incidence of acute graft‐versus‐host disease (GVHD) or chronic GVHD. The HID and MRD groups were comparable in terms of the median time to diagnosis (HIDs: 24 days, MRDs: 20 days, p = 0.316) and the presentation and severity of SOS. For patients diagnosed with SOS, the 2‐year cumulative incidences of relapse were 22.7% and 22.4% in patients receiving HID and MRD transplantations, respectively (p = 0.584). OS at 2 years was 10.4% and 38.5% in the two groups, respectively (p = 0.113). The TRM at 100 days was 60.9% in the HID group and 38.5% in the MRD group (p = 0.178). According to the multivariate analysis, significant independent risk factors for the occurrence of SOS were delayed platelet engraftment (p = 0.007) and an advanced disease status at the time of HSCT (p = 0.009). The frequency of SOS did not differ significantly in terms of the donor type (p = 0.222).Summary/Conclusion:Haploidentical transplantation may achieve results similar to those of transplantation with matched related donors in terms of the SOS incidence and outcomes. The occurrence of SOS did not differ by donor type.

Spectrum of Infections with a Protocol of Dual T-Lymphocyte Suppression Using ATG and PTCy for Gvhd Prophylaxis in Allogeneic Transplants for High-Risk Hematological Malignancies

Introduction ATG and PTCy have been individually shown to reduce rates of GVHD in allogeneic transplants. We adopted a combination regimen of ATG and PT-Cy for GVHD prophylaxis in allogenic transplants for high risk hematological malignancies in our centre, to decrease the rates of acute and chronic GVHD. Objectives We analysed the spectrum of infections in patients who received this dual T lymphocyte suppression protocol. Patients and methods Reduced intensity conditioning consisted of iv Fludarabine, iv Busulphan, and low dose TBI. GVHD prophylaxis was with Thymoglobulin 4.5mg/kg total dose, PT-Cy 100 mg/kg total dose and cyclosporine. The stem cell source was G-CSF stimulated PBSCs. Results 197 patients (median age 57 y, range 19-74y) with high-risk hematological malignancies were treated with this protocol. The donor types were as follows-10/10 matched unrelated donor (MUD) in 76, 9/10 mismatched unrelated (MMUD) in 26, 10/10 matched related donor(MRD) in 43 and haplo-identical (HI) donors in 52 patients. The median follow-up in the entire cohort was 12 months. The 1year OS in the MUD, MMUD, MRD and HI groups were 75%, 50%, 63.3% and 56.7% respectively. The overall percentages of proven bacterial, viral, and fungal infections were 49%, 62% and 11% respectively (Table 1). The overall incidence of CMV reactivation was 48% and was significantly different among the 4 donor groups (p=0.00). We also observed high rates of EBV reactivation (33%) and BK cystitis (18%). There were 14 pathologically confirmed cases of post-transplant lympho-proliferative disorder (PTLD), of which 1 responded to discontinuation of immune-suppression and the rest needed treatment with Rituximab. There was one death attributed to PTLD. Infections were the primary cause of death in 18 patients (23% of deaths) and a contributory cause of death in an additional 16 patients (20% deaths). The overall incidence of grade 3-4 acute GVHD in our patients was 10.1 % and of moderate/severe NIH stage chronic GVHD was 11.6% which is low compared to conventional GVHD prophylaxis regimes. Only 10% of deaths were attributable to GVHD. Conclusion Our experience shows that dual T lymphocyte suppression with PT-Cy and ATG for GVHD prophylaxis results in low rates of acute and chronic GVHD, but is associated with high rates of infections, especially viral reactivation and PTLD.

Combination of ATG and Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched and Mismatched Donor Peripheral Blood Stem Cell Transplants for Myeloid Malignancies

