Severe Acute Graft-versus-host Disease Research Articles

Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial

AbstractGraft-versus-host disease (GVHD) is the most important complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). We performed a prospective randomized, multicenter, phase 3 trial to study whether posttransplant cyclophosphamide (PT-Cy) combined with a short course of cyclosporine A (CsA) would result in a reduction of severe GVHD and improvement of GVHD-free, relapse-free survival (GRFS) as compared with the combination of CsA and mycophenolic acid (MPA) after nonmyeloablative (NMA) matched related and unrelated peripheral blood alloHSCT. Between October 2013 and June 2018, 160 patients diagnosed with a high-risk hematological malignancy and having a matched related or at least 8 out of 8 HLA-matched unrelated donor were randomized and allocated in a 1:2 ratio to CsA/MPA or PT-Cy/CsA; a total of 151 patients were transplanted (52 vs 99 patients, respectively). The cumulative incidence of grade 2 to 4 acute GVHD at 6 months was 48% in recipients of CsA/MPA vs 30% following PT-Cy/CsA (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29-0.82; P = .007). The 2-year cumulative incidence of extensive chronic GVHD was 48% vs 16% (HR, 0.36; 95% CI, 0.21-0.64; P < .001). The 1-year estimate of GRFS was 21% (11% to 32%) vs 45% (35% to 55%), P < .001. With a median follow-up of 56.4 months, relapse incidence, progression-free survival, and overall survival were not significantly different between the 2 treatment arms. PT-Cy combined with a short course of CsA after NMA matched alloHSCT significantly improves GRFS due to a significant reduction in severe acute and chronic GVHD.

Serum follistatin level as a prognostic marker in Haploidentical stem cell transplantation

BackgroundThe treatment of hematological diseases with Haploidentical transplantation has made significant progress. Follistatin is an angiogenic factor that is elevated in the circulation after allogeneic Hematopoietic Cell Transplantation (HCT). Elevated follistatin levels have been linked to poor survival after graft versus host disease (GVHD). ObjectivePre- and post-transplant Follistatin levels were measured in patients subjected to Haploidentical HSCT and correlated with transplant outcomes. Patients and methodsThis study included 45 patients who underwent allogeneic stem cell transplants from Haploidentical donors. ResultsThe mean Follistatin level before stem cells infusion (88.81 ± 49.11 ng/ml) and at day 28 post-transplant (78.61 ± 45.50 ng/ml). The mean follistatin level was higher among the patients who had acute severe GVHD grade 3–4 pre-transplant at day zero and day 28 without statistical significance.The incidence of veno-occlusive disease was higher in patients with elevated serum follistatin levels on day 0 (108.58 ± 64.12 Vs 82.16 ± 46.05 ng/ml. p value = 0.134) and day 28 (112 ± 49.36 vs 66.06 ± 38.96 ng/ml) with statistically significance at day 28 post-transplant (p value = 0.011).After 180 days of follow-up, patients with high serum follistatin (i.e. >60 ng/ml) on day 28 post-transplant had lower OS, (P = 0.381). ConclusionIn the setting of Haploidentical HSCT, higher follistatin levels post-transplant are associated with severe acute GVHD and inferior overall survival.

Elevated RAP1A expression correlates with the severity of acute GVHD after umbilical cord blood transplantation

BackgroundAcute graft-versus-host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation. Ras-related protein 1A (RAP1A) has been recently identified as a novel oncoprotein in several human malignancies. However, its specific role in aGVHD remains unclear. ObjectiveTo study the role of RAP1A in the pathogenesis of aGVHD. Material and methodsStudy participants included six patients with grade 2–4 aGVHD, 13 patients with grade 1 aGVHD, 11 patients without aGVHD, and 12 healthy people. The expression level of RAP1A in whole cells was detected by western blot and qRT-PCR. The proportions of CD4+CD25+FoxP3+ Treg cells (T regulatory cells) and the expression of RAP1A in Treg cells in peripheral blood mononuclear cells (PBMCs) were detected by flow cytometry and the levels of related cytokines in the serum was detected by cytometric bead array. ResultsWe found the level of RAP1A was higher in patients than in healthy individuals. A negative correlation was noted between RAP1A and the number of Treg cells. In addition, the level of IL-10 in patients with grade 2–4 aGVHD was significantly lower than that in healthy donors, however, the level of TNF-ɑ in patients with grade 2–4 aGVHD was higher. Furthermore, we found a negative correlation between levels of IL-10 and RAP1A, and a positive correlation between TNF-ɑ and RAP1A. ConclusionThe expression of RAP1A in patients with aGVHD was significantly increased, and shows potential as a target for the prevention and treatment of aGVHD.

Risk and Predictive Factors for Candidemia After Allogeneic Hematopoietic Cell Transplantation: JSTCT Transplant Complications Working Group

Although antifungal prophylaxis that covers Candida species is a standard of care in allogeneic hematopoietic cell transplantation (HCT), candidemia mainly caused by non-albicans Candida species still occurs and is associated with a high mortality rate. This study aimed to evaluate the risk factors for candidemia after allogeneic HCT. Particularly, we evaluated the impact of patient factors such as hematopoietic cell transplantation–specific comorbidity index (HCT-CI) and performance status (PS) in addition to well-recognized risk factors including donor type, delayed engraftment, and graft-versus-host disease (GVHD). By using data from a Japanese transplant registry database, we analyzed 26,236 pediatric and adult patients with hematological malignancies who underwent their first allogeneic HCT. The posttransplant period was divided into early (days 0-40), late (days 41-100) and very late (days 101-365) phases. The 1-year cumulative incidence of candidemia was 1.8%. When we analyzed pretransplantation factors, age ≥40 years (hazard ratio [HR] 1.85), male (HR 1.34), HCT-CI (HCT-CI 1-2, HR 1.56; HCT-CI ≥ 3, HR 2.21), PS ≥ 2 (HR 2.01), high-risk disease (HR 1.78) and donor type including HLA-mismatched related donor (MMRD) (HR 1.96), HLA-mismatched unrelated donor (HR 2.05), and cord blood (CB) (HR 2.85) were significantly associated with an increased incidence of candidemia. Focusing on the early phase (days 0-40), HCT-CI, PS, high-risk disease and CB transplantation together with engraftment and severe acute GVHD significantly affected the development of candidemia. In the late phase (days 41-100), higher HCT-CI, male, and donor type including MMRD, and CB were associated with the occurrence of candidemia together with acute GVHD and disease relapse. In the very late phase (days 101-365), HCT-CI ≥ 3 and high-risk disease significantly affected the occurrence of candidemia together with acute and chronic GVHD, and disease relapse. In addition to well-recognized risk factors including donor type, engraftment and GVHD, patient factors such as HCT-CI and PS were associated with the development of candidemia, which suggests that severely ill patients with transplantation-associated complications are more likely to develop candidemia.

