Unrelated Donor Stem Cell Transplantation Research Articles

Post-Transplant Cyclophosphamide (PTCY) Results in Remarkably Low Incidence of Chronic Graft-Versus-Host Disease in Unrelated or Matched Sibling Donor Stem Cell Transplantation without Compromising Immune Reconstitution and Graft-Versus-Leukemia Effect

Post-Transplant Cyclophosphamide (PTCY) Results in Remarkably Low Incidence of Chronic Graft-Versus-Host Disease in Unrelated or Matched Sibling Donor Stem Cell Transplantation without Compromising Immune Reconstitution and Graft-Versus-Leukemia Effect

The Impact of Post-Transplant Cyclophosphamide (PTCy) with or without MMF in the Prevention of De Novo and Progressive / Relapsing Chronic Graft-Versus-Host Disease after HLA-Matched Donor Transplant

Background: We previously showed that PTCy/Tac ± MMF is associated with a significant reduction in the rate of chronic graft-versus-host disease (cGvHD) as compared to Tac/MTX after HLA-matched sibling (MSD) but not after HLA-matched unrelated (MUD) donor stem cell transplant (SCT). Notably, ATG was used with Tac/MTX in MUD but not in MSD. [ Transplant Cell Ther. 2022;28(10):695] We aimed to further elucidate the epidemiology of cGvHD with the use of PTCy/Tac by comparing the impact of Tac/MTX vs PTCy/Tac ± MMF on de novo and progressive/relapsing cGvHD. Methods: Recipients of a MSD (Tac/MTX no ATG, or PTCy-based) or MUD (Tac/MTX with ATG, or PTCy-based) peripheral blood SCT between 2015-21 at our institution were eligible. To evaluate the impact of prophylaxis on the incidence of de novo and progressive/relapsing cGvHD, we performed two separate landmark analyses starting 3 months (mo) post-SCT among patients who had not and those who had been diagnosed with acute GvHD (aGvHD) within 3 mo post-SCT, respectively. Patients who died or experienced relapse of malignancy (n=135) or were diagnosed with cGvHD within 3 mo post-SCT (n=13) were excluded from the landmark analyses. There was no difference in the rate of early death/relapse or cGvHD by prophylaxis. Results: 1040 patients met the eligibility criteria. Median follow-up in survivors was 28 mo (IQRT: 18, 50). The cumulative incidence (CumInc) of cGvHD in the Tac/MTX, PTCy/Tac without MMF, and PTC/Tac with MMF groups was 39% (34-45, reference), 20% (14-29, p<0.001) and 20% (13-30, p=0.003) respectively in MSD; and 23% (18-30, reference), 17% (12-26; p=0.2), and 19% (14-26; p=0.6) respectively in MUD. Consistent with our previous findings, within the PTCy/Tac group, MMF was not associated with the overall rate of cGvHD in MSD (HR=1.2, 95% CI 0.6-2.1, p=0.6) or MUD (HR=1.3, 95% CI 0.7-2.2, p=0.4). However, in the current study, stratified analyses performed to evaluate the impact of prophylaxis on the risk of de novo vs progressive/relapsing cGvHD revealed a potential role for MMF in the development of de novo cGvHD. Subsequent results are presented separately for the de novo and progressive/relapsing cGvHD risk cohorts (Table). The de novo cGvHD risk cohort included patients (N=442) who had not been diagnosed with aGvHD within 3 mo post-SCT. AML / MDS (60%) and CML / MPD (16%) were the most common diagnoses. 124 cases of cGvHD were diagnosed 3 -36 mo post-SCT with a CumInc of32% (27-37). In multivariate analysis (MVA), compared to Tac/MTX, the use of PTCy/Tac without MMF (HR=0.3, 95% CI 0.2-0.6, p<0.001) was associated with a significant reduction in the incidence of cGvHD. Such reduction was not observed (Figure) with PTCy/Tac with MMF (HR vs Tac/MTX=1.0, 95% CI 0.6-1.5, p=0.9). Additional independent predictors were myeloablative conditioning (HR=1.9, 95% CI 1.3-2.9, p=0.001) and MSD (HR=1.5, 95% CI 1.2-2.6, p=0.003). Notably, progression-free survival (PFS) was similar in PTCy/Tac/MMF (univariate HR: 0.8, 95% CI 0.5-1.4, p=0.4) vs PTCy/Tac. The progressive/relapsing cGvHD risk cohort included patients (N=450) who had been diagnosed with grade 1 (27%), 2 (59%) or 3-4 (14%) aGvHD within 3 mo post-SCT. AML / MDS (64%) and CML / MPD (14%) were the most common diagnoses. 109 cases of cGvHD were diagnosed 3 -36 mo post-SCT with a CumInc of 28% (24-33). In MVA analysis, the impact of prophylaxis differed by donor type. As compared with Tac/MTX, PTCy/Tac ± MMF was associated with significantly lower rate of progressive/relapsing cGVHD in MSD (HR=0.2, 95% CI 0.1-0.4, p<0.001) but not in MUD (HR=0.6, 95% CI 0.4-1.1, p=0.09). This may be related to the use of ATG with Tac/MTX in MUD which was not used in MSD. HCT-CI ≥3 was the only other significant predictor of cGvHD (HR=0.6, 0.4-0.9, p=0.03). PFS was similar in PTCy/Tac ± MMF vs Tac/MTX in MSD (univariate HR: 0.8, 95% CI 0.5-1.3, p=0.3) or MUD (univariate HR: 0.8, 95% CI 0.5-1.2, p=0.3). Conclusions: PTCy/Tac ± MMF prophylaxis slows the development of progressive/relapsing cGvHD in MSD vs (Tac/MTX no ATG), but not in MUD (vs Tac/MTX with ATG). The addition of MMF to PTCy/Tac (vs PTCy/Tac) has no significant impact on the risk of progressive/relapsing cGVHD in MSD or MUD; but is associated with a higher risk of de novo cGvHD in MSD and MUD. Our data suggest that multi-center studies are warranted to determine whether MMF should be excluded from cGvHD prevention regimens in the HLA-matched donor setting with PTCy- based GvHD prophylaxis.

