Incidence Of Acute GVHD Research Articles

S114 POST‐TRANSPLANT CYCLOPHOSPHAMIDE VS ATG FOR GRAFT‐VERSUS‐HOST DISEASE PROPHYLAXIS IN T‐REPLETE HAPLOIDENTICAL TRANSPLANTATION FOR ACUTE LYMPHOBLASTIC LEUKEMIA: A REPORT OF THE ALWP/EBMT

Background:The two leading strategies for Graft‐versus‐Host Disease (GvHD) prophylaxis in the setting of non‐T‐cell‐depleted (T‐replete) haploidentical stem cell transplantation (HaploSCT) are post‐transplant cyclophosphamide (PTCy) and anti‐thymocyte globulin (ATG). We have previously compared outcomes between these two approaches in patients undergoing HaploSCT for acute myelogenous leukemia (AML) in the registry of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT; Ruggeri A, Hematologica, 2017), however results may differ in patients treated for acute lymphoblastic leukemia (ALL).Aims:To compare PTCy with ATG‐based GvHD prophylaxis in patients undergoing HaploSCT for ALL.Methods:We analyzed all adult patients (≥ 18 years) reported to the EBMT with ALL in first or second complete remission (CR) or advanced disease at time of transplantation who underwent HaploSCT between 2007–2017 as first allogeneic transplantation. Haplo was defined as related donor with > 2 mismatched HLA alleles. Outcomes were compared using multivariable Cox regression analysis (MVA).Results:A total of 434 ALL patients were included; 336 received PTCy‐based regimen and 98 received ATG. Median follow‐up was 24 months (interquartile range 12–40). Median age was 35.6 (range 18–76) years, and 63% of patients were male. B‐ALL predominated (69%), with 32% of patients Philadelphia (Ph)‐negative, 36% were Ph+ while 32% had T ALL. The majority of patients (48%) was in first CR, with 20% of patients in advanced disease. Karnofsky performance status ≥ 90 was observed in 72% of patients. 53% of patients received peripheral blood (PB) grafts while 47% BM graft, and 75% of patients were treated with myeloablative conditioning while 25% reduced intensity conditioning. Patients who received ATG were treated earlier than those who received PTCy, with median year of transplantation 2011 and 2015, respectively (p < 0.0001), and were more likely to have advanced disease (31% vs 16%, p = 0.01). Patients treated with PTCy were more likely to have received PB grafts (68% vs 48% ATG, p < 0.001) and TBI‐based conditioning (45% vs 26%, p < 0.001).Similar outcomes were seen for engraftment (92.7% ATG vs 93.54% PTCy), as for 100 day incidence of acute GVHD both > Gr II and severe (Gr. II+, 32.7% vs 30.5%; Gr. III+, 11.6% vs 14.1%), and chronic GvHD (27.7% vs 31.7%). In both groups, infection accounted for 32% and 30% of deaths. In MVA, relapse incidence was lower in PTCy vs ATG: 2 year RI: 33.8% vs 43%; hazard ratio [HR] 0.61 [95% CI: 0.39–0.94], p = 0.03), with a trend toward lower non‐relapse mortality (NRM) as well (26.7% vs 32.9%; HR 0.68 [0.42–1.11], p = 0.12). Both 2 year leukemia‐free (LFS) and overall survival (OS) were higher for PTCY when compared with ATG (40.3% vs 24.1%; HR 0.67 [0.46–0.96], p = 0.03, and 48.4% vs 27.4%; HR 0.60 [0.42–0.84], p = 0.003, respectively) (Fig). Active disease and lower KPS were associated with lower LFS, OS and GRFS, while PB grafts were associated with higher incidence of both acute and chronic GvHD.Summary/Conclusion:Among ALL patients receiving T‐replete HaploSCT, GvHD prophylaxis with PTCy resulted in significantly lower RI and superior LFS and OS compared to ATG. These results are similar to previous observations in HaploSCT for AML.image

PF642 REDUCED INTENSITY ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IS A SAFE AND EFFECTIVE TREATMENT OPTION IN HIGH RISK MYELOMA PATIENTS – A SINGLE CENTRE EXPERIENCE

Background:The role of allogeneic hematopoietic stem cell transplantation (AHCST) remains controversial in myeloma, with myeloablative regimens associated with an unacceptable transplant‐related mortality (TRM). Despite this, even in an era of increasing drug treatments, AHCST remains one of the only curative options. Previous studies have included a mixture of different conditioning regimens in a variety of patients. Here we report our results using a non‐myeloablative (NMA) approach in a selected higher‐risk myeloma patient population at our institution.Aims:We report the outcomes of 37 patients with myeloma, transplanted using an NMA Fludarabine/Cyclophosphamide (FC) conditioning regimen without T cell depletion.Methods:We reviewed all patients receiving AHSCT at our centre between November 2000 and October 2017 All patients received fludarabine 25 mg/m2/day for 5 days and cyclophosphamide 1 g/m2/day for 2 days. Short course methotrexate and ciclosporin were used for GVHD prophylaxis without T‐cell depletion. Standard supportive care was employed.Results:37 myeloma patients (median age 52 years, range 31–63) underwent AHCST with 28 (76%) IgG, 5 (14%) IgA, 3 (8%) LC‐only and 1 (3%) non‐secretory disease. For those with recorded ISS (33), 8 (24%) were ISS1, 12 (36%) ISS2 and 13 (39%) ISS3. For those with recorded cytogenetics (19), high risk features (defined as t(4;14), t(14;16), t(14;20), 17p‐ or 1q+) were present in 14 cases (74%).At the time of transplant, patients had received a median of 2 prior lines of therapy (range 1–5), with 19 (51%) in 1st remission, 16 (43%) in 2nd, and 2 (5%) in 3rd. Status at the time of transplant was as follows: CR 27 (73%), VGPR 1 (4%), PR 2 (5%), SD 3 (8%), PD 4 (11%). 34 (92%) had a received previous autograft. All patients received peripheral blood stem cells from either HLA‐matched sibling (59%) or unrelated (41%) donors.TRM was very low (3% at 1 year and 9% at 5 years) precluding analysis of specific risk factors. Incidence of acute GvHD (including late onset acute GvHD with cessation of ciclosporin up to day 180) was 38% (Grade 1–4) and 14% (Grade 3–4). The incidence of chronic GvHD was 55%.Incidence of progression was 26% at 1 year and 49% at 5 years, and was significantly higher in patients who had received >1 prior line of therapy (p = 0.05, Log Rank test) and those in less than a VGPR at the time of transplant (p = 0.05). Patients who developed aGvHD had a significantly lower incidence of relapse (p = 0.05) consistent with a graft‐versus‐myeloma effect.Progression‐free and overall survival were 74% and 91% at 1 year, and 57% and 66% at 5 yearsrespectively, with worse outcome in those who received >1 prior line of treatment (p = 0.04) and in those without aGvHD (p = 0.03).Summary/Conclusion:NMA T‐replete AHSCT using a low dose Fludarabine/Cyclophosphamide platform is a safe approach with very low TRM. In this group of carefully selected younger patients with predominantly high‐risk myeloma, PFS was achieved in > 50% of patients at 5 years which is likely to represent a cure. Less heavily pre‐treated patients in a deeper response had better outcomes, with GVHD associated with freedom from relapse, providing evidence for a graft‐versus‐myeloma effect. This approach should be considered as a treatment option in young, high‐risk patients.image