Introduction ATG and post-transplant cyclophosphamide (PTCy) have been individually shown to be efficacious in reducing rates of GVHD in HLA matched and mismatched transplants. We adopted a combination regimen of ATG and PTCy for GVHD prophylaxis in HLA matched and mismatched transplants for myeloid malignancies in our centre, to decrease the rates of acute and chronic GVHD. Objectives We assessed the overall and progression free survival, incidence of acute and chronic GVHD, relapse rates and non-relapse mortality with this protocol. Patients and Methods Reduced intensity conditioning protocol consisted of iv Fludarabine, iv Busulphan, and low dose TBI. GVHD prophylaxis was with Thymoglobulin total dose 4.5mg/kg, PTCy total dose 100 mg/kg and cyclosporine. The stem cell source was G-CSF stimulated PBSCs. Results 169 patients (median age 58 y, range 19-74y) with high-risk myeloid malignancies (AML-64.5%, MDS-19%, MPN-12%) were treated with this protocol after obtaining institutional approval. The donor types were as follows-10/10 matched unrelated donor (MUD) in 67, 9/10 mismatched unrelated (MMUD) in 24, 10/10 matched related donor(MRD) in 35 and haplo-identical (HI) donors in 43 patients. The median follow-up in the entire cohort was 12 months. The 1year OS in the MUD, MMUD, MRD and HI groups were 73%, 54%, 74% and 56% respectively and the corresponding 1 year PFS were 66%, 38%, 49% and 51% respectively. The percentage of graft failure (primary and/or secondary) in the 4 groups were 1.5%, 12.5%, 0% and 16.3% respectively. The relapse rates were 21% in MUD, 42% in MMUD, 29% in MRD and 14% in HI groups. The MMUD patients had significantly inferior OS (p=0.03), and PFS (p=0.003), and significantly higher risk of relapse(p=0.009), compared to MUD patients. The overall incidence of grade 3-4 acute GVHD in our patients was 10 % and of moderate/severe NIH stage chronic GVHD was 11.6% which is low compared to conventional GVHD prophylaxis regimes. The percentages for grade 3-4 acute GVHD according to donor type were 16.4% in MUD, 4.2% in MMUD, 5.8% in MRD and 9.3% in HI groups and that of moderate/severe NIH stage chronic GVHD were 7.5%, 8.4%, 11.4% and 16.3% respectively. There were high rates of viral reactivation observed with this dual T lymphocyte suppression strategy. The overall incidences of CMV, and EBV reactivation and BK cystitis were 48%, 33% and 17% respectively. In addition, there were 12 pathologically confirmed cases of post-transplant lympho-proliferative disorder. Conclusion Our experience shows that PT-Cy and ATG can be combined for GVHD prophylaxis in PBSCTs for high risk myeloid malignancies and results in low rates of Gr3-4 acute GVHD and moderate/severe chronic GVHD across different donor types with acceptable relapse rates. High rates of viral re-activation are a concern and need close monitoring.

Allocation to Matched Related or Unrelated Donor Results in Similar Clinical Outcomes without Increased Risk of Failure to Proceed to Transplant among Patients with Acute Myeloid Leukemia: A Retrospective Analysis from the Time of Transplant Approval

Clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-SCT) from unrelated donors (URDs) approach those of matched related donor (MRD) transplants in patients with acute myeloid leukemia (AML). Yet, available data fail to account for differences in pretransplantation outcomes between these donor selection strategies. In this regard, URD allo-HSCT is associated with longer waiting times to transplantation, potentially resulting in higher probabilities of failure to reach transplant. We retrospectively analyzed 108 AML patients accepted for first allo-HSCT from the time of approval to proceed to transplant. Fifty-eight (54%) patients were initially allocated to MRD, while URD search was initiated in 50 (46%) patients. Time to transplant was longer in patients allocated to a URD when compared with patients assigned to an MRD (median 142 days versus 100 days; p < .001). Forty-three of 58 (74%) patients in the MRD group and 35 of 50 (70%) patients in the URD group underwent transplantation (odds ratio [OR], 1.22; p = .63). Advanced disease status at the time of allo-HSCT approval was the only predictor of failure to reach transplantation in the multivariate analysis (OR, 4.78; p = .001). Disease progression was the most common cause of failure to reach allo-HSCT (66.7%) in both the MRD and URD groups. With a median follow-up from transplantation of 14.5 (interquartile range, 5 to 29) months, the 2-year estimate of overall survival (OS) from allo-HSCT was 46% in the MRD group and 57% in the URD group (p = .54). There were no differences in OS according to donor type allocation in the multivariate analysis (hazard ratio, 1.01; p = .83). When including patients from the time of transplant approval, 2-year OS was 39% in the MRD group versus 42% in the URD group. Our study suggests that allocation of AML patients to URDs may result in comparable clinical outcomes to MRD assignment without a significant increase in the risk of failure to reach transplant.

Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients. MRD and URD recipients received 4 days of busulfan and 4 days of fludarabine. HRD recipients received low-dose cyclophosphamide for 2 days, fludarabine for 5 days, 2 to 3 days of busulfan depending on cytogenetics, and 200 cGy total body irradiation. MRD and URD recipients received tacrolimus and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. HRD recipients received high-dose post-transplant cyclophosphamide (PTCy) followed by tacrolimus and mycophenolate mofetil. At a median follow-up of 24 months (range, 9 to 50), 19 of 22 patients were alive with reversal of the disease phenotype and correction of the myelodysplastic syndrome, including eradication of cytogenetic abnormalities. Three patients died: 1 from refractory acute myelogenous leukemia, 1 from GVHD, and 1 from sepsis. There was a 26% incidence of grades III to IV acute GVHD in the MRD and URD groups and no grades III to IV acute GVHD in the HRD cohort. Similarly, there was a 46% incidence of chronic GVHD in the MRD and URD cohorts, whereas only 28% of HRD recipients developed chronic GVHD. Despite excellent overall disease-free survival (86%), GVHD remains a limitation using standard prophylaxis for GVHD. We are currently extending the use of PTCy to the MRD and URD cohorts to reduce GVHD.

Hematopoietic stem cell transplantation in children with acute leukemia: similar outcomes in recipients of umbilical cord blood versus marrow or peripheral blood stem cells from related or unrelated donors

PurposeThis study compared outcomes in children with acute leukemia who underwent transplantations with umbilical cord blood (UCB), bone marrow, or peripheral blood stem cells from a human leukocyte antigen (HLA)-matched related donor (MRD) or an unrelated donor (URD).MethodsThis retrospective study included consecutive acute leukemia patients who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) at Samsung Medical Center between 2005 and 2010. Patients received stem cells from MRD (n=33), URD (n=46), or UCB (n=41).ResultsNeutrophil and platelet recovery were significantly longer after HSCT with UCB than with MRD or URD (P<0.01 for both). In multivariate analysis using the MRD group as a reference, the URD group had a significantly higher risk of grade III to IV acute graft-versus-host disease (GVHD; relative risk [RR], 15.2; 95% confidence interval [CI], 1.2 to 186.2; P=0.03) and extensive chronic GVHD (RR, 6.9; 95% CI, 1.9 to 25.2; P<0.01). For all 3 donor types, 5-year event-free survival (EFS) and overall survival were similar. Extensive chronic GVHD was associated with fewer relapses (RR, 0.1; 95% CI, 0.04 to 0.6; P<0.01). Multivariate analysis showed that lower EFS was associated with advanced disease at transplantation (RR, 3.2; 95% CI, 1.3 to 7.8; P<0.01) and total body irradiation (RR, 2.1; 95% CI, 1.0 to 4.3; P=0.04).ConclusionSurvival after UCB transplantation was similar to survival after MRD and URD transplantation. For patients lacking an HLA matched donor, the use of UCB is a suitable alternative.

ALLOGENEIC STEM CELL TRANSPLANTATION FOR MYELODYSPLASTIC SYNDROMES IN CHILDREN: A Report from the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON)

Introduction: Experience with the use of allogeneic hemopoietic stem transplantation (AHSCT) in pediatric myelodisplastic syndrome (MDS) in Spain is reviewed. Methods and patients: Twenty-four children with MDS were analyzed retrospectively. Median age of the patients was 10 years. Twenty patients received a bone marrow graft and 4 an unrelated cord blood (UCB) transplant; 12 bone marrow grafts were from a matched related donor (MRD) and 8 from a matched unrelated donor (MUD). Conditioning regimen consisted of chemotherapy alone in 17 patients (busulfan and cyclophosphamide ± melfalan) Seven patients received TBI and cyclophosphamide. Results: Ten patients died from transplant-related toxicity and 4 had relapse or disease progression post-AHSCT. Nine patients are alive and event-free with a median follow-up of 120 months. EFS rate in the MRD group was 0.48 (SE 0.13) versus 0.25 (SE 0.12) in the MUD/UCB group (p =. 07). Lansky score in survivors is ≥90%. Conclusions: In this historical series of children with MDS, in spite of severe transplant–related toxicity, encouraging EFS outcomes have been achieved after AHSCT with good quality of life.