5 years DKMS Chile: approach, results and impact of the first unrelated stem cell donor center in Chile.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed worldwide to treat blood cancer and other life-threatening blood disorders. As successful transplantation requires an HLA-compatible donor, unrelated donor centers and registries have been established worldwide to identify donors for patients without a family match. Ethnic minorities are underrepresented in large donor registries. Matching probabilities are higher when donors and patients share the same ethnic background, making it desirable to increase the diversity of the global donor pool by recruiting donors in new regions. Here, we report the establishment and the first 5 years of operation of the first unrelated stem cell donor center in Chile, a high-income country in South America with a population of over 19 million. We used online and in-person donor recruitment practices through patient appeals and donor drives in companies, universities, the armed forces, and public services. After confirmatory typing donors were subjected to medical work-up and cleared for donation. We recruited almost 170,000 donors in 5 years. There were 1,488 requests received for confirmatory typing and donor availability checks, of which 333 resulted in medical work-up, leading to 194 stem cell collections. Products were shipped to Chile (48.5%) and abroad. Even when the COVID-19 pandemic challenged our activities, the number of donors recruited and shipped stem cell products remained steady. In Chile there was an almost 8-fold increase in unrelated donor transplantation activity from 16 procedures in 2016-2018 to 124 procedures in 2019-2021, mainly for pediatric patients following the center's establishment. We estimate that 49.6% of Chilean patients would find at least one matched unrelated donor in the global DKMS donor pool. Establishing a DKMS donor center in Chile has significantly increased donor availability for Chilean patients and contributed to an increase of unrelated donor stem cell transplant activity.