Antithymocyte Globulin Potentially Could Overcome an Adverse Effect of Acute Graft-versus-Host Disease in Matched-Related Peripheral Blood Stem Cell Transplantation

Previous Japanese studies have shown that bone marrow transplantation (BMT) is associated with better survival compared with peripheral blood stem cell transplantation (PBSCT) from a matched related donor (MRD). PBSCT recipients have shown higher incidences of severe graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) compared with BMT recipients. In recent years, the efficacy and safety of antithymocyte globulin (ATG) for PBSCT recipients has been evaluated worldwide. In the present study, we aimed to compare BMT and PBSCT recipients to identify current improvements and unmet needs among MRD PBSCT recipients. In addition, we evaluated the impact of ATG administration on the outcomes of PBSCT recipients. We retrospectively analyzed patients age ≥16 years with acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia who underwent their first BMT or PBSCT from an MRD between 2009 and 2018 in Japan. A total of 3599 transplantations were performed (BMT, n=1218; PBSCT without ATG [PBSCT-ATG(-)], n=2288; PBSCT with ATG [PBSCT-ATG(+)], n=93). The PBSCT-ATG(-) group had a higher NRM (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.08 to 1.57; P=.005) and lower overall survival (OS) (HR, 1.16; 95% CI, 1.04 to 1.30; P=.011) compared with the BMT group. Furthermore, the PBSCT-ATG(-) group had higher incidences of grade III-IV, stage 2-4 gut, high-risk, and steroid-refractory acute GVHD compared with the BMT group. Acute GVHD had a negative impact on NRM and OS. The PBSCT-ATG(-) group also was associated with an elevated risk of chronic GVHD (HR, 1.89; 95% CI, 1.24 to 2.57; P < .001) and extensive chronic GVHD (HR, 1.44; 95% CI, 1.23 to 1.68; P < .001). The incidences of acute GVHD, chronic GVHD, and NRM and chronic GVHD-free relapse-free survival rates were comparable between the PBSCT-ATG(+) and BMT groups. The OS of patients with acute GVHD was similar in the 3 donor groups. Patients treated with reduced-intensity conditioning in the PBSCT-ATG(+) group had a higher relapse rate and lower OS rate compared with those in the BMT group. In this Japanese cohort, standard calcineurin inhibitor-based GVHD prophylaxis was not sufficient for recipients of MRD PBSCT because of the high incidence of severe acute GVHD. Prophylactic ATG was found to be a promising strategy against GVHD.

Rehabilitation after Allogeneic Haematopoietic Stem Cell Transplantation: A Special Challenge.

Simple SummaryAfter undergoing an allogeneic haematopoietic stem cell transplantation (alloHCT), patients need intensive physiological and psychological rehabilitation. This should start immediately after discharge from the transplant ward as in- or outpatient rehabilitation. The rehabilitation centres should be qualified and experienced because this patient group exhibits problems that differ from those of patients who have undergone oncological therapies or autologous HCT. An experienced multidisciplinary team in close consultation with the primary transplantation centre should perform the rehabilitation therapy. This review will show the special challenges of these patients according to different timepoints after HCT. Because there is so little data available, personal experience and general guidelines on patient care after alloHCT are presented.The general population is getting older and suffer more haematological malignancies despite being physically fit. These malignancies are mainly only curable via an alloHCT, and they are now carried out more frequently. Patients benefit from intensive rehabilitation earlier and may need it repeatedly in cases of severe side effects (e.g., graft-versus-host disease). They can suffer many problems that other cancer patients do not experience, such as severe infections, continued immunosuppression, nutritional restrictions, acute or chronic GvHD, or organ impairments (e.g., lung, eyes). They may also encounter various associated psychological problems, e.g., feeling like a chimera. Rehabilitation centres willing to care for patients after alloHCT should have an experienced multidisciplinary team and should work in close co-operation with the primary transplant centre.

Post-Transplantation Immunosuppression After TCRΑβ/CD19 Graft Depletion Does Not Improve HSCT Outcomes in Primary Immunodeficiency

We recently demonstrated that TCRαβ+/CD19+ graft depletion successfully prevents severe acute and chronic graft-versus-host disease (GVHD) in pediatric patients with primary immunodeficiencies (PID) receiving transplants from both matched unrelated and mismatched related donors. However, in all patients, short-term post-hematopoietic stem cell transplantation (HSCT) immunosuppressive therapy (IST) was used. There are limited data on TCRαβ+/CD19+ graft depletion with no post-HSCT IST implementation. In the current study 74 PID patients who underwent first HSCT from matched unrelated (n=51) or mismatched related donors (n=23) with TCRαβ+/CD19+ graft depletion were included. All received as a conditioning regimen a combination of treosulfan with fludarabine and either melphalan or thiotepa. In all, thymoglobulin 5 mg/kg (days −5, −4, −3) and rituximab at day −1 were used. In 48 patients, various approaches to short-term post-transplantation IST were used, and 26 patients received no post-HSCT IST. The rates of engraftment, acute and chronic GVHD, survival, and mortality were similar in those who received and did not receive IST, with a slightly higher incidence of graft rejection in patients not receiving IST: 19% in the non-IST group against 13% in the IST group (P = .41). The incidence of cytomegalovirus reactivation was 50% and 39% (P = .50) and Epstein-Barr virus reactivation 10% and 0 (P = .20) in the IST and non-IST groups, respectively. No grade 4 adverse events were seen in both groups, although in 19 of 40 (47.5%) patients receiving calcineurin inhibitors, the therapy was discontinued before day 45. More robust immune recovery with both T- and B-lymphocytes was observed in the non-IST group. To conclude, TCRαβ+/CD19+ in combination with particular serotherapy effectively prevents severe acute and chronic GVHD in PID. Regarding remaining risks of infectious complications and additional drug-related toxicity, there are no benefits to post-HSCT IST use in these patients.