PS1530 POST‐TRANSPLANT CYCLOPHOSPHAMIDE IN HLA MATCHED AND HAPLOIDENTICAL TRANSPLANT RECIPIENTS RECEIVING MYELOABLATIVE TIMED SEQUENTIAL BUSULFAN CONDITIONING REGIMEN: RESULTS OF A PHASE II STUDY

Background:Timed sequential busulfan with fludarabine (Bu‐Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplant (HCT), which is well tolerated and yields low non‐relapse mortality (NRM) in older patients and those with significant comorbidities. [Popat et al, Lancet Haematology 2018]. However, this concept was not tested in the haploidentical setting. Also, whether this approach can be used with post‐transplant cyclophosphamide (PTCy) in MSD, MUD and haploidentical HCT is unknown.Aims:We started a prospective phase II trial to assess (a) if PTCy could be safely incorporated in our timed sequential Bu‐Flu regimen, and (b) whether this approach could be used in patients undergoing MSD, MUD and haploidentical HCT. The objectives were safety and to obtain preliminary evidence of efficacy.Methods:Patients with hematological malignancies received fixed dose busulfan 80 mg/m2 intravenously (i.v.) either on days −13 and −12 (n = 45), or on days −20 and −13 (n = 10). Then, all patients received fludarabine 40 mg/m2 i.v. on days −6 to −2 followed by busulfan i.v. on days −6 to −2, dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5 mg/kg i.v. was given on day −7 to the haploidentical group. GVHD prophylaxis included PTCy 50 mg/kg i.v. given on days +3 and +4 and tacrolimus starting day +5. Haploidentical and later MUD recipients also received mycophenolate mofetil.Results:We enrolled 55 patients with a median age of 47 years (range, 15–65). Diagnoses were acute myeloid leukemia or myelodysplastic syndrome (n = 30), chronic myeloid leukemia or myeloproliferative disorder (n = 9), acute lymphoblastic leukemia (n = 6), lymphoma (n = 5) and myeloma (n = 5). About half had haploidentical donor (n = 26, 47%), one‐third had MUD (n = 18) and the rest had MSD (n = 11, 20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. HCT‐comorbidity index was ≥3 in 22 (40%) patients.45 patients experienced grade 3–5 events within 100 days. These included culture‐negative neutropenic fever (32 events), infections (28 events), gastrointestinal (22 events) – predominantly grade 3 mucositis (13 events), pulmonary (11 events; including 6 episodes of pneumonia) and hepatic (11 events – mostly asymptomatic hyperbilirubinemia; 6 events). Three patients suffered diffuse alveolar hemorrhage, 1 of which was terminal. There were 4 cases of venoocclusive disease, with 1 being fatal.There were no graft failures. The median time to neutrophil engraftment was 17 days (95% CI 13–39) and that of platelets (≥ 20K/μL, n = 49) was 25 days (95% CI 11–167). The rate of grade II‐IV aGVHD was 38% (95% CI 25–51%) and that of grade III‐IV acute GVHD was 9% (95% CI 1–17%) at day 100. Rates of chronic GVHD and extensive chronic GVHD were 10% (95% CI 2–28%) and 8% (95% CI 0–15%), at 1‐year respectively.With a median follow up of 17 months (range, 5–28), 1 year OS was 71% (95% CI 60–84%), NRM was 20% (95% CI 9–31%), and relapse rate was 17% (95% CI 7–27%). One year OS in the MSD was 91% (95% CI 75–100%); it was 72% (95% CI 54–96%) in the MUD group, and 62% (95% CI 45–83%) the haploidentical group; P = 0.11 [Figure].Summary/Conclusion:Myeloablative timed sequential busulfan with fludarabine and PTCy is safe in MSD, MUD and haploidentical HCT. It appears to reduce the incidence of severe acute GVHD and chronic GVHD without an apparent increase in relapse.image

PS1537 CO‐TRANSPLANTATION OF MESENCHYMAL STEM CELLS CAN AMELIORATES ACUTE GVHD AND VIREMIA AFTER ALLO‐HSCT FOR APLASTIC ANEMIA: A MULTI‐CENTER RETROSPECTIVE STUDY OF 75PATIENTS