FRI100 Lipoprotein X In Graft Vs. Host Disease Affecting Liver

Abstract Disclosure: D. Vedamurthy: None. C. Vitali: None. M. Cuchel: None. D. Soffer: None. D. Rader: None. Introduction: Lipoprotein-X (LpX) is an abnormal lipoprotein rich in phospholipid and unesterified cholesterol (UC) found in patients with cholestatic liver disease, lecithin-cholesterol acyl transferase (LCAT) deficiency, and after lipid emulsion infusion. LpX has been detected in patients with graft-versus-host disease (GVHD) of the liver. Cholestasis leads to the accumulation of bile salts and UC in the circulation, promoting the formation of LpX. This condition is often not well-recognized, partly because the detection of LpX is technically challenging and requires specialized laboratory assays. Case Description: A 66-year lady with acute myeloblastic leukemia (AML) underwent an allogeneic matched unrelated donor stem cell transplant (SCT) which was complicated by graft-versus-host disease (GVHD) affecting the liver, eyes, lungs, and skin. Past medical history includes hypertension. Family history was significant for coronary artery disease in the mother. She is a reformed smoker. Her post-transplant course was highly complicated with infections, GVHD affecting the liver, eyes, lungs, and skin, and vascular events including myocardial infarction and stroke. Laboratory testing revealed abnormal liver enzymes (ALT=268, AST=173, ALKP =402 U/L), and a markedly abnormal lipid profile (TC=500, Non-HDL-C=358, TG= 345 mg/dL). Her thyroid panel and viscosity were normal, but apolipoprotein B levels were discordantly low (77mg/dL). The ratio of ApoB: Non-HDL cholesterol was abnormally low (0.215). She was started on ezetimibe, evolocumab, and omega-3 fatty acids by her neurovascular team for cardiovascular risk reduction. A physical exam revealed a thin, frail woman with mild oral and nail GVHD changes. The rest of the exam was notable for the abdomen showing chronic patchy hyperpigmentation with sclerodermatous changes anteriorly and posteriorly. She had no significant focal neurologic deficits. Her lipid levels were improved with therapy, but TC, non-HDL-C, UC, and triglycerides levels were still elevated (TC=353, non-HDL=258, UC=163, TG=414 mg/dL), UC: TC ratio was high (0.46). FPLC separation of TRL-depleted plasma revealed the presence of LpX. LpX is not very atherogenic, and we recommended continuing current medical therapy as the serum viscosity was within normal limits. Conclusion: The presence of LpX should be suspected in the setting of GVHD accompanied by markedly elevated TC. LpX may cause hyperviscosity, which can induce end-organ ischemia. While the direct assessment of LpX is challenging and requires specialized techniques, ApoB and non-HDL-C levels are available in most clinical laboratories, and a very low ApoB: Non-HDL-C ratio in GVHD patients may indicate the presence of LpX. The treatment goal is to resolve the underlying causes of cholestasis. If hyperviscosity is present, Lp-X can be acutely treated by plasma exchange or lipoprotein apheresis. Presentation: Friday, June 16, 2023

CD3+TCRαβ/CD19+-Depleted Mismatched Family or Unrelated Donor Salvage Stem Cell Transplantation for Graft Dysfunction in Inborn Errors of Immunity

A minority of children experience significant graft dysfunction after an allogeneic hematopoietic stem cell transplant (HSCT) for inborn errors of immunity (IEI). The optimal approach to salvage HSCT is unclear with respect to conditioning regimen and stem cell source. This single-centre retrospective case series reports the outcomes of salvage CD3+TCRαβ/CD19 depleted mismatched family or unrelated donor stem cell transplantation (TCRαβ-SCT) between 2013 - 2022 for graft dysfunction in 12 children with IEI. Outcomes of interest were overall survival (OS), event free survival (EFS), graft-versus-host disease (GvHD)-free and event-free survival (GEFS), toxicities, GvHD, viremia and long-term graft function. A retrospective audit of patients who underwent second CD3+TCRαβ/CD19 depleted mismatched donor graft using Treosulfan-based reduced toxicity myeloablative conditioning. Median age at first HSCT was 8.76 months (range, 2.5 months - 6 years) and at second TCRαβ-SCT was 3.6 years (1.2 - 11 years). Median interval between first and second HSCT was 1.7 years (3 months - 9 years). The primary diagnoses were: severe combined immunodeficiency (SCID) (n=5) and non-SCID IEI (n=7). The indications for second HSCT were: primary aplasia (n=1), secondary autologous reconstitution (n=6), refractory aGVHD (n=3) and secondary leukemia (n=1). Donors were either haploidentical parental donors (n=10) or mismatched unrelated donors (n=2). All received TCRαβ/CD19-depleted-PBSC with a median CD34+ cell dose of 9.3 × 106/kg (2.8-32.3 × 106/kg) and a median TCRαβ+ cell dose of 4 × 104/kg (1.3-19.2 × 104/kg). All engrafted with median days to neutrophil and platelet recovery of 15 (12-24) and 12 (9-19). One developed secondary aplasia and one had secondary autologous reconstitution, but both underwent a successful third HSCT. Four (33%) had grade II aGvHD and none had grade III-IV aGvHD. None had cGvHD but one developed extensive cutaneous cGVHD after third HSCT using PBSC and ATG. Nine (75%) were noted to have at least one episode of blood viremia with HHV6 (n=6, 50%), adenovirus (n=6, 50%), EBV (n=3, 25%) or CMV (n=3; 25%). Median duration of follow-up was 2.3 years (range: 0.5 - 10 years) and the 2-year OS, EFS and GEFS were 100% (95% confidence interval, 0-100%), 73% (37-90%) and 73% (37%-90%) respectively. TCRαβ-SCT from mismatched family or unrelated donors, using a chemotherapy only regimen, is a safe alternative donor salvage transplant strategy for second HSCT in patients without a suitably matched donor.

National experience with adenosine deaminase deficiency related SCID in Polish children.