Post-Transplantation Cyclophosphamide for Gvhd Prophylaxis in Related and Unrelated Allogeneic Hematopoietic Cell Transplantation: Study from the SFGM-TC Registry

Rational: The significant increase in haplo-identical allogeneic cell transplantation (Allo-HCT) has led to the more frequent use of cyclophosphamide (Cy) after transplantation for graft-versus-host disease (GVHD) prophylaxis (PT-Cy). This strategy has subsequently been used in related and unrelated allogeneic HCT settings as well with some controversial results.Patients and Methods: We analyzed all consecutive Allo-HCTs from matched related (MR) and unrelated donors (HLA matched and mismatched: MUD and MMUD) reported to the SFGM-TC registry from January 2014 to December 2019 and who have received PT-Cy alone or in combination with other immunosuppressive molecules (IS). We therefore performed a pair-matched analysis (1/2) with transplantations using classic GVHD prophylaxis with (w) or without (wo) anti-thymocyte globulins (ATG). The primary objective was to evaluate the incidence and severity of acute and chronic GVHD in PT-Cy compared to other strategies. Secondary objectives included: modalities of PT-Cy and IS, cumulative incidence of relapse (CIR), non-relapse mortality (NRM), overall survival (OS), GVHD and relapse free-survival (GRFS), infection rates.Results: We analyzed a total of 1190 patients (pts), 386 (32%) received PT-Cy and matched with 804 (68%) pts who received classic GVHD prophylaxis (no PT-Cy). Among PT-Cy patients, 59% were males with a median age of 55.3 years (3.4-75.5), 49% were AML, 14% ALL, 20% MDS and MPS, 12.5% NHL and HL, and 4.5% Multiple Myeloma. Before transplantation, 61% of pts were in complete remission (CR), 34% not in CR, 2% in stable disease and 3% were not treated. Conditioning regimen was myeloablative in 35% of patients, 86% received peripheral blood stem cells, 31% were CMV negative pairs, 58% were sex-matched and 51% were ABO compatible. There was no significant difference between the PT-Cy and no PT-Cy groups regarding all the variables. We identified four groups: group 1: PT-Cy + IS (n=259), group 2: PT-Cy + ATG + IS (n=120), group 3: ATG w or wo IS (n=651) and group 4: other IS (n=160). We observed significant differences between the 4 groups for age (p<0.001), type of disease (p<0.001), disease status (p=0.016), conditioning intensity (p=0.002), HC source (p<0.001), HLA matching (p<0.001) and ABO compatibility (p<0.001).The cumulative incidence of acute GVHD grades II, III/IV, chronic GVHD, relapse and NRM, the probability of OS and GRFS are shown in Table 1. The results of multivariate analysis (Table 2) showed a significant lower incidence of acute GVHD gr II, III, IV and chronic GVHD after PT-Cy + IS and a significant higher TRM after ATG ± IS. In addition, other well-known parameters were found to have a significant impact as age on OS and GRFS, use of unrelated donor on OS and CIR and PBSC on chronic GVHD. Regarding severe infections after HCT, there was no difference between PT-cy and pair-matched patients except for pneumonia (12.5% vs. 8% respectively, p=0.08) and septicemia (12% vs. 1.7% respectively, p<0.001).In conclusion, there was a significant lower incidence and severity of acute and chronic GVHD in the PT-Cy group after related, HLA matched and mismatched unrelated Allo-HCT compared to matched patients with other GVHD prophylaxis with a higher NRM when patients received ATG. We did not observe significant translation into GRFS improvement probably due to the higher toxicity of PT-Cy. [Display omitted] DisclosuresYakoub-Agha: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huynh: Jazz Pharmaceuticals: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

Encouraging Survival and High Rates of Toxicity: Allogeneic Hematopoietic Cell Transplantation after Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Aggressive Lymphoma Patients