Allogeneic Hematopoietic Stem Cell Transplantation in Adult Acute Lymphocytic Leukemia: Impact of Donor Source on Survival

We studied the relative impact of donor source on outcomes following myeloablative hematopoietic stem cell transplantation (HSCT) for adult patients with acute lymphocytic leukemia (ALL). In this single center study, 138 patients aged 18-61 (median 31) years underwent myeloablative conditioning followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 90, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14, and HLA 0-2 (A, B, DRB1) mismatched umbilical cord blood (UCB) in 19 patients. At the time of HSCT, 70 patients were in first clinical remission (CR1), 57 in CR2, and 11 in ≥CR3. Twenty-one patients had T-lineage disease; 43 patients (31%) had high-risk cytogenetics of either t(9;22) (n = 33), t(4;11) or t(1,19) abnormalities, with the remainder (69%) having normal cytogenetics. White blood cell count (WBC) ≥30 × 10 9/L at diagnosis was documented in 33%. Demographics and disease characteristics were similar in all 4 groups except all UCB recipients were treated since 1996 and received growth factors. Overall survival (OS) at 3 years for the UCB group was 66% (95% confidence interval [CI] 44%-89%) compared to 27% (95% CI 17%-36%) in the MRD group, and only 13% (95% CI 0%-31%) and 14% (95% CI 0%-33%) in the URD:M and URD:MM groups, respectively. Similarly leukemia free survival (LFS) at 3 years was better in the UCB group at 61% (95% CI 38%-84%) than 27% (95% CI 18%-36%) in the MRD and only 13% (95% CI 0%-31%) in the URD:M group and 14% (95%CI 0%-33%) in URD:MM group. Relapse rates at 3 years were 5% (95% CI 0%-15%) in the UCB group compared to 26% (95% CI 16%-35%) in the MRD, 20% (95% CI 1%-39%) in the URD:M groups, and 0% in the URD:MM groups. Transplant-related mortality (TRM) at 3 years was the lowest in the UCB group at 34% and higher in the other donor groups: MRD 47%, URD:M 67%, and URD:MM 86%. In multiple regression analysis, 5 independent risk factors were significantly associated with poorer OS and LFS: use of URD:MM (relative risk [RR] 2.5, 95% CI, 1.2-5.1, P = .01), ≥CR3 at HSCT (RR 3.5, 95% CI, 1.2-9.6, P = .02), WBC ≥30 × 10 9/l (RR 1.9, 95% CI, 1.2-3.0, P = .01) at diagnosis, recipient and donor (R/D) cytomegalovirus (CMV) seropositive (RR 3.8, 95% CI, 2.0-7.4, P < .01), and ≥2 induction regimens to achieve initial CR (RR 3.5, 95% CI, 1.2-9.6, P = .02). Graft-versus-host disease (GVHD) was associated with improved LFS (RR 0.4, 95% CI, 0.2-0.6, P < .01). When compared with URD:M, OS with UCB was better (RR 0.3, 95% CI, 0.1-0.7, P = .01), supporting the use of UCB as an alternative stem cell source for adults with ALL.

Comparative Analysis of Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation in Treatment of Patients with Chronic Myeloid Leukemia.

Allogeneic HSCT offers a long term remission for CML patients. We compared results of MRD and MUD HSCT in 82 pts with CML, treated between 1999 and 2005. In MRD group, 61 pts (median age 39, range 8–54 yrs) were conditioned with BuCy2 regimen. 50 pts were in chronic, 7 in acceleration and 4 in 2nd chronic phase. 38 pts received peripheral blood (PB) and 23 bone marrow (BM) cells. Prophylaxis of graft versus host disease (GVHD) consisted of cyclosporin (CsA) and methotrexate (MTX). 21 pts (median age 31, range 11–51 yrs) transplanted from MUD were conditioned with BuCy2 (n=13) or TBI-based regimen (n=8). All MUD patients received thymoglobulin. This group comprised of 14 pts in chronic and 3 with accelerated, 1 in blastic phase and 3 in 2nd chronic phase. 10 pts received PB and 11 BM cells. CsA+MTX was given as GVHD prophylaxis. MUD group differed from MRD group by following factors: younger age (p=0.020), longer time to HSCT (p<0.001), use of imatinib before HSCT (p=0.039), and higher pre-transplant (Gratwohl) risk score (p<0.001). Results: Hematopoietic recovery occurred in all pts in MRD group, and in 95% in MUD group. Probability of overall survival for all pts was OS=0.72±0.05. 42 pts developed acute GVHD >2 grade (26 in MFD and 16 in MUD) and 27 pts extensive chronic GVHD (23 in MFD and 4 in MUD). Mean survival, estimated 5-yrs OS, probabilities of GVHD incidence, relapse and non-relapse mortality (Kaplan-Meier method) with respect to transplantation method, are shown in Table.TABLE:Results of transplantation in MRD and MUD groupsProbabilityMRD-HSCT (n=61)MUD-HSCT (n=21)PMean survival (years)5.6 (95%CI=4.9–6.3)3.6 (95%CI=2.4–4.7)0.0020Overall survival0.75±0.050.60±0.110.0759Relapse incidence0.12±0.040.25±0.120.1950Non-relapse mortality0.22±0.050.41±0.110.0311Acute GVHD≥20.45±0.060.79±0.100.0175Chronic extensive GVHD0.47±0.07 (n=57)0.35±0.14 (n=15)0.3103Factors predicting negative outcome by multivariate analysis were: acute GVHD≥2 (p=0.0097, HR=1.81, 95%CI=1.12−2.94), and pre-transplant risk score >2 (p=0.0280, HR=1.61, 95%CI=1.06−2.00). MUD-HSCT or use of imatinib before HSCT did not predict for OS. Conclusion: In the era of tyrosine kinase inhibitors, results of MRD− and MUD-HSCT show that HSCT still remains an important therapeutic option for CML patients.