Deficiency of adenosine deaminase (ADA) manifests as severe combined immunodeficiency (SCID), caused by accumulation of toxic purine degradation by-products. Untreated patients develop immune and non-immune symptoms with fatal clinical course. According to ESID and EBMT recommendations enzyme replacement therapy (ERT) should be implemented as soon as possible to stabilize the patient's general condition, normalize transaminases, treat pulmonary proteinosis, bone dysplasia, and protect from neurological damage. Hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) is a treatment of choice. In absence of such donor, gene therapy (GT) should be considered. HSCT from a matched unrelated donor (MUD) and haploidentical hematopoietic stem cell transplantation (hHSCT) are associated with worse prognosis. We retrospectively evaluated the clinical course and results of biochemical, immunological and genetic tests of 7 patients diagnosed in Poland with ADA deficiency since 2010 to 2022. All patients demonstrated lymphopenia affecting of T, B and NK cells. Diagnosis was made on the basis of ADA activity in red blood cells and/or genetic testing. Patients manifested with various non-immunological symptoms including: lung proteinosis, skeletal dysplasia, liver dysfunction, atypical hemolytic-uremic syndrome, and psychomotor development disorders. Five patients underwent successful HSCT: 3 patients from matched unrelated donor, 2 from matched sibling donor, and 1 haploidentical from a parental donor. In 4 patients HSCT was preceded by enzyme therapy (lasting from 2 to 5 months). One patient with multiple organ failure died shortly after admission, before the diagnosis was confirmed. None of the patients had undergone gene therapy. It is important to diagnose ADA SCID as early as possible, before irreversible multi-organ failure occurs. In Poland HSCT are performed according to international immunological societies recommendations, while ERT and GT are less accessible. Implementation of Newborn Screening (NBS) for SCID in Poland could enable recognition of SCID, including ADA-SCID.

Immunotherapy with CD25/CD71-allodepleted T cells to improve T-cell reconstitution after matched unrelated donor hematopoietic stem cell transplant: a randomized trial

Background aimsDelayed immune reconstitution is a major challenge after matched unrelated donor (MUD) stem cell transplant (SCT). In this randomized phase 2 multi-center trial, Adoptive Immunotherapy with CD25/71 allodepleted donor T cells to improve immunity after unrelated donor stem cell transplant (NCT01827579), the authors tested whether allodepleted donor T cells (ADTs) can safely be used to improve immune reconstitution after alemtuzumab-based MUD SCT for hematological malignancies. MethodsPatients received standard of care or up to three escalating doses of ADTs generated through CD25+/CD71+ immunomagnetic depletion. The primary endpoint of the study was circulating CD3+ T-cell count at 4 months post-SCT. Twenty-one patients were treated, 13 in the ADT arm and eight in the control arm. ResultsThe authors observed a trend toward improved CD3+ T-cell count at 4 months in the ADT arm versus the control arm (230/µL versus 145/µL, P = 0.18), and three ADT patients achieved normal CD3+ T-cell count at 4 months (>700/µL). The rates of significant graft-versus-host disease (GVHD) were comparable in both cohorts, with grade ≥2 acute GVHD in seven of 13 and four of eight patients and chronic GVHD in three of 13 and three of eight patients in the ADT and control arms, respectively. ConclusionsThese data suggest that adoptive transfer of ADTs is safe, but that in the MUD setting the benefit in terms of T-cell reconstitution is limited. This approach may be of more use in the context of more rigorous T-cell depletion.

TCRαβ-Depleted Haploidentical Grafts Are a Safe Alternative to HLA-Matched Unrelated Donor Stem Cell Transplants for Infants with Severe Combined Immunodeficiency

Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8–16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52–99%) for TCRαβ-HaploSCT, 80% (41–98%) for MFD, 87% (36–98%) for MUD, and 89% (43–98%) for CB (p = 0.89). Cumulative incidence of grade II–IV acute graft-versus-host disease was 11% (2–79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7–100%) after MUD, and 11% (2–79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0–100%) versus unconditioned transplant (median 3%, 0–9%) (p < 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p < 0.001). TCRαβ-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.

Adolescent and young adult (AYA) versus pediatric patients with acute leukemia have a significantly increased risk of acute GVHD following unrelated donor (URD) stem cell transplantation (SCT): the Children's Oncology Group experience.