BackgroundApproximately 60% of patients with aggressive large B-cell lymphoma (ALBCL) treated with anti-CD19 chimeric antigen receptor T-cell (CAR T) will ultimately progress or relapse. Allogeneic hematopoietic cell transplantation (Allo-HCT) is a potentially curative treatment for lymphoma patients who relapse after CAR T-cell therapy. However, the efficacy and toxicity profile of allo-HCT following CAR T in aggressive lymphoma patients are not well defined. Herein, we report our experience.Methods and patientsA total of 29 adult patients (median age 45 years [IQR 40-55]) who received allo-HCT for ALBCL between 2017 to 2021 were included. All patients were previously treated with anti-CD19 CAR T-cell (academic CD28-costimulatory domain product [n=23, 79%]; tisagenlecleucel [n=6, 21%]). Twenty-five (86%) and 4 (14%) had a diagnosis of DLBCL and PMBCL, respectively. Median number of previous therapies before CAR T was 3 (IQR 2-4). Eight (28%) patients underwent a previous autologous HCT. No patient underwent a previous allo-HCT. Median hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was 3 (IQR 2-3). Six (21%) patients had a Karnofsky performance status ≤ 80%.Allo-HCT was performed at a median of 4.1 months (IQR 2.2-5.4) post CAR T, with the majority of patients (48%) receiving transplant as first-line post CAR T. Reasons for allo-HCT were consolidation of complete response (CR) to CAR T in high-risk disease (n=4, 14 %), partial response (PR) to CAR T (n=7, 24%) and relapse /progression after CAR T (n=18, 62%). Disease response before allo-HCT was CR (n=11, 38%), PR (n=11, 38%) and progressive disease (n=7, 24%). Donors were matched siblings (n=13, 45%), matched unrelated (n=9, 31%) and mismatched unrelated /haploidentical donors (n=7, 24%). Myeloablative and reduced-intensity conditioning regimens were given in 13 (45%) and 16 (55%) patients, respectively. Methotrexate-based graft versus host disease (GVHD) prophylaxis was used in 20 (69%) patients. Antithymocyte globulin and post-transplantation cyclophosphamide were administered in 13 (45%) and 5 (14%), respectively.ResultsMedian follow-up was 33 months (IQR 13-41). Neutrophil engraftment rate was 93% (two early deaths before engraftment due to infection and multi-organ failure). Two-year overall survival (OS) and progression-free survival were 44% (95% CI: 28-68) and 30% (95% CI: 17-55), respectively. Two-year cumulative relapse incidence and non-relapse mortality were 45% (95% CI: 25-63) and 25% (95% CI: 11-43), respectively (Figure). In a univariable Cox regression, factors significantly associated with a shorter OS were number of interim therapies between CAR T and allo-HCT (Hazard ratio [HR] 2.2 [95% CI: 1.3-3.9], p 0.006) and the length of time between CAR T and allo-HCT (HR 3.8 [95% CI: 1.2-12.1], p 0.02). Best response to CAR T and disease response before allo-HCT were not significant risk factors for a shorter OS.High rates of grade ≥ 3 hyperbilirubinemia (total bilirubin >3 ULN) and hepatic sinusoidal obstruction syndrome (SOS) were observed in 10 (35%) and 5 (17%) patients, respectively. These liver insults were not contributed to acute GVHD. All patients with SOS were treated with defibrotide and two patients died from related complications. Interestingly, 4/5 patients with SOS were conditioned with fludarabine and thiotepa.One-year cumulative incidence of grade II-IV acute GVHD was 34% (n=10; 95% CI: 18-52). Notably, 6 patients had grade IV acute GVHD, 4 of them were refractory to corticosteroids and 3 patients died due to acute GVHD. Two-year cumulative incidence of chronic GVHD was 23% (n=5; 95% CI: 7-46). Chronic GVHD was considered extensive in 4 of them.Bloodstream bacterial infection was documented in 11 (38%) patients. Invasive fungal infection occurred in 6 (21%) patients and included brain aspergillosis, cutaneous aspergillosis, 2 lung aspergillosis, hepatosplenic candidiasis and an ocular mucor mycosis.ConclusionAllogeneic hematopoietic cell transplantation is feasible after failure of CAR T-cell therapy in aggressive lymphoma, although with a relatively high rate of SOS and severe acute GVHD in these heavily pretreated patients. Overall survival is encouraging with approximately 30% of patients remaining alive and disease-free at two years. Larger scale studies are required to better define the role of allo-HCT in this setting. [Display omitted] DisclosuresShouval: Medexus: Consultancy. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avigdor: Takeda: Consultancy, Honoraria; Janssen: Research Funding; BMS: Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Long-Term Follow-up of Allogeneic Hematopoietic Stem Cell Transplantation after Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Introduction: Chimeric antigen receptor T-cell (CART) Therapy has induced high complete remission (CR) in the patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), but the median event-free survival is only 6.1 months (Park JH. et al. NEJM 2018). To achieve durable leukemia-free survival (LFS), it may helpful to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CR with CART therapy.Objective: In current study, safety and long-term outcomes of allo-HSCT after CART therapy in r/r B-ALL were assessed and risk factors for overall survival (OS) and LFS were analyzed.Methods: Between June 2017 to June 2020, 137 patients with r/r B-ALL who achieved CR with CD19 or CD22 CART then bridge to allo-HSCT in our hospital were evaluated. The median age was 9.7 years (1.8-56). Bone marrow (BM) samples were collected to detect somatic gene mutations of leukemic cells. Blood samples from patients, parents, and potential related donors were collected to analyze germline mutations of hematological and immunological hereditary predisposition genes. The disease status before transplant was minimal residual disease (MRD) negative in 114 (83.2%) patients and MRD positive in 23 (16.8%) patients. The median time from CART infusion to allo-HSCT was 51 days (29-94). The types of transplant were haploidentical (105, 76.6%), unrelated (26, 19.0%), and identical siblings (6, 4.4%). Myeloablative reduced-toxicity conditioning (RTC) with either total body irradiation (TBI)/fludarabine-based (84, 61.3%) or busulfan (BU) /fludarabine-based (53, 38.7%) were applied. Cyclosporine, mycophenolate mofetil and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis.Results: Full donor engraftment was achieved in all patients. The median time for neutrophil and platelet engraftment was 15 days (9-21) and 13 days (5-33). With a median follow-up of 653 days (481-783), two-year OS was 74.1% (64.4-81.5) and two-year LFS was 64.4% (54.6-72.6). The incidences of grade Ⅱ to Ⅳ and severe acute GVHD (aGVHD) were 27%, 14.5%, respectively. Twenty-five (18.2%) cases developed chronic GVHD (cGVHD) (limited 18, extensive 7). The incidences of CMV and EBV viremia were 20.1%, 12.5%. Hemorrhagic cystitis was found in 32 (22.2%) cases. Thirty-six (26.3%) cases relapsed after transplant, 28/114 (24.6%) in MRD negative cohort and 8/23 (43.5%) in MRD positive cohort. Thirty (21.9%) patients died (relapsed 22, infection 5, multiple organ failure 2, thrombotic microangiopathy 1). Transplant-related mortality was only 5.8%. Total 137 patients with 99 kinds of somatic mutations, the most frequent 15 mutations were TP53, CYP2C19, KRAS, NRAS, PTPN11, CREBBP, KMT2D, KIT, NR3C1, STK11, FLT3, NF1, NUDT15, ABL1, ADAMTS13. LFS was significantly reduced in patients with TP53, KIT, NF1 mutation (P < 0.0001; P < 0.025; P < 0.003). Total 114 evaluable patients with 93 kinds of hematological and immunological hereditary predisposition gene mutations, the most frequent 15 mutations were BLTA, SERPINE1, CYP2C19, F7, TP53, DPYD, MLH1, TNFAIP3, YARS2, HIFIA, ATM, EP300, KIT, ADAMTS13, BRCA2. LFS was significantly reduced in patients with germline EP300 mutation (P < 0.00027). Univariate analysis showed that BU-based regimen (P=0.0194), somatic TP53 mutation (P= 0.002), fungal infection (P= 0.0217), viral infection (P=0.0187) and MRD positive before transplant (P= 0.0227) were adverse factors of OS. The negative factors of LFS were BU-based regimen (P=0.0139), germline EP300 mutation (P<0.001) and fungal infection (P =0.0002). Multivariate analysis showed that TBI-based regimen (P=0.019) and aGVHD (P=0.047) increased LFS remarkably, but fungal infection (P=0.002), somatic TP53 mutation (P<0.001) and germline EP300 mutation (P<0.001) decreased LFS significantly.Conclusions: Our large series and long-term outcomes have demonstrated that LFS and OS have been improved remarkably in r/r B-ALL who achieved CR with CART then quick bridge to RTC allo-HSCT. Our study has shown the somatic and germline mutation profiles in r/r/ B-ALL and found that somatic TP53 mutation and germline EP300 mutation are negative factors for LFS. TBI-based regimen , MRD negative before transplant and aGVHD have positive impact on LFS, and fungal infection, somatic TP53 and germline EP300 have negative impact on LFS. DisclosuresNo relevant conflicts of interest to declare.

Phase I/II Study of Reduced Dosing of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Haploidentical Bone Marrow Transplantation