Background:Mesenchymal stem cells (MSCs) are known to exhibit immunomodulatory, anti‐inflammatory, and pro‐angiogenic properties, and therefore have the potential to improve the outcome of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) for severe aplastic anemia (AA).Aims:To explore the efficacy and safety of allo‐HSCT by co‐transplantation with MSCs in AA patientsMethods:We conducted a multi‐center retrospective study to comparing the incidence and severity of acute GvHD, transplant‐related complication and overall survival (OS) of allo‐HSCT with or without co‐injection of MSCs in AA patients. A total of 75 consecutive severe AA patients (43males/32 females) undergoing allo‐HSCT at 4 hospitals from January 2012 to February 2018 were analyzed. 45 patients transplanted with donor HSCs only,and 30 patients transplanted with HSCs and MSCs. MSCs infusion dose was 0.5–3.0 × 106/kg, at day0/+1 following HSCs infusion.Results:All patients achieved successful engraftment within one month post transplant. There was no difference in time to leukocyte and platelet engraftment in the two groups. There was a trend to a lower incidence of aGVHD in the MSC group (13.3% versus 26.7%,χ2 = 2.066 P = 0.151). Moreover, a lower incidence of CMV replication in the MSC group was observed (CMV:26.7% vs 64.4 %,P = 0.003). With a median follow‐up time of 615 days (range:29–2315ays),the 2‐yr OS was similar in both groups (76.2% vs 77.3%,P = 0.883). A combination of bone marrow and peripheral blood as the sources of stem cells co‐transplanted with MSCs (n = 9) demonstrated an improved survival benefit (2‐yr OS = 100%).Summary/Conclusion:These data support that co‐transplantation with MSCs could ameliorate the challenges of aGVHD and viremia and facilitate survival in allo‐HSCT for AA patients.

PF677 DNA HYPERMETHYLATION EMERGES AS THE STRONGEST PREDICTOR FOR POOR OUTCOME AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML)

Background: JMML is a childhood hematopoietic malignancy characterized by hyperactive RAS signaling. For most patients early allogeneic hematopoietic stem cell transplantation (HSCT) is the therapy of choice. Risk factors for early death and relapse following HSCT are represented by age ≥ 2 yrs, low platelet count and HbF elevated for age. Most recently, genome-wide DNA methylation profiles (Lipka, Nat Comm 2017) identified distinct methylation signatures predictive for outcome. Aims: This study evaluates the clinical significance of these epigenetic changes in a large cohort of uniformly transplanted children registered to the European Working Group of MDS in Childhood (EWOG-MDS). Methods: We analyzed the outcome of 153 children with JMML (96 males, 57 females; median age at HSCT 2.7 yrs [0.3–11.5]) given a HSCT after a preparative regimen consisting of busulfan, cyclophosphamide, and melphalan. Results: Thirty-seven patients (pts) were transplanted from an HLA-identical sibling donor (MSD) and 116 from a matched unrelated donor (UD). Stem cell source was bone marrow (n = 122) or peripheral blood (n = 31). GVHD prophylaxis was CSA only in 25 (68%) MSD procedures, CSA/MTX/ATG was administered in 88 (76%) of UD-HSCT recipients. All but 9 pts engrafted. The cumulative incidence of grades II-IV acute GVHD was 44% (37–52). Thirty-three of the 133 pts at risk developed chronic GVHD, which was limited in 20 and extensive in 13 pts. With a median follow-up of 3.7 years (0.1–17.5), the 5-year leukemia-free survival (LFS) was 61% (53–69), while the cumulative incidence of non-relapse mortality (NRM) and relapse (CIR) were 13% (8–20) and 26% (20–35), respectively. There was no difference in outcome between MSD and UD-HSCT recipients. Of the 153 pts, 76 had a somatic PTPN11 mutation, 21 had neurofibromatosis type 1, 22 belonged to the NRAS- and 18 to the KRAS-mutated subgroup, while RAS pathway alterations were absent in 16 pts (“all negative”). 5-year CIR was higher in PTPN11-mutated JMML (35%) compared to that of the NF1 (24%), NRAS (23%), KRAS (11%) or all negative subtypes (14%). Methylation status was high (HM), intermediate (IM) or low (LM) in 61, 52 or 40 pts, respectively. 5-year LFS and CIR of pts of the LM class was similar to that noted in the IM class with 76% vs 69%, and 8% vs 13%, respectively. In contrast, children of the HM class had a significantly inferior LFS (44%, 31–57, p < 0.01) due to a high CIR (50%, 38–65, p < 0.01). NRM in the 3 methylation groups (LM 16%, IM 19%, HM 6%) did not differ. There was a clear correlation between methylation class and molecular genetic subtype: PTPN11-mutated JMML was less common in the LM class and the proportion of KRAS-mutated pts was highest in the LM class. Also, patients in the HM class had a higher median age at HSCT (3.8 yrs) than pts in the IM (2.1 yrs) or LM class (1.1 yrs). Multivariate analysis identified methylation class (HM vs IM: RR 5.3 [1.8–15.3], HM vs LM RR 7.6 [1.6 – 37.3]) as the only independent variable predicting relapse when analyzed with age at HSCT, platelet count and molecular genetic type (PTPN11-mutated vs others). Summary/Conclusion: Patient outcome in genome-wide methylation classes nicely recapitulated earlier data applying a DNA methylation score of candidate gene regions (Olk-Batz, Blood 2011). Thus, DNA methylation classifiers are exceptionally consistent allowing prospective assignment of DNA methylation categories for molecularly-driven risk stratification. Future research needs to be directed at better understanding the mechanistic link of epigenetic dysregulation and resistance to treatment.