Outcome of Stem Cell Transplantation for Pediatric Acute Lymphoblastic Leukemia: Comparison of Matched Related Donor Verses Matched Unrelated Donor. Important Role of Graft Versus Host Disease in Preventing Relapse.

Seventy percent of children with acute lymphoblastic leukemia (ALL) who benefit from stem cell transplantation (SCT) lack a human leukocyte antigen (HLA) matched related donor (MRD). For these children SCT from a matched unrelated donor (MUD) represents an alternative therapeutic option. Our objective was, to review the outcome of children (0–18years) with ALL whom received a fully matched marrow allografts at our institution between July 1998 - December 2003. All children were conditioned with cyclophosphamide (50mg/kg infused over 1 hour daily for 4 days) followed by fractionated total body irradiation (TBI; 1200cGy, 6 fractions over 3 days). Cyclosporine A and a short course of methotrexate were used for graft versus host disease (GVHD) prophylaxis.Results: We performed 23 fully MRD and 23 fully MUD SCT during the study period. Median age at time of SCT was 10.2 y (range 2.2–17.5) and 8.2 y (range 1–16.5) for the MRD and MUD groups, respectively. Remission status at time of SCT; For the MRD group, complete remission (CR) 1, 2 and 3 were 5, 15 and 3 patients, respectively. For the MUD group, CR 1, 2 and 3 were 6, 14 and 3 patients, respectively. All patients engrafted for neutrophils (defined as absolute neutrophil count (ANC) of > 0.5 x 109/l for 2 consecutive days) with a median time of 18 days (range 12–28) and 16 days (range 10–25) for the MRD and MUD groups, respectively. In both groups, low grade acute(a) GVHD (I-II) occurred in 50% of the cases. However, high grade aGVHD (III-IV) occurred in 7/23 patients in the MUD group compared to only 1 patient with grade III aGVHD in the MRD group. Three years event free survival (EFS) for the whole group was 47 ± 8% with overall survival (OS), 50 ± 8%. EFS (3y) according to remission status was; 64 ± 15% for CR1, 51 ± 10% for CR2 and 33 ± 19% for CR3, P = 0.06. Twelve out of thirteen deaths in the MRD group were caused by leukemia relapse versus 3 out of 8 deaths in the MUD group. Transplant related mortality (TRM) was 5/8 deaths in the MUD group versus 1/13 deaths in the MRD group. Three years EFS and overall survival (OS) were, 37 ± 11%, 39 ± 11% for the MRD group and 63 ± 10%, 64 ± 10% (P = 0.16) for the MUD group. For the whole group, EFS according to aGVHD was, 29 ± 15% for no aGVHD, 51 ± 11% for low grade aGVHD and 60 ± 15% for high grade.Conclusion: Acute graft versus host disease is associated with less relapse post SCT for pediatric ALL, presumably through a graft-versus-leukemia effect. Our data suggests that outcomes can be improved further through exploring means of inducing aGVHD while reducing the toxicity of SCT. In MRD SCT where the likelihood of aGVHD is less and therefore relapse rate is higher, and in order to maximize survival in the non aGVHD group, attempts for aGVHD induction by early manipulation of the immunosuppressive medications or a low dose pre-emptive donor lymphocyte infusion in the first 60 days post engraftment, need to be explored in future studies.