Background: Post-transplantation cyclophosphamide (PTCy) is widely used for graft-versus-host-disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). However, the standard PTCy dose (50 mg/kg/day) and timing (given on days +3 and +4) were largely extrapolated from murine skin allografting models, and these have never been rigorously tested to determine if they are optimal. We have shown in murine HCT models that an intermediate PTCy dose of 25 mg/kg/day on days +3/+4 is superior at preventing severe GVHD compared with 50 mg/kg/day on days +3/+4 (Wachsmuth et al., JCI. 2019). Furthermore, PTCy 25 mg/kg/day given on day +4 alone is equivalent to 25 mg/kg/day given on days +3/+4 at preventing severe GVHD (Wachsmuth et al. BBMT. 2019). Thus, the standard clinical dosing may be higher than necessary and potentially come at the cost of increased toxicity, delayed engraftment, and impaired immune reconstitution.Methods: This is a single institutional prospective phase I/II study (NCT03983850) to de-escalate PTCy exposure for adult patients with hematologic malignancies. All patients received myeloablative conditioning with IV daily busulfan/fludarabine, HLA-haploidentical bone marrow, and GVHD prophylaxis with PTCy (dose and timing based on Dose Level (DL)), mycophenolate mofetil (days +5 to +35), and sirolimus (days +5 to +80).The first 5 patients received PTCy 50 mg/kg/day on days +3/+4 (standard dosing, Dose Level 1) for comparative data. This was followed by a 3+3 dose de-escalation design testing 25 mg/kg/day on days +3/+4 (experimental, Dose Level 2) and 25 mg/kg on day +4 only (experimental, Dose Level 3), followed by a phase II expansion cohort at the better experimental dose level. The primary endpoint and dose limiting toxicity for the dose de-escalation was grade III-IV acute GVHD.Results: Phase I enrolled 19 patients, and the phase II expansion has enrolled 13 of 14 patients, 9 of whom have sufficient follow-up (60 days) to be considered evaluable for the primary endpoint; median follow-up of survivors evaluable for the primary endpoint is 288 (range 60-676) days. Patient and disease characteristics and outcomes for these patients are summarized in Table 1.No grade III-IV acute GVHD was seen at either experimental DL, and there have been no cases of grade II-IV acute GVHD at DL2 (Figure 1). Based on more reliable early engraftment (see below) but less intense and shorter duration of engraftment fevers, DL2 was taken to phase II.Engraftment was faster at the experimental DLs but was most consistent with DL2. Median neutrophil engraftment was at day 14 at DL2 compared with day 19 at the standard dosing (p=0.0004) (Figure 2A). Median platelet engraftment was at day 23 at DL2 compared with day 33 at the standard dosing (p=0.026) (Figure 2B). Correspondingly, transfusional requirements were lessened with DL2 (Figure 2C-D). Engraftment syndrome, manifesting as fever, rash, and mild transaminitis, occurred in 1 patient at DL2 and 2 patients at DL3, but resolved rapidly without intervention in all cases. Primary graft failure was seen in 1 patient at DL2, and relapse prior to engraftment was seen in 1 patient at DL3.Mucositis was less severe and shorter in duration for both experimental DLs when compared with standard PTCy dosing (Figure 2E). CMV reactivation requiring pre-emptive therapy was less frequently seen after lower PTCy dosing (Figure 3A). Symptomatic BK virus-associated cystitis in at-risk patients was shorter in duration for patients receiving lower PTCy; median duration was 74 days for the standard DL versus 26 days at DL2 and 7 days at DL3 (Figure 3B). At DL2, there have been 3 cases to date of chronic GVHD requiring systemic immunosuppression among the 13 engrafting patients with at least 100 days of follow-up.Conclusions: De-escalating PTCy exposure is feasible and effective in maintaining protection against severe acute GVHD while promoting more rapid engraftment and less early post-transplant toxicity. Two-day dosing of 25 mg/kg/day PTCy appears to allow for more consistent early engraftment and protection against protracted engraftment fevers compared with day +4 only. Longer follow-up and comparative studies are needed to understand if de-escalated PTCy is superior to the standard dosing schedule. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:The use of cyclophosphamide as graft-versus-host disease prophylaxis

A Phase II Study of Ruxolitinib Pre-, during- and Post-Hematopoietic Celltransplantation for Patients with Primary or Secondary Myelofibrosis

▪Background:Myelofibrosis (MF) is a lethal hematological malignancy associated with somatic mutations in JAK2, CALR or MPL. Ruxolitinib is the first JAK1/2 inhibitor approved for treatment of MF. Ruxolitinib does not prevent disease progression and thus, allogeneic hematopoietic stem cell transplantation (HSCT) remains the recommended therapy for eligible patients treated with curative intent. Ruxolitinib discontinuation, in preparation for HSCT is challenging as patients experience return of symptoms/splenomegaly. Therefore, ruxolitinib is often continued during and after HSCT in an off-label fashion, yet little is known about the safety of this approach. In addition, ruxolitinib is now utilized to treat steroid refractory acute and chronic graft versus host disease (GVHD) irrespective of underlying disease.Methods:This is a phase II, multi-center, investigator-initiated trial investigating ruxolitinib given pre-, during- and post-HSCT for patients with primary or secondary MF (NCT03427866). The study utilizes ruxolitinib during and after HSCT in MF patients for one year after HSCT. The accrual goal is 48 patients with 1-year GVHD free and relapse free survival (GRFS) as the primary endpoint. Secondary endpoints include overall and progression free survival, engraftment and incidence of acute and chronic GVHD, respectively. Patients are treated with reduced intensity conditioning with fludarabine (30mg/m 2/day x 5 days) and melphalan (100mg/m 2 or 140mg/m 2 x 1). HSCT grafts are with 7/8 or 8/8 HLA-matched peripheral blood stem cells with tacrolimus and methotrexate as standard GVHD prophylaxis.Results:This pre-planned interim analysis includes 26 MF patients who underwent HSCT between September 2018 and January 2021. An interim analysis was included in the trial design to ensure safety of this approach midway through accrual. Median age was 66 (range, 46-75) and 65% were male. 88% had 8/8 matched related grafts, and 92% had intermediate-2 or high DIPSS risk at the time of transplant. 14 (54%) patients were previously treated with ruxolitinib. At HSCT, 58% had JAK2, 12% CALR, 12% MPL, and 35% ASXL1 mutations (Figure A). There were no unexpected toxicities related to ruxolitinib therapy. The most common grade 3/4 hematologic adverse events (AE) were anemia (n=4), thrombocytopenia (n=3). There were few observed grade 3/4 non hematologic AEs and included infection (n=2) and hypertriglyceridemia (n=1). Median time to neutrophil engraftment was 15 days (range 11-38) after HSCT. All but one patient achieved successful neutrophil engraftment. Median day 30 donor all cell chimerism was 100% (range 95-100). Clinical outcomes are summarized in Figure B. With median follow-up among survivors of 12 months (range 3-24), 1-yr GRFS was 65%. OS, PFS, and cumulative incidence of NRM and disease relapse were 77%, 71%, 13% and 17%, respectively (Figure C). There was no grade IV acute GVHD and only one case of grade III acute GVHD. Cumulative incidence of all chronic GVHD and moderate-severe chronic GVHD was 14% and 5%, respectively. There was no severe chronic GVHD and only one patient developed moderate chronic GVHD.As part of the study, next generation sequencing (NGS) was obtained pre- and 100 days post-HSCT. 14 patients have paired samples, including 6 with ASXL1 mutations. All but one patient, who remains in remission at last follow up, no longer had mutations detected by NGS at day 100 (Figure D). Ongoing studies will assess for the presence of low-level mutation not detectable by clinical NGS testing.Discussion:The interim results of our multicenter study demonstrate safety of ruxolitinib administration pre, during and post-HCT with very favorable engraftment rates and no unexpected toxicities of ruxolitinib use. In addition, we demonstrate superior PFS, OS and GRFS compared to historical observations. Incidence of severe acute and chronic GVHD are thus far minimal, indicating excellent GVHD control with prophylactic and continued ruxolitinib use. [Display omitted] DisclosuresHobbs: Bayer: Research Funding; Incyte Corporation: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; AbbVie.: Consultancy; Merck: Research Funding; Novartis: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding. Byrne: Karyopharm: Research Funding. Defilipp: Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Omeros, Corp.: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Chen: Gamida: Consultancy; Incyte: Consultancy. OffLabel Disclosure:Will describe the use of ruxolitinib in the ongoing clinical trial.