PF546 THE SFGM‐TC MDS SCORE AT DAY 180 IS ASSOCIATED WITH POST‐TRANSPLANT OUTCOMES IN PATIENTS WITH MYELODYSPLASTIC SYNDROME WHO UNDERWENT CD34+ SELECTED ALLOGENEIC STEM CELL TRANSPLANT

Background:In the past decade, advances in therapy and supportive care, along with a wider donor availability due to the haplotrasplant, the number of elderly patients who are able to undergo Allo‐HSCT with curative intent has been increased. One strategy that has been developed to reduce one of the most important transplant‐related morbidity and mortality variables (graft‐versus‐host disease, GVHD) is Ex vivo CD34+ selected T‐cell depletion (TCD). Despite all these advances, several questions remain unanswered in the pre‐HSCT, HSCT and remarkably in the post‐HSCT setting.Because outcomes for patients with MDS are heterogeneous, individual risk stratification using tools is important in managing patients. Most published scoring systems have focused on prognostic variables measured before allo‐HSCT. While these scores are helpful for decision in terms of transplant, they fail to notice key transplant‐related variables.Aims:The aim of this study is to investigate the prognostic ability of a recently published scoring system (SFGM‐TC) in a cohort of patients with MDS who underwent TCD transplants.Methods:109 patients underwent a first TCD AlloHCT for MDS from 2007 to 2018. The SFGMTC score (Caulier et al. Curr Res Transl Med. 2018) is performed at day 100 and ranges from 0‐ 8, discriminating low (0), intermediate (1–3), and high risk (4–8). Additional analyses were performed at day 180 and day 365. A landmark analysis was done at each time point for the day 100, 180, and 365 analyses, respectivelyResults:Median age was 61 years (range 20 to 72 years), and 64 patients (59%) were male. 89 patients (82%) had a matched related or unrelated donor. All patients received myeloablative conditioning and ex vivo T cell depleted PBSC grafts (Table 1). With a median follow‐up of 57.5 months (3.5, 114.7) among survivors, 1 and 3‐year OS was 85.1% (95% CI, 76.8–90.6) and 66.9% (95% CI, 56.7–75.1), respectively. 70 patients (64.2%) were alive at last follow up. At post‐transplant day 180, 72 patients had a SFGM‐TC low risk and 29 patients an intermediate/high score. In contrast to the analysis at day 100, the SFGM‐TC score at day 180 was associated with outcomes. Using the day 180 score, OS was significantly worse in the intermediate/high risk group (p‐value 0.002, HR 3.25 [95%CI 1.60, 6.60]) (Figure 1) as compared to the low group. There was no significant difference in the SFGM‐TC score using a day 100 (p‐value 0.117, HR of Intermediate/high group: 1.89 [0.89, 4.01]) or day 365 landmark (p‐value 0.098, HR of Intermediate/high group: 2.01 [0.88, 4.59]).Summary/Conclusion:In patients with MDS undergoing TCD‐HCT, the SFGM‐TC score at day 180 is significantly associated with survival. The lower incidence of acute GVHD in recipients of CD34‐ selected transplants and the use of myeloablative condition regimens, with lower relapse, may explain the difference with the original finding that the SFGM‐TC was predictive at day 100 in unmodified grafts.image

Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.

7007 Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]

A phase II study of myeloablative allogeneic hematopoietic stem cell transplantation (aHSCT) for acute lymphoblastic leukemia (ALL) in older patients using fludarabine and total body irradiation (Flu/TBI).

TPS7069 Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status, and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative aHSCT. The 1-year disease free survival (DFS) for patients ≥ 40 years who receive an aHSCT for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of TBI-based regimens in adults with ALL when combined with cyclophosphamide (Cy). Reduced intensity conditioning for ALL patients has fallen out of favor due to high relapse rate forfeiting the benefit of reduced NRM. High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI (12 Gy) is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing aHSCT, but with less NRM confering survival benefit over Cy/TBI 12 Gy. Methods: This study is a single center, single-arm phase II clinical trial of Flu 40 mg/m2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. Patients aged 40-65 years with ALL in CR, KPS ≥ 70, adequate organ function, and having HLA-matched sibling or unrelated donor will be eligible. The primary endpoint of the study is 1-year DFS post-transplant. Secondary endpoints include 1-year overall survival (OS), incidence and severity of acute and chronic GVHD, immune reconstitution and regimen related toxicity. The study has just finished accrual (January 2019) enrolling a total of 16 patients. This number of patients was pre-determined to give a probability ≤ 0.05 of concluding that the 1-year DFS rate exceeds 45%, and a probability of at least 0.80 of concluding that the 1-year DFS rate exceeds 45% (expecting 1-year DFS of 75%). Clinical trial information: NCT01991457.

Haploidentical transplantation outcomes are comparable with those obtained with identical human leukocyte antigen allogeneic transplantation in Chilean patients with benign and malignant hemopathies

IntroductionPatients with benign or malignant blood disorders, who require allogeneic stem cell transplantation and lack an identical human leukocyte antigen HLA identicalHL sibling donor, could be transplanted with hematopoietic stem cells from unrelated adult or umbilical cord donors. However, in our country, both approaches are costly and time-consuming options. MethodsOver the last few years, haploidentical modalities have been investigated as an alternative donor source, showing similar results to those obtained with identical HLA donors. We started using T-cell-replete haploidentical with post-transplant cyclophosphamide in 2012 and we presented our experience with patients undergoing haploidentical ransplantation compared to SIB. ResultsSince January 2012 to date, 91 allogeneic transplants have been performed, of which 49 were haploidentical and 42 were HLA identical. The mean age of the patients was 35 years (range: 17–62). The mean CD34/kg×106 infused per group was 5.93 and 5.89, respectively. Time to granulocyte and platelet engraftment was 11 and 15 days, respectively, for haploidentical, and 12 and 14 days, respectively, for HLA identical (p=0.10). The 100-day cumulative incidence of global acute GVHD was 34% for haploidentical and 29% for SIHLA identical (p=0.9). The 2-year overall global graft-versus-host disease was 43% for haploidentical and 41% for HLA identical (p=0.8). Overall survival, relapse, and transplant and relapse-related mortality were similar between both groups. ConclusionOur experience showed that haploidentical has similar outcomes to those obtained with HLA idential and can be performed in our country safely.