Outcomes of Transplantation with Matched-Related Donor (MRD) and Alternative Donor (AD) Stem Cells in Children with Severe Thalassemia.

Allogeneic stem cell transplant (SCT) from an HLA identical family donor is an accepted option for severe thalassemia. However, the availability of MRD is only 30%. Therefore, AD is another option. The aim of this study is to explore the outcomes of allogeneic SCT with MRD and AD in our institution. We studied 46 consecutive patients (pts) who received MRD (n = 24) or AD; matched unrelated and haploidentical donors (n = 22) stem cells (SCs) for severe thalassemia between September 1992 and July 2004. In MRD group, 3 pts received 1 Ag HLA-mismatched SCs and in AD group, 2 pts received haploidentical SCs. The characteristics of both groups were followed.The conditioning regimen consisted with busulfan 16 mg/kg, cyclophosphamide 200 mg/kg for MRD and additional ALG (Fresineus) 40 mg/kg for matched unrelated donor (MUD) and CBT and busulfan 8–12 mg/kg, fludarabine 175 mg/m2, ALG, + thiotepa, and + total lymphoid irradiation for NST. GVHD prophylaxis was cyclosporin and MTX for MRD, FK 506 and MTX or MMF for MUD, cyclosporin, and prednisolone for CBT, and FK 506 and MMF for NST. The 2 yr thalassemia free survival rate for MRD is 83% and AD 81% (p = 0.6). The 2 yr overall survival rate for MRD is 95% and AD 90 % (p = 0.5). Two (8%) pts of MRD and 2 (9%) of AD had severe acute GVHD grade 3–4. Three pts of MRD had chronic GVHD (2;limited, 1;extensive). Three pts of AD had limited chronic GVHD. Rejection rate of MRD group is 12.5% (n=3). Two of 3 MRD pts who had graft failure after first transplant were successful for second transplant. Rejection rate of AD group is 9% (n=2). In conclusion, the outcomes of transplantation with MRD and AD stem cells in children with severe thalassemia are both equally favorable. Further study should be investigated in a larger group of patients to confirm our findings.MRD (n = 24)AD (n = 22)Age (yr) (median)2-19 (4)1-17 (7)β thalassemia major89β thalassemia / HbE1613Lucarelli class I1216Lucarelli class II and III126Bone Marrow Transplant (BMT)1119Peripheral Blood Stem Cell Transplant (PBSCT)8–Cord Blood Transplant (CBT)31Nonmyeloablative Stem Cell Transplant (NST)22

Single‐centre experience with allogeneic bone marrow transplantation for acute lymphoblastic leukaemia in childhood: similar survival after matched‐related and matched‐unrelated donor transplants

Seventy percent of children with acute lymphoblastic leukaemia (ALL) who may benefit from bone marrow transplant (BMT) lack a human leucocyte antigen (HLA)-matched related donor (MRD). For these children, BMT from a matched unrelated donor (MUD) represents a therapeutic option. We reviewed the course of 62 children with ALL who received fully matched marrow allografts at our institution between 1990 and 1998: 36 with MRDs and 26 with MUDs. Clinical characteristics were similar in the two groups. The interval from attainment of pre-BMT complete remission to transplant was significantly longer in the MUD group. Conditioning (etoposide/total body irradiation) and graft-versus-host disease (GVHD) prophylaxis regimens were the same for all patients, and all received T cell-replete bone marrow. There was no significant difference in probability of engraftment, or time to engraftment, in the two groups. MUD BMT recipients had a significantly greater incidence of grade II-IV acute GVHD (58% versus 24% in the MRD group; P = 0.02), and demonstrated a trend towards more chronic GVHD (39% versus 15%; P = 0.06). Three years post BMT, the probabilities of transplant-related mortality were 33 +/- 11% and 20 +/- 8% in MUD and MRD groups respectively (P = 0.38); the probabilities of relapse were 28 +/- 12% and 41 +/- 9% respectively (P = 0.19). Lansky or Karnofsky performance scores in event-free survivors were 90-100 in 87% of the MUD group and 83% of the MRD group. With a median follow up of 38 months (range, 3-97), 3-year event-free survival was 49 +/- 11% and 47 +/- 9% in the MUD and MRD BMT groups respectively (P = 0.71). These results suggest that MUD BMT is a valuable therapy for children with ALL in whom BMT is indicated, and underscore the importance of efforts aimed at expediting unrelated donor searches for patients lacking a MRD.