Outcomes Are Similar Following Allogeneic Hematopoietic Stem Cell Transplant for Newly Diagnosed Patients Who Received Venetoclax + Azacitidine Versus Intensive Chemotherapy

Background: Venetoclax-based therapy regimens are now FDA-approved for treatment of acute myeloid leukemia (AML) in older patients or those unfit to tolerate intensive chemotherapy (IC). Remission rates are high at 60-70% but relapses do frequently occur. Outcomes for newly-diagnosed patients who receive venetoclax-based therapies and proceed to a potentially curative allogeneic stem cell transplant (SCT) have largely been unreported. In the current study we compare outcomes of patients who received SCT following either IC or venetoclax + azacitidine (ven/aza) at the University of Colorado Hospital.Methods: Patients 18 years or older who received SCT in first remission of AML between 2010-2020 were included in the analysis. Patients were stratified into the IC arm if they initially received a backbone of cytarabine and an anthracycline; some patients in this cohort received IC in combination with other targeted agents. Patients who received ven/aza as first-line therapy followed by SCT were grouped in a separate cohort. Demographic and clinical information - including flow cytometry-based (MCF) MRD - was extracted from the electronic medical record.Comparisons of demographic and clinical variables between IC and ven/aza groups were made with t-test, Chi-squared, or Fisher's exact test depending on the nature of the variable. Relapse-free (RFS) and overall (OS) survival were calculated from the day of SCT to the respective endpoint or last documented follow-up using log-rank statistics. Finally, a Cox proportional hazards model was used to assess the interplay between variables pre- and post-SCT. P-values <0.05 were considered significant.Results: We identified 179 patients who received SCT for AML in first remission. Of these patients, 151 received IC and 28 received ven/aza prior to SCT. Patients in the ven/aza group had higher median age than those in the IC group, as well as a higher proportion with adverse ELN genetic risk scoring. Patients in the ven/aza group received less intensive conditioning regimens. Sex, rates of MCF MRD negativity pre-BMT, incidence of severe acute or chronic GVHD, and causes of death were not significantly different between the two groups. There was no difference between the two groups in post-transplant RFS or OS (Figure 1). In a multivariate Cox model of pre-transplant variables predicting OS, the only factor that achieved significance was pre-SCT MCF MRD; the induction regimen was not a multivariate factor. Negative MCF MRD going into SCT was associated with decreased likelihood of relapse, GVHD, and death, respectively.Conclusions: In our cohort of AML patients receiving SCT, we found that ven/aza as a pre-transplant therapy yielded equivalent post-transplant outcomes compared to IC, in a population of older age and with higher ELN genetic risk. MCF MRD pre-SCT was confirmed as a key prognostic factor for post-SCT outcome. These findings support ongoing use of ven/aza as a first line therapy for elderly patients with AML as well as its exploration as a candidate therapy for younger patients. [Display omitted] DisclosuresPollyea: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Aprea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kiadis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Syndax: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Agios: Other, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, Servier: Other; Pfizer: Research Funding; Syros: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: advisory board; Foghorn: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: advisory board; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board.

Characterizing Safety in Patients with Hematologic Malignancies Receiving Allogeneic Stem Cell Transplant (Allo-SCT) Following Pembrolizumab Therapy

Characterizing Safety in Patients with Hematologic Malignancies Receiving Allogeneic Stem Cell Transplant (Allo-SCT) Following Pembrolizumab Therapy

Association of Donor and Recipient Interleukin-1 Gene Single Nucleotide Polymorphisms with Outcome after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for hematological malignancies, genetic diseases, and severe immune deficiencies. Despite the matching of the human leucocyte antigens (HLA), HSCT is still associated with a considerable rate of morbidity and mortality caused by infections, relapse, and graft-versus-host disease (GVHD). Therefore, non-HLA polymorphisms like cytokines and their receptors are considered as important contributing factors. Interleukin-1 (IL-1) is a cytokine that initiates and maintains the immune response as well as the development of GVHD in the recipient. Single nucleotide polymorphisms (SNPs) of the IL-1 gene are associated with a higher risk of malignancies, an elevated death rate because of infections, and a higher chance to suffer from autoimmune or chronic diseases. This study aimed to analyze the association of IL-1 gene SNPs with outcome in a pediatric population undergoing allogeneic HSCT.Methods: We included 270 pediatric patients with a median age of 9 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL-1-alpha rs1800587 (-889, A/T), IL-1-beta rs1143627 (-31, A/T), and IL-1-beta rs16944 (-511, A/T). The underlying diseases were acute lymphoblastic leukemia (n=89), acute myeloid leukemia (n=63), chronic myeloid leukemia (n=10), juvenile myelomonocytic leukemia (n=9), myelodysplastic syndrome (n=29), lymphoma (n=7), solid tumor (n=11), genetic disease (n=41), and aplastic anemia (n=11). The stem cell sources were bone marrow (n=178), peripheral blood (n=90) or umbilical cord blood (n=2). Two hundred donors were HLA-matched, and 70 donors were HLA-mismatched. Conditioning regimen was myeloablative in all cases and based on chemotherapy in 180 children or total body irradiation in 90 children. The predominant post-transplant immunosuppression was cyclosporine A and methotrexate in 148 patients or cyclosporine A alone in 55 patients. The genotyped SNPs were compared using the Kaplan-Meier method for event-free survival (EFS) and overall survival (OS) and the Gray test for acute GVHD, chronic GVHD, relapse rate (RR), and transplant-related mortality (TRM).Results: We observed a significant association between the SNP IL-1-alpha rs1800587 (-889, A/T) of the donor and the rate of acute GVHD. The genotypes of IL-1-alpha rs1800587 had the following distributions in the donor: CC genotype n=132 (49%), CT genotype n=114 (42%), and TT genotype n=24 (9%). Overall, 63 children (23%) suffered from moderate to severe acute GVHD (grade II-IV). We found a significantly increased incidence of moderate to severe acute GVHD (grade II-IV) if the patient was transplanted from a donor with the CC/CT genotype compared to the TT genotype (25% versus 4%; p=0.028). We found no significant associations of the SNP IL-1-alpha rs1800587 (-889, A/T) for chronic GVHD, RR, TRM, EFS, and OS. In addition, we observed no significant associations of the other studied genotypes IL-1-beta rs16944 (-511, A/T) and rs1143627 (-31, A/T) in either donors or recipients for acute and chronic GVHD, RR, TRM, EFS, and OS.Conclusion: Our study identified the IL-1-alpha rs1800587 CC/CT genotype of the donor as a genetic risk factor for the development of moderate to severe acute GVHD (grade II-IV) in pediatric allogeneic HSCT recipients. After confirmation in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the risk of acute GVHD in children. DisclosuresGruhn: AmgenGmbh: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel costs; Bellicum Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees, Other: travel costs; EUSA Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: travel costs; Novartis Pharma Inc.: Honoraria, Other: travel costs; pfizer: Honoraria; servier: Honoraria, Other: travel costs; Neovii Biotech GmbH: Other: travel costs; medac GmbH: Other: travel costs.