Donor-derived CD4+/CCR7+ T-cell impact on acute GVHD incidence following haplo-HCT after reduced intensity conditioning and posttransplant cyclophosphamide.

In previous studies, we and others observed in patients undergoing HLA-matched hematopoietic cell transplantation that high proportion of donor-derived CD4+/CCR7+ T cells were associated with an increased risk of acute GVHD without any interference in relapse incidence. We investigated the impact of donor-derived CD4+/CCR7+ T cells on patient outcome in haploidentical settings where posttransplant cyclophosphamide is used. We analyzed T-cell subsets in grafts of 29 adult patients who underwent first haploidentical transplant following reduced intensity conditioning. The median CD4+/CCR7+ subset proportion was 69.2% among donor CD4+ T cells. With a median follow-up of 28.1 months (range: 11.0-44.3), 16 patients (55%) developed acute GVHD; this includes 5 patients with grade 3 acute GVHD. Fifty-four percent of patients who received > 69.2% of CD4+/CCR7+ T cells and 12% of patients who received < 69.2% CD4+/CCR7+ T cells developed acute GVHD (p = 0.028). In multivariate analysis, a high proportion of CD4+/CCR7+ T cells was the only factor that impacted acute GVHD (HR = 4.925, 95% CI [1.020-23.775], p = 0,047) with no impact on overall survival. Our results confirm the impact of a high proportion of CD4+/CCR7+ T cells on acute GVHD incidence in patients undergoing haploidentical transplant despite the use of posttransplant cyclophosphamide.

Feasibility and Cost Analysis of Day 4 Granulocyte Colony-Stimulating Factor Mobilized Peripheral Blood Progenitor Cell Collection from HLA-Matched Sibling Donors

Feasibility and Cost Analysis of Day 4 Granulocyte Colony-Stimulating Factor Mobilized Peripheral Blood Progenitor Cell Collection from HLA-Matched Sibling Donors

Early Positive Biopsy in Asymptomatic Post-Allogenic Hematopoietic Stem Cell Transplant Recipients Is Not Associated with the Development of Clinical Chronic Graft-Versus-Host Disease

Background Histopathology is the gold standard for diagnosis of chronic graft-versus-host disease (cGVHD). The phenomenon of a positive early oral biopsy in the absence of clinical symptoms (asymptomatic positive biopsy [APB]) has been previously noted in the literature. but the diagnostic and prognostic value of this finding has not been investigated. The purpose of this study was to investigate the diagnostic and prognostic value of this phenomenon. Methods Oral buccal mucosal biopsies were taken near day 90 post-transplant from patients who had undergone allogeneic hematopoietic stem cell transplantation (alloHSCT) at the NIH Clinical Center (NCT00391170), and who were free of clinical oral GVHD. Scanned, de-identified images of hematoxylin and eosin (H&E)-stained slides of baseline oral biopsies were evaluated by four oral pathologists experienced in evaluating oral GVHD. The incidence of APB and the individual histopathologic features most common in the APB samples were calculated. Pathology data were combined with clinical and demographic data, including pre-transplant conditioning, incidence of acute GVHD, and incidence of mucositis, to determine clinical significance and predictive value of the histopathologic findings. Results At baseline, based on agreement of three of four pathologists' reads, 17 of the 38 biopsies (45%) analyzed were classified as possible or likely oral GVHD. All cases (100%) exhibited inflammation in the lamina propria, and most of this was lymphocytic (94%), while acanthosis was frequently noted (82%). This pathological assessment was not predicted by type of transplant (myeloablative or not), prior acute GVHD or prior mucositis. Patients with cGVHD at more than one site within one year post alloHSCT were likely to also have clinical oral GVHD (Fishers exact test, p Conclusions Oral mucosal biopsies taken early after transplant (

Haploidentical BMT Using Fully Myeloablative Conditioning, T Cell Replete Bone Marrow Grafts, and Post-Transplant Cyclophosphamide (PT/Cy) Has Limited Toxicity and Promising Efficacy in the First Prospective Multicenter Trial for Pediatric, Adolescent, and Young Adult Patients with High Risk Acute Leukemias and Myelodysplastic Syndrome

Promising results have been reported for patients with high-risk hematologic malignancies undergoing T-cell-replete myeloablative bone marrow transplant (BMT) from HLA-haploidentical donors with post-transplantation cyclophosphamide (PT/Cy). Here, we report results from the first prospective multicenter pilot trial in the Pediatric Blood and Marrow Transplant Consortium (PBMTC) for pediatric, adolescent, and young adult patients with high risk acute leukemias and myelodysplastic syndrome (MDS) in the US and Canada. Nine centers transplanted 32 patients with acute leukemias or MDS in complete remission (CR) who received myeloablative conditioning consisting of IV Busulfan (pharmacokinetically adjusted) and Cyclophosphamide (Cy, 50 mg/kg/day) days –2 and –1 except for patients with acute lymphocytic leukemia who received Cy (50 mg/kg/day x 2) and total body irradiation (1200cGy). T-cell-replete bone marrow from haploidentical related donors was used for all patients. Postgrafting immunosuppression consisted of Cy (50 mg/kg/day) days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 90-180 days. Median age of patients was 12y (range, 1-23) and donors was 35y (range, 4-53). Diagnoses included AML (CR1 = 7, CR2 = 6), ALL (CR1 = 8, CR2 = 5), mixed lineage leukemia (1), and MDS (5). One patient had received a prior BMT. Donor engraftment occurred in 27/32 (84%). Primary graft failures included 3 patients with MDS and 2 with AML (CR1 = 1, CR2 = 1); three of these patients had received suboptimal bone marrow grafts (TNC/kg ≤2e8) and all successfully engrafted after second transplants. Median time to neutrophils >500/μL was 22 days and platelets >20,000/μL was 21 days. Transplant related mortality (TRM) at 180 days, our primary objective, was 0%. Cumulative incidence of acute GVHD grades II-IV at Day 100 was 13%. No patients developed severe acute GVHD grades III-IV. The cumulative incidence of mod-severe chronic GVHD at 1 year was 4%. The cumulative incidence of relapse at 1y was 32%. With a median follow-up of surviving patients of 477 days (range, 180-1127), actuarial overall survival is 77% at 1y. With a median follow-up of event-free patients of 451 days (180-1127), actuarial event-free survival is 68% at 1y. For this first reported multicenter pediatric myeloablative HLA-haploidentical HSCT for high-risk leukemias and MDS with T-cell replete bone marrow and PT/Cy, we have demonstrated a 0% TRM, low cumulative incidences of acute and chronic GVHD, and favorable rates of relapse and survival. Further investigation as to potential reasons for graft failure and consideration of any changes needed to ensure engraftment for certain disease groups are underway. A larger trial comparing haploidentical BMT with other alternative donor sources is in development.