Adolescent and young adult (AYA) patients with acute leukemia (AL) have inferior outcomes in comparison to younger patients, and are more likely to develop acute and chronic GVHD than younger children following HLA matched sibling donor stem cell transplant (SCT). We compared the incidence of grade II-IV acute GVHD, chronic GVHD, and survival in AYA (age 13-21 years) to younger children (age 2-12 years) who received an unrelated donor SCT for acute leukemia on Children's Oncology Group trials between 2004-2017. One hundred and eighty-eight children and young adults ages 2-21 years underwent URD SCT. Sixty-three percent were aged 2-12 and 37% were age 13-21. Older age was a risk factor for grade II-IV acute GVHD in multivariate analysis with a hazard ratio (HR) of 1.95 [95% confidence interval (CI) 1.23-3.10], but not for chronic GVHD, HR 1.25 [95% CI 0.57-2.71]. Younger patients relapsed more often (34.5 ± 4.4% vs. 22.8 ± 4.0%, p = 0.032), but their Event-Free Survival (42.6 ± 4.7% vs. 51.8 ± 6.1%, p = 0.18) and Overall Survival at 5 years (48.5 ± 4.9% vs. 51.5 ± 6.4%, p = 0.56) were not different than AYA patients. AYA patients who receive an URD SCT for acute leukemia are significantly more likely to develop grade II-IV acute GVHD, though survival is similar.

Post-Transplant Cyclophosphamide, Abatacept, and Short Course of Tacrolimus Combination (CAST) Is Safe and Seems Highly Effective in Preventing Graft-Versus-Host Disease Following Haploidentical Peripheral Blood Stem Cell Transplantation

The introduction of post-transplant cyclophosphamide (PTCy) has circumvented the need for T-cell depletion following haploidentical stem cell transplantation (SCT). By expanding the donor pool for patients from certain ethnic minorities, this has addressed to some degree an important health care disparity issue in SCT. However, a recent registry study showed increased incidence GvHD and inferior outcomes in patients receiving haploidentical SCT with PTCy, tacrolimus and mycophenolate mofetil for GvHD prevention as opposed to matched unrelated donor SCT with PTCy-based GvHD prevention. Seeking to improve the results of GvHD prevention in the setting of haploidentical SCT, we examined a combination of PTCy, abatacept and a short course of tacrolimus (CAST). Abatacept is a recombinant soluble fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) fused to the Fc region of IgG1. Abatacept blocks CD28-CD80I86 axis and prevents T-cell co-stimulation. In early studies, abatacept has shown promising results when added to methotrexate and tacrolimus in matched and mismatched donor SCT. We initiated a phase Ib-II clinical trial for patients with hematological malignancies undergoing haploidentical SCT. Patients received G-CSF mobilized peripheral blood grafts from related haploidentical donors. GvHD prevention consisted of PTCy 50mg/kg IV on day +3 and +4 with forced hydration, abatacept 10mg/kg IV on day +5, +14 and +28 and tacrolimus. Tacrolimus was started on day +5 at 0.02mg/kg/day by continuous IV and adjusted thereafter to maintain a trough level of 5-12ng/mL. Tacrolimus taper was planned to begin on day +60 and complete by day +90 in the absence of GvHD. All patients received standard supportive care including levofloxacin until neutrophil engraftment, posaconazole until day +75, acyclovir for 1 year and, if CMV positive by serology, letermovir until day +100. Pneumocystis Jiroveci prophylaxis was started after neutrophil engraftment and continued until 6 months post-transplant. G-CSF was administered routinely until neutrophil engraftment.Since September 2020, 19 patients were enrolled. Three patients are too early in their post-transplant course and were excluded from this analysis. Patients' characteristics are summarized in the table. All but 2 patients received cryopreserved products. Median times to ANC and platelet engraftment were 18.5 days (14-30) and 28.5 (16-61). All 16 patients achieved full whole blood donor chimerism by day +30. There was no secondary graft failure. With a median follow-up was 149.5 days (41-308) with 10 patients having >120 days and 8 >180 days of follow-up, 4 patients developed skin acute GvHD (all grade I). No patient developed grade II-IV acute GvHD. Two patients developed skin chronic GvHD (limited, both moderate). Both cases were diagnosed following COVID-19 vaccination. Fifteen patients completed tacrolimus taper by day +90. Two patients received systemic steroids, one for treatment of cGvHD. The remaining patients required no further immunosuppressive therapy beyond day +90. CMV activation rate was 25%. One patient had EBV reactivation and required preemptive therapy with 2 weekly rituximab doses. There were no cases of adenovirus, HHV-6 virus or BK virus reactivation. Four patients developed renal insufficiency (3 in the setting of acute sepsis and 1 with thrombotic microangiopathy, which resolved after tapering off tacrolimus. One patient with adult T-cell leukemia/lymphoma relapsed and died. All other patients are alive and well.In summary, our preliminary results suggest that CAST with shortened course of tacrolimus is feasible and seems to offer very promising outcomes with low rates of acute GvHD. The study is accruing actively and the results of a larger cohort with longer follow-up will be presented at the meeting. If confirmed, by improving the outcomes of haploidentical SCT, this regimen may further address a health care disparity issue, offering almost every patient in need of allogeneic SCT an alternative donor option with equal outcomes. [Display omitted] DisclosuresAl-Homsi: Daichii Sanyko: Consultancy; Celyad: Other: Advisory Board. Abdul-Hay: Abbvie: Consultancy; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Takeda: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:Abatacept - off label use as GvHD prevention Cyclophosphamide - off label use as GvHD prevention