A Prospective Phase 2 Study Testing High Dose Post-Transplant Cyclophosphamide As Sole Ghvd Prophylaxis after Matched Allotransplant Using Baltimore-Based Reduced-Intensity Conditioning Regimens and PBSC As Source of Graft

Introduction: The use of high-dose post-transplant cyclophosphamide (PTCY) has revolutionized graft-versus-host disease (GVHD) prophylaxis and allowed to successfully reconsider haplotransplant in recent years. As this strategy significantly reduces the incidence of both acute and chronic GVHD, PTCY has been thereafter considered not only in matched settings but also as sole GVHD prophylaxis, at least when considering myeloablative allotransplant using matched sibling (MSD) or unrelated (MUD) donors and bone marrow as source of graft. Here, PTCY, as a sole GVHD prophylaxis, was tested in a reduced-intensity conditioning (RIC) setting, using peripheral blood stem cells (PBSC) as source of graft considering that this platform is currently broadly used worldwide in adults.Methods: This prospective monocentric phase 2 study was designed with the main objective to demonstrate the feasibility and safety of using only PTCY (without cyclosporine A nor mycophenolate mofetyl after transplant) in adults (18-70 years old) eligible for a RIC PBSC transplant with MSD or MUD. The Baltimore platform with 2 days of PTCY 50mg/kg/day on days 3 and 4 post infusion was considered as conditioning regimen, using fludarabine for lymphoid disease or clofarabine for myeloid disease. The primary objective was to appreciate the incidence of corticosteroid-resistant acute grade 3-4 GVHD (CR 3-4 GVHD) within 100 days post-transplant. According to statistical rules, patients have to be included in a step by step fashion (3, 3, 6, 15, 15 and 17 patients) for a total of 59 evaluable patients (meaning having received PTCY), in order to stop the protocol soon enough in case of excessive rate of deleterious severe acute GVHD (graded according to Mount Sinai International Consortium). Thus, the trial had to be stopped in case of documentation of > 2 CR 3-4 GVHD for the first 3 patients, >3 CR 3-4 GVHD for the first 6 patients, > 4 CR 3-4 GVHD for the first 12 patients, > 6 3-4 CR GVHD for the first 27 patients, > 8 CR 3-4 GVHD for the first 42 patients and finally as soon as > 9 CR 3-4 GVHD for the last included patients. All patients gave informed consent. The trial was registered at ClinicalTrials.gov Identifier: NCT03263767.Results: The results of the first 27 first patients (males n=17 and female n=10; median age: 59 years old (yo), range: 26-70) are reported here. They were included between February 2018 and November 2020. Diagnoses were AML (N=8), MDS (N=5), CMML (N=2), myelofibrosis (N=5), CML (N=1), DLBCL (N=1), T-cell lymphoma (N=1), Philadelphia positive B-ALL (N=1), CLL (N=1), lymphoblastic lymphoma (N=1) and mixed phenotype acute leukemia (N=1). Donors were MSD in 10 cases and MUD in 17.Only one primary graft failure was documented in a 61 yo MDS patient with active disease at transplant. He is however still alive in response after autologous reconstitution. With a median follow-up of 17.6 months (range: 10-42) for alive patients at the time of analysis (July 2021), 1-year and 2-year survivals were 80.9+7% and 74.7+9%, respectively, for both OS et DFS. GVHD-free/relapse-free survival (GRFS) at 1-year and 2-year was 58.7+9% and 52.2+10%, respectively. Three relapses (11%) and 6 deaths occurred. Deaths were due to acute GVHD in 4 patients (including 1 with sepsis and 1 with SARS-COVID 19 infection) and relapse in 2. Grade 2, 3 and 4 acute GVHD occurred in 11, 1 and 4 patients, respectively, for a total of 59% of grade 2-4 acute GVHD. CR 3-4 GVHD was observed in all of 5 patients with acute grade 3-4 GVHD and 4 died related to GVHD. Moderate/severe chronic GVHD occurred in 5/22 (22.7%) evaluable patients, including 4 still on immunosuppressive therapy at 40, 28, 25 and 16 months post-transplant. Overall non-relapse mortality (NRM) was 14.8% and related to acute GVHD. However, the number of cases conducting to stop the protocol was not reached.Conclusion: PTCY as a sole GVHD prophylaxis is here demonstrated as possible and relatively safe for adults receiving a matched PBSC Baltimore-based RIC allograft. The very good survivals reported here may be related to a strong GVL effect associated with the high incidence of acute GVHD. However, because of this high incidence and the fact that NRM was related to GVHD after this first analysis, we have now made an amendment to test the addition to PTCY of one day of anti-thymoglobulin (ATG) 2.5 mg/kg on day-2 for the next 32 patients to be included. This second cohort receiving PTCY+ATG as a sole prophylaxis is ongoing. DisclosuresMoreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria.

Post-Transplant Cyclophosphamide Versus Tacrolimus and Methotrexate to Prevent Graft-Versus-Host Disease in Recipients of Matched Donor Transplantation: Comparison of Sequential Cohorts in a Prospective Trial

Post-Transplant Cyclophosphamide Versus Tacrolimus and Methotrexate to Prevent Graft-Versus-Host Disease in Recipients of Matched Donor Transplantation: Comparison of Sequential Cohorts in a Prospective Trial

Impact of donor telomere length on survival in patients undergoing matched sibling donor transplantation for aplastic anaemia.