Clinical Outcomes Using Mycophenolate and Tacrolimus for Graft Versus Host Disease Prophylaxis in Patients Undergoing Allogeneic Stem Cell Transplant: A Single Institution Experience

Introduction Graft versus host disease [GVHD] remains the major factor underlying transplant induced morbidity and mortality among recipients of allogeneic stem cell transplant [allo-SCT]. Mycophenolate mofetil [MMF] plus calcineurin inhibitor [CNI] combination is mostly used in reduced intensity [RI] and nonmyeloablative conditioning [NMAC] whereas methotrexate and CNI combination is preferred in myeloablative conditioning [MAC]. We present single institution outcomes in patients undergoing allo-SCT with MMF and CNI as the only combination for GVHD prophylaxis. Methods Data from all adult patients who underwent allo-SCT at our institution from 2007 to 2016 was collected from our Center for Blood and Marrow Transplant Research [CIBMTR] portal. Results Total 141 patients were included with the median age of 50 years. Most patients were female [52%] and white [85%]. Disease characteristics included AML 56.7%, ALL 14.2%, CML 7.7%, MDS/MPD 7.7%, HL/NHL 6.4% and others 7%. MAC was used in 75.2% whereas NMAC/RI conditioning was used in 24.8% of the patients. Peripheral blood was the predominant source of stem cell graft [81%]. Donor status included 30.5% HLA matched related, 63.8% HLA mismatched/matched unrelated and 4.9% HLA mismatch related. Incidence of acute GVHD at day 100 was 49.6% [grade I 16.5%; grade II-IV 33.1%], acute GVHD at day 365 was 59.6%, and chronic GVHD at day 365 was 48.1% [limited 13.5%; extensive 34.6%]. 1-year overall survival was at 51% [95% CI 42-59%] and significantly associated with race and conditioning regimen. Discussion Based on historical cohort, combination of methotrexate and tacrolimus is associated with acute graft versus host disease in 89% [grade I 11%; grade II-IV 78%], chronic graft versus host disease in 94% [limited 32%; extensive 65%] and 1-year overall survival of 47%. Hence our institutional analysis shows that the combination of mycophenolate and tacrolimus is superior to methotrexate and tacrolimus combination for prevention of acute and chronic graft versus host disease as well as 1-year overall survival.

Allogeneic Stem Cell Transplantation for T-Cell Lymphomas in the Modern Era: A Single Center Experience

Introduction T-cell lymphomas are heterogenous group of neoplasms associated with generally unfavorable outcomes. High dose chemotherapy and autologous stem cell transplant (SCT) consolidation is a standard approach in first remission while allogeneic SCT (alloSCT) is recommended in the relapsed/refractory setting. Data on outcomes after alloSCT are limited, particularly in the era of brentuximab. Methods We retrospectively analyzed data from patients (pts) with T-cell lymphomas who underwent alloSCT in our institution from 11/2010–6/2018. Patient and disease characteristics were summarized using median and range for continuous data, and frequency and percentage for categorical data. Kaplan-Meier analysis was used to estimate progression free survival (PFS) and overall survival (OS) from the day of receipt of transplant. Survival probabilities were expressed by 95% confidence limits (CI). Results Thirty-three pts received alloSCT. Median age at transplant was 57 years (range [R], 22-73). T-cell lymphoma types included: cutaneous T-cell lymphoma, n = 12; NK-T cell, n = 4; peripheral T-cell lymphoma subtypes, n = 9; angioimmunoblastic T lymphoma, n = 6; T-cell rich B-cell, n = 2. Median lines of therapy prior to alloSCT were 4 (R, 2-13), including six with prior autologous SCT. Sixteen pts were transplanted in CR1, five in CR2, and three in CR3. Pentostatin/TBI was the most common pretransplant conditioning regimen (n = 23) followed by haplo regimen of Flu/TBI/Cy (n = 4). Donor transplant sources were MRD (16), MUD (8); Haplo (4), MMUD (5). Median days to neutrophil and platelet engraftment were 12 (R, 10-19) and 13 (R, 10-30), respectively. Cumulative incidence of grade II-IV acute and chronic GVHD were 24.2% and 45.4%, respectively. One-year PFS and OS probabilities were 69.5% (95% CI, 54.7- 88.4) and 87.1% (95% CI, 54.7-88.4), respectively. With a median follow up of 53 months (R, 2-97), 25 (75%) are alive and 24 are disease free. Four died from transplant related mortality (TRM) and 3 from relapse. The median time to relapse was 3.9 months [R, 2.2-12.5]). The cumulative incidence of GVHD was higher among patients who were relapse-free (71% vs 22% in relapsed pts, p=0.02). Seven of the 9 who relapsed were treated with brentuximab vedotin; of these 4 responded, including two patients who had haplo transplants. Conclusions Results from our study suggest that alloSCT in T-cell lymphomas with reduced intensity regimens are associated with overall favorable outcomes. Treatment of post-transplant relapse with brentuximab is feasible and should be explored further in long-term prospective studies.