AUTOIMMUNE & INFLAMMATORY NMD: EP.15 Severe Guillain-Barre syndrome associated with nelarabine with good prognosis

Nelarabine is a purine nucleoside analogue which has T-cell specificity and is highly active in relapsed and refractory T-cell lymphoma. Neurotoxicity occurs in approximately 20% of patients treated with nelarabine and is predominantly peripheral neuropathy. Reports of recovery are variable. We report a severe nelarabine related neuropathy with quadriparesis and respiratory failure and excellent recovery. Diagnosis of stage III biphenotypic lymphoblastic lymphoma was made at 11 years of age in a previously healthy male who presented with supraclavicular lymphadenopathy. He was treated according to UKALL 2011 schedule B. Two months later, as there had been no response to treatment, he received nelarabine. Within two weeks he developed limb weakness and sensory symptoms, weakness progressed rapidly to quadriparesis and respiratory failure. MRI scan of spine showed diffusely thickened nerve roots with contrast enhancement, CSF was acellular with protein 3.27 g/L, initial nerve conduction study showed attenuated motor responses and absent F-waves. He had five cycles of plasmapheresis and IVIG. He required ventilation for 50 days. Muscle weakness slowly improved. He received a matched unrelated donor stem cell transplant (SCT) 6 months after his neuropathy onset. At review, 21 months post-SCT, he remains in remission from his lymphoma, has only mild residual ankle dorsiflexion weakness and no functional impairment. This case of neuropathy temporally associated with nelarabine administration fulfills diagnostic criteria for GBS and raises the possibility that the neuropathy was immune-mediated rather than due to direct neurotoxicity. GBS like presentation of neuropathy following nelarabine administration may have a better prognosis with implications for continuation of life-sustaining treatment and treatment of the malignancy.

Interpretation of TEG Studies in Management of a Severe Glanzmann Thrombasthenia Patient

Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder which can result in mild to severe mucocutaneous bleeding. Patients with GT usually have normal platelet count, no clumping noted on peripheral blood smear and distinctly abnormal platelet dysfunction studies. NovoSeven®RT has been approved for treatment of this disease, however some patients have ongoing bleeding in spite of treatment with NovoSeven®RT and platelet transfusions. To add to the complexity of the treatment plan, sometimes the bleeding is retropharyngeal and children swallow blood making a timely assessment even more difficult. This case report summarizes additional tools used to control nasal bleeding and the use of TEG (Haemonetics Corporation) to assess therapeutic interventions.Our patient is a 6 year old female with GT who has behavioral issues and has lived in numerous foster homes. Severe nasal and retropharyngeal bleeds have resulted in repeated emergent transfusions. Part of the difficulty in her management has been her ability to swallow large amounts of blood without notifying her caregiver. She has had multiple blood transfusions and has had an allergic response to platelet plasma requiring washed platelet products with premedication (Benadryl/Solumedrol/Tylenol). Consideration for unrelated HLA donor stem cell transplant had been explored, however our patient's behavioral issues made her less likely to tolerate the transplant process. Her current treatment plan was developed to address local control, systemic control and to attempt to develop a means of assessing therapeutic interventions.Both nares and her retropharyngeal region were her primary bleeding sites. ENT evaluation identified numerous telangiectasias (AFP= 0.09). Repeated surveillance and cauterization followed by estrogen cream applied to the nasal mucousa twice daily greatly diminished the number of telangiectasias. Amicar® nasal spray (compounded as 10% nasal spray, used as 0.1 mL spray in each nostril), Zyrtec® nasal spray, nightly use of humidifier, normal saline nose gel, and cellulose gauze are medications used for local prevention and have been effective in preventing minor mouth and nose bleeds from becoming major bleeds.Systemic prevention regimen consisted of NovoSeven®RT prophylaxis BID 2 mg (90 mcg/kg/dose), Amicar® BID and behavioral support to avoid causing self induced trauma/bleeding. Since starting this regimen, all of her bleeds have been related to trauma or digital manipulation. NovoSeven®RT administered every 2 hours in addition to Amicar® TID and 1 to 2 units of washed pheresis platelets were utilized for treatment of active bleeding.Because of 2 prolonged bleeding episodes following transfusion with a single washed pheresis platelet unit, we attempted to find testing to assist us with evaluation.TEG Studies and InterpretationI. Table 1With a single dose of NovoSeven®RT our patient's RTEG value (time to produce thrombin) improved. However, the rate of clot development/propagation only improved to varying degrees (ANGLE TEG). The overall clot strength (MATEG) remained virtually unchanged.II. Table 2With a single washed pheresis unit of platelets, RTEG normalized and MATEG as well as the rate of propagation of the clot improved, however these values were not normal.With more than one washed pheresis platelet unit and NovoSeven®RT, TEG values almost normalized or returned to normal range, including clot strength represented by MATEG. These findings suggested the greater number of normal platelets transfused increased the likelihood of normal thrombin generation and clot formation. The loss of platelet product from washing likely resulted in decreased platelet numbers, perhaps decreasing the effectiveness of a single washed pheresis unit.We have utilized these findings to assist with the treatment of severe bleeds and to determine if more washed platelets would be beneficial when clinically the extent of bleeding cannot be determined in a short amount of time (i.e retropharyngeal bleeding). TEG is especially suited for rapid assessment and frequently used in Adult Trauma Centers. Treatment of a pediatric patient with significant bleeding and behavioral concerns requires a tool box of supportive measures. With local, systemic measures and use of TEG, we have been able to improve the safety of our GT patient, with decreases in major bleeds over the last year. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Thiotepa-Busulfan-Fludarabine in Comparison to Busulfan-Cyclophosphamide As Myeloablative Conditioning Regimen Pre Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background. Busulfan plus Cyclophosphamide (BuCy) is the traditional myeloablative conditioning (MAC) regimen pre allogeneic stem cell transplantation (SCT) for acute myelogenous leukemia (AML). The Thiotepa, Busulfan, Fludarabine (TBF) protocol was initially developed for cord blood SCT and subsequently employed in haploidentical SCT; however, there is limited data assessing the TBF regimen in SCT from sibling (MSD) and unrelated donor (URD) for AML and no comparison between the two preparative protocols has been performed.Patients and methods. We analyzed transplantation outcomes of 2523 adult patients (pts) with AML in remission (CR1, CR2+) aged 18-50 years that underwent a first SCT from MSD or URD between 2007 and 2015 and reported to the ALWP of the EBMT. One hundred and three patients received TBF and 2370 pts received BuCy. Pts who received oral busulfan, manipulated grafts, or transplant from <=8/10 HLA-matched donor were excluded. All pts received MAC regimen (defined by Busulfan dose>=9.6 mg/kg). As compared to BuCy, the TBF group included significantly older pts, who were transplanted more recently, had longer interval from diagnosis to transplant, and were more likely to have received BM as stem cell source and URD as donor type. In order to minimize the bias due to differences in pts characteristics, a 1:3 pair-matched analysis was performed. One hundred and forty-six pts receiving TBF were compared with 438 pts receiving BuCy; matching factors included age, year of SCT, disease status at SCT, interval from diagnosis to SCT, donor type, CMV serostatus of both the donor and patient, stem cell source, GVHD prophylaxis and use of anti-thymocyte globulin.Results. With a median follow-up of 22 months, incidence of grade II-IV and III-IV aGVHD after TBF vs BuCy was 29% vs 23% (p=0.23) and 15% vs 8% (p=0.04), respectively. The 5-year cumulative incidence of cGVHD and severe cGVHD was 36% vs 43% (p=0.66) and 16% vs 22% (p=0.72) for TBF vs BuCy, respectively. The 1-year and 5-year non-relapse mortality (NRM) rates were 10% and 22% for TBF vs 9% and 13% for BuCy, respectively (p=0.36). The 1-year and 5-year relapse incidence (RI) rates were 17% and 25% for TBF vs 21% and 37% for BuCy, respectively (p=0.32). No significant difference was observed in leukemia-free survival (LFS), being the 1-year and 5-year LFS rates 73% and 53% for TBF vs 70% and 50% for BuCy, respectively (p=0.56). Overall survival (OS) was also similar, being 80% and 54% for TBF vs 79% and 59% for BuCy, respectively (p=0.88). The composite endpoint graft-vs-host disease-free, relapse-free survival (GRFS) at 5 years was 48% for TBF and 40% for BuCy (p=0.48). Notably, when the analysis was restricted to pts in CR1, a significant difference in RI rate was observed (1-year and 5-year RI: 10% and 18% for TBF vs 20% and 38% for BuCy, respectively, p=0.003) leading to a trend for better LFS for TBF as compared to BuCy (1-year and 5-year LFS: 78% and 57% for TBF vs 72% and 50% for BuCy, respectively, p=0.07), with no difference in OS. When examining separately pts receiving SCT from MSD or URD, no significant difference was observed between TBF and BuCy regimens in terms of transplant outcome. In multivariate analysis, TBF was associated with lower RI compared to BuCy (HR 0.6, p=0.02), while no difference was observed in terms of NRM, LFS, OS and GRFS (HR 0.8, p=0.12 for GRFS). TBF was also associated with lower incidence of cGVHD (HR 0.7, p=0.04) and a trend for lower incidence of severe cGVHD (HR 0.6, p=0.1); on the contrary we observed a trend for higher incidence of grade III-IV aGVHD following TBF as compared to BuCy (HR 1.79, p=0.06).Conclusions. These results suggest that TBF is a valid myeloablative conditioning pre MSD or URD SCT for AML pts < 50 years of age and in remission, with similar transplantation outcome as compared to the traditional BuCy preparative regimen. These data may serve as the scientific background for a well designed randomized two arm study comparing TBF to BuCy as MAC pre SCT in AML pts below the age of 50 years in CR. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau.