Although telomere shortening is seen frequently in patients with aplastic anaemia (AA), there are no data on its association in matched sibling donor (MSD) transplants. We evaluated the effect of pre-transplant telomere length of patients and donors, measured by quantitative real-time polymerase chain reaction in 163 recipients undergoing MSD transplants. The median age of patients and donors was 24 and 26years, respectively. Fludarabine and cyclophosphamide was the main conditioning regimen used and all received peripheral blood stem cell grafts. Engraftment occurred in 89% with graft failure (primary and secondary) in 6%. Acute and chronic graft-versus-host disease (GVHD) occurred in 28% and 24%, respectively. At a median follow-up of 37months, 117 patients (72%) were alive. All patients and donors were divided into short and long telomere length based on their median and quartile values. Patient telomere length was not associated with severity of AA, neutrophil recovery, graft failure, acute GVHD or chronic GVHD. Longer donor telomere length was associated with better overall survival [hazard ratio (HR)=0·2, P=0·006] but did not influence neutrophil recovery, graft failure, acute or chronic GVHD. The five-year overall survival was significantly better (94·9±3·5% vs 65·4±4·3%, P=0·002) for donors with long (highest quartile, DTL-HQ) versus short (lower three quartiles, DTL-LQ) telomeres, respectively. On multivariate analysis, longer donor telomere length, recipient age and acute GVHD continued to remain significant. This is the first study demonstrating an association of donor telomere length on overall survival following MSD transplant for AA but it needs to be confirmed in larger studies.

GRAFT VERSUS HOST DISEASE IN AUTOLOGOUS STEM CELL TRANSPLANT: AN UNCOMMON ENTITY

Identify in literature the graft versus host disease (GVHD) incidence after autologous hematopoietic stem cell transplantation (HSCT). We searched the PubMed database using a broad search strategy to identify studies related to GVHD complication after autologous stem cell transplant. The primary search was conducted using the terms: “GVHD in autologous transplant”, and publication date less than 5 years. 91 free full articles were identified, but 7 were better related to the purpose of the study. Two articles present cases of gastrointestinal tract (GIT) GVHD in recipients of autologous HSCT. Two patients with multiple myeloma had GVHD and the clinical and endoscopic presentations were distinct. Another patient developed severe acute GVHD 93 days post autologous HSCT for Hodgkin's lymphoma. PET and CT findings included characteristic patterns of bowel inflammation with bowel wall thickening, mural stratification, and enhancement with high FDG-uptake of the involved regions, as well as typical extra intestinal findings such as ascites, engorgement of the vasa recti and stranding of the mesenteric fat. A case report of membranous nephropathy succeeding autologous HSCT described that this is a rarely entity (3% post-autologous vs . 97% post-allogeneic HSCT). In autologous HSCT populations, there have been reports of associated glomerular disease, because of any type of immune dysregulation. Based on literature, 6% of all patients with glomerulonephritis after HCT had received Autologous transplants. And the last case report presents a 4-year-old girl with metastatic neuroblastoma who spontaneously developed AGVHD after autologous HSCT. One article said the risk of GVHD in an autologous transplant is zero and the last one related the skin cancer with the delayed immune recovery and persistent immunodeficiency in GVHD. GVHD following stem cell transplantation (SCT) is a common complication in patients that have undergone allogenic SCT but rare in recipients of autologous SCT. With the emergence of autologous HSCT, GVHD and its complications were expected to be eliminated. However, autologous GVHD has been described in some patients, and your prophylaxis mainly consists of post-transplant administration of immunosuppressive drugs and may impair the post-transplant immunologic reconstitution. After the sixth month, immune recovery occurs progressively towards complete recovery, but GVHD may develop. In chronic case, patients with only liver and skin involvement have a better prognosis. Patients with extensive involvement of multiple organs the prognosis may be poor. Recent studies have indicated that two major factors are necessary for the induction of autologous GVHD: the first factor was a disruption of thymic-dependent immune reconstitution and the second one was a failure to reestablish peripheral self-tolerance. On another hand, autologous GVHD has been thought of as an autoimmune syndrome and a milder form of GVHD than its counterpart in allogeneic transplantation, the presence of autoantibodies in relation to the HSCT provides evidence for the involvement of the B cell. The difficulty of finding articles related to the study shows GVHD in autologous HSCT is an uncommon entity, but although this fact, these cases are important to further the understanding of the various presentation of this manifestation and be awake to the possibilities of differential diagnoses.

MIDOSTAURIN ADDED TO CYTOSINE ARABINOSIDE PLUS IDARUBICIN (“7+3”) IN NEWLY DIAGNOSED FLT3-MUTATED ACUTE MYELOID LEUKEMIA

The combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia (AML) for more than four decades. Fetal liver tyrosine kinase 3 (FLT3) mutations are among the most frequently found mutations in newly diagnosed AML. According to the results of RATIFY trial, midostaurin was approved for use together with intensive chemotherapy (cytarabine plus daunorubicin). Recently, idarubicin has been more frequently favored over daunorubicin. Report the outcome of patients with AML and FLT3 mutated treated with a combination of cytosine arabinoside plus anthracycline (“7+3”regimen) and midostaurin. Herein, we retrospectively analyzed the treatment outcome of three patients with newly diagnosed AML and confirmed FLT3-ITD were eligible. The treatment consisted induction with “7+3”regimen and midostaurin (administered at a dose of 50 mg orally twice daily on days 8 through 21). All were male with age between 21 and 38 years old. A normal karyotype was found in all cases. Patients received cytarabine, idarubicin and midostaurin for induction and all experienced febrile neutropenia and two necessitated preemptive liposomal amphotericin B. One patient developed neutropenic enterocolitis. A second course of induction chemotherapy was administered to 2 patients. Relapse was observed in 1 patient (after Allo-HCT). One patient died after allo-HCT due to severe acute GVHD and one patient is alive in CR1. We showed that young patients, who had AML and a FLT3-ITD mutation, can be treated with the combination of cytarabine, idarubicin and midostaurin. The RATIFY study (Stone et al., 2017) and the German-Austrian AML Study Group (Schlenk et al., 2019) used daunorubicin 60 mg/m2 for induction, in combination with cytarabine and midostaurin. The complete remission rates in these trials were 59.8% (CR – Ratify) and 77.9% (CR+Cri - German-Austrian trial). In contrast with these two studies, idarubicin was used for induction in 53.5% of cases and was favored over daunorubicin in a more recent trial (Sierra et al. 2020). Of note, the results of FLT3 are necessary before the day 8 of induction. Hence, some patients may have already received the all three planned doses of anthracycline (idarubicin) before the information on results of FLT3 mutation. The recent approvals of new drugs for treating AML will modify the treatment algorithm and our data indicate that the use of idarubicin in combination with cytarabine and midostaurin is feasible in young patients with FLT3-mutated AML.