Does Outcomes of HSCT Differ According to Patients’ Socioeconomic Status? Real-World Data from an Outpatient-Based Center in Mexico

Introduction The relationship between socioeconomic status (SES) and HSCT outcomes has not been well described in developing countries. Our center has established an outpatient-based HSCT program to reduce costs and improve its access to patients with different socioeconomic backgrounds. Nevertheless, post-HSCT follow-up implies an economic spending that many patients are unable to afford and may have a clinical impact. Objective We aimed to study the relationship between SES in transplant patients and clinical outcomes. Methods From August 2017 to May 2018, adult patients who received an HSCT and continued follow-up in our unit were recruited. They were enrolled into one of two cohorts: Cohort A included patients who received their first HSCT from January 2007 to July 2017, and Cohort B included those who were transplanted from August 2017 to May 2018. A validated questionnaire was applied to determine patients’ SES and demographic features. Clinical data were also obtained. Study endpoints included appearance of infections, mucositis, and hospitalizations by day 100. In patients with allo-HSCT, the cumulative incidence (CI) of acute GVHD (aGVHD) by day 100, and one-year CI of chronic GVHD (cGVHD) were assessed. In patients from Cohort B, one-year overall survival (OS) and disease-free survival (DFS) were analyzed by Kaplan-Meier method. Results We included 83 patients: 50 in cohort A and 33 in cohort B. Thirty-seven patients received auto-HSCT (44.6%), 22 HLA-identical allo-HSCT (26.5%), and 24 HLA-haploidentical allo-HSCT (28.9%). Most common diagnosis were lymphoma, acute leukemia, and myeloma (30.1, 25.3 and 21.7%, respectively). Median follow-up was 9 months (1-107). Patients were divided into 3 groups according to SES. Excluding CMV status, there were no significant differences in pre-transplant features (Fig 1). We compared outcomes according to SES. We found more infectious episodes and hospitalization requirements by day 100 in patients with low-SES (70.8 and 62.5%, respectively), whereas incidence of mucositis was greater in patients with high-SES (58.3%); p>0.05. In patients receiving allo-HSCT, CI of aGVHD was higher in those with high-SES (33.3%), while patients with low-SES had a superior one-year CI of cGVHD; p>0.05 (Fig 2). One-year OS and DFS in patients from Cohort B were 93.5 and 74.1%, respectively. There was a trend to find a decreased one-year OS and DFS in subjects with low-SES compared to those with middle and high-SES (90 and 62.5% vs 94.1 and 77.8% vs 100 and 100%, respectively); p>0.05. Conclusion Outcomes after HSCT can be favorable even in low resource settings. There was a trend to find HSCT-related complications more frequently in patients with low-SES, including infections, cGVHD and reduced DFS. Special attention should be given to patients with limited socioeconomic conditions and adequate compliance must be emphasized to achieve satisfactory outcomes.

Haploidentical Young Donor Versus Fully Matched Elderly Donor for Patients Aged 50 Years or Older

Introduction Currently the ideal stem cell donor is a fully matched HLA sibling; nonetheless, an elderly patient has a high probability of an also aging donor. Age has been related to worse transplant outcomes, mainly due to the higher incidence of acute and chronic GVHD and higher mortality rates when compared to patients performing transplantation with younger donors, in addition to possible comorbidities that may make them ineligible for donation. Objectives Considering the excellent results of transplants with haploidentical donors, which are comparable to those obtained with fully matched donors, the present study aims at assessing which would be the best donor for the patient witch has a fully matched sibling of 50 years of age and older and a younger haploidentical child. Methods This is a consecutive retrospective descriptive observational epidemiological study involving all patients who underwent hematopoietic progenitor cell transplantation with a fully matched or partially matched (haploidentical) related donor during the period from January 2010 to October 2017. Overall survival of patients aged 50 years or older was the primary outcome of the study. Results An amount of 47 patients was included in the study. In 72% the diagnosis was acute myelogenous leukemia or myelodysplastic syndrome.Regarding the compatibility, in 31 (65.9%) of the procedures the donor was fully matched and in 16 (34.1%) the donor was haploidentical. The mean age of the patients was 63 years in both groups, but the mean age of donors was significantly higher among the fully matched donors, who were on average 60 years with a range between 32 and 82. All of these donors were siblings of the receptor. About the haploidentical donors, the mean age was 37 years, ranging from 21 to 66 years, and 87% were children of the recipient. We did not observe a statistically significant difference in overall survival between patients whose donor was fully matched or haploidentical. The age of the donor ( The time of hospitalization of patients submitted to haploidentical transplantation was greater than that patients whose donor was fully matched (69.6 days and 36.7 days respectively, p = 0.001). Conclusion The results obtained in the study demonstrate the non-inferiority of the donor haploidentico in relation to the fully matched donor for patients aged 50 years or more.

Myeloablative Conditioning Using Timed Sequential Busulfan in Older Patients with Acute Myeloid Leukemia: Long Term Results of a Prospective Phase II Clinical Trial

Background Myeloablative conditioning (MA) reduces relapse as compared to reduced intensity (RIC), [Scott BL JCO 2017]. But it is avoided in older patients and those with comorbidities due to high non-relapse mortality (NRM), whose outcomes remain dismal. A CIBMTR study of AML patients ≥60 years (100% CR1) showed NRM of 32-34%, relapse rate of 33-37%, progression free survival (PFS) of 31-34% and overall survival (OS) of 34-36% at 2 years. [McClune. JCO 2010] A prospective trial in AML (≥60 years, 100% CR1) showed better 2-year PFS (42%) and OS (48%). [Devine. JCO 2015] Herein, we report the results of MA HCT using timed-sequential (TS) busulfan (Bu) in 71 AML patients up to age 73. Methods Patients received intravenous Bu in TS manner targeted to achieve an area under the curve of 16,000-20,000 μmol.min, with fludarabine (flu) 40 mg/m2 intravenously for four days. Results Median age was 64 years (range, 29-73). Donor was HLA matched unrelated (n=45, 63%) or related (n=26, 27%). Most received peripheral blood graft (n=46, 65%). Only 26% (n=18) had MRD-negative CR1/2 at HCT; others had MRD-positive CR1/2 (13%, n=9), primary induction failure (PIF; 45%, n=32) or relapsed disease (16%, n=11). Nearly half (47%) had the European LeukemiaNet (ELN) adverse risk disease. More than half (55%) had HCT-CI ≥ 3. Median follow-up was 40 months (range, 21-63). The cumulative incidences of grade II-IV and III-IV acute GVHD at day 100 were 39% (95% CI, 28-51%) and 10% (95% CI, 3-17%), respectively and extensive chronic GVHD at 1 year was 20% (95% CI, 10-29%). NRM was 6% (95% CI, 0-11%) at day 100 and 24% (95% CI, 14-34%) at 2 years. At 2 years, relapse was 28% (95% CI, 3-53%) in the CR/MRD-negative group vs 48% (95% CI, 34-62%) in others; progression-free survival (PFS) was 78% (95% CI, 61-99.6%) vs 25% (95% CI, 16-40%) and overall survival (OS) was 78% (95% CI, 61-99.6%) vs 33% (95% CI, 22-48%), respectively. [Fig 1a] Two year OS was was 67% (95% CI 51-87%) in the CR group, irrespective of MRD [Fig 1b]. In multivariate analysis (MVA) adjusted for covariates higher dose Bu vs lower dose [HR 0.39, 95% CI 0.18-0.85, p=0.02] was the only significant predictor of lower relapse risk. In MVA adjusted for age, Bu dose and ELN risk, not being in CR/MRD-negative state was the only predictor of significantly inferior PFS [HR 3.2, 95% CI, 1.3-8.2, p=0.01]. For OS, MVA adjusted for age, Bu dose and ELN risk, HCT-CI ≥3 [HR 1.98, 95% CI, 1-3.9, p=0.05] and not being in CR/MRD-negative state [HR, 2.7, 95% CI 0.98-7.2, p=0.05] were associated with higher mortality. Conclusion Our outcomes of MA HCT in an extremely high risk older population are promising especially in CR patients, whose outcomes approach that of younger patients. This was achieved by delivering Bu in TS manner which minimized toxicity and potentially increased efficacy. This approach warrants further investigation.

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.

The Optimal Dosage of Methotrexate for Graft-Versus-Host Disease Prophylaxis in Umbilical Cord Blood Transplantation

Introduction The combination of methotrexate (MTX) and a calcineurin inhibitor is widely used for GVHD prophylaxis in umbilical cord blood transplantation (UCBT). However, the optimal MTX dosage for GVHD prophylaxis in UCBT remains unclear. Methods We investigated the impact of the MTX dosage on clinical outcomes of UCBT. We retrospectively analyzed a cohort of 70 patients who received first UCBT between October 2002 and December 2017 in our hospital. Of the 70 recipients, 37 received MTX at doses of 10 mg/m2 on day 1, and 7 mg/m2 on days 3 and 6 (low-dose MTX: LD-MTX), and 33 received MTX at doses of 15 mg/m2 on day 1, and 10 mg/m2 on days 3 and 6 (standard-dose MTX: SD-MTX), in combination with tacrolimus (TAC).The following conditions within day 180 were considered to be transplant-related complications with endothelial cell damage: sinusoidal occlusive syndrome, systemic transplant-associated microangiopathy (TAM), intestinal TAM, capillary leak syndrome, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage. We defined grade 3-4 acute GVHD and/or transplant-related complications with endothelial cell damage as severe transplant-related complications in this study. Results The characteristics of patients and transplantation procedures were comparable between the two groups. T-cell depletion was not used as GVHD prophylaxis in our study. The median follow-up period for surviving patients was 1504 days (range, 302-3864). The cumulative incidence of neutrophil engraftment by day 42 was 97.3% (95% CI, 71.5%-99.8%) for the LD-MTX group and 93.9% (95% CI, 73.1%-99.8%) for the SD-MTX group (P = 0.36). The cumulative incidence of platelet engraftment by day 60 was 78.4% (95% CI, 60.6%-88.8%) for the LD-MTX group and 87.9% (95% CI, 69.0%-95.6%) for the SD-MTX group (P = 0.40). Univariate analysis findings revealed that the risk of grade 3-4 acute GVHD was significantly lower in the SD-MTX group than in the LD-MTX group (P = 0.013). Multivariate analysis findings revealed that SD-MTX was significantly associated with a lower incidence of severe transplant-related complications (HR = 0.25; 95% CI, 0.07-0.87; P = 0.029). Non-relapse death was not observed in patients with standard-risk disease in the SD-MTX group (n = 22). There was no significant difference between the two groups in the 2-year incidence of relapse: 27.0% (95% CI, 13.9%-42.0%) for the LD-MTX group and 15.3% (95% CI, 5.4%-29.7%) for the SD-MTX group (P = 0.55). Conclusion Our study demonstrated that the GVHD prophylaxis consisting of SD-MTX and TAC led to a significantly lower incidence of severe acute GVHD and/or TRC-EC than the combination of LD-MTX and TAC without increasing the risk of graft failure and relapse. Thus, while our findings need to be further verified by multicenter studies with larger cohorts of patients, for now SD-MTX is optimal in combination with TAC for GVHD prophylaxis in UCBT.