283 - Comparison of Haploidentical Donor Versus 7/8 Mismatch Unrelated Donor Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome

283 - Comparison of Haploidentical Donor Versus 7/8 Mismatch Unrelated Donor Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome

341 - Comparison of Post-Transplant Cyclophosphamide and Rabbit Anti-Thymocyte Globulin in 7/8 HLA-Mismatched Unrelated Donor Stem Cell Transplantation for AML and MDS

341 - Comparison of Post-Transplant Cyclophosphamide and Rabbit Anti-Thymocyte Globulin in 7/8 HLA-Mismatched Unrelated Donor Stem Cell Transplantation for AML and MDS

Paediatric severe aplastic anaemia treatment: where to start?

Paediatric severe aplastic anaemia treatment: where to start?

Abatacept is effective as GVHD prophylaxis in unrelated donor stem cell transplantation for children with severe sickle cell disease

AbstractWe report results of a phase 1 multicenter stem cell transplantation (SCT) trial from HLA-matched (n = 7) or one-antigen–mismatched (n = 7) unrelated donors (URD) using bone marrow or cord blood as stem cell source, following reduced-intensity conditioning (RIC) in severe sickle cell disease (SCD). Conditioning included distal alemtuzumab, fludarabine, and melphalan (matched donors), with thiotepa (mismatched donors). Abatacept, a selective inhibitor of T cell costimulation, was added to tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis to offset GVHD risks, and was administered for longer duration in bone marrow recipients than in cord blood recipients because of increased incidence of chronic GVHD with bone marrow. Median age at transplant was 13 years (range, 7-21 years). The incidence of grades II to IV and grades III to IV acute GVHD at day +100 was 28.6% and 7%, respectively. One-year incidence of chronic GVHD was 57% and mild/limited in all but 1 patient who received abatacept for a longer duration. Only 1 patient developed reversible posterior encephalopathy syndrome and recovered. With a median follow-up of 1.6 years (range, 1-5.5 years), the 2-year overall and disease-free survival was 100% and 92.9%, respectively. The encouraging results from the phase 1 portion of this RIC SCT trial, despite risk factors such as older age, URD, and HLA-mismatch, support further evaluation of URD SCT in clinical trial settings. The phase 2 portion of the trial is in progress. This trial was registered atwww.clinicaltrials.govas NCT03128996.

Pediatric Patients with Severe Aplastic Anemia Treated with Combined Immunosuppressive Therapy, Eltrombopag and Eculizumab and Their Clinical Course to Stem Cell Transplant

Acquired aplastic anemia (AA) in children is a rare disorder characterized by pancytopenia and hypocellular bone marrow. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoetic stem cell (HCT) disorder characterized by complemented-mediated hemolysis, thrombosis and bone marrow failure secondary to deficiency of glycosylphosphatidylinositol-anchored proteins (GPI-AP) on hematopoetic stem cells. PNH and acquired AA are closely related; up to 50% of patients with AA have detectable PNH-clones at the time of diagnosis and small percentage of them can have clonal expansion throughout their disease course requiring close monitoring. Current standard therapy for severe aplastic anemia (SAA) patients without matched related donor (MRD) is immunosuppressive therapy (IST) regimen with anti-thymoglobulin (ATG), cyclosporine (CSA), and recent addition of eltrombopag. Eculizumab is a recombinant humanized monoclonal antibody that blocks complement protein C5 and prevents cell lysis. While it has been shown to be effective in children with PNH, concomitant treatment with IST for patients with SAA is unknown. To our knowledge, there has been no pediatric data on combined IST, eltrombopag and eculizumab treatment for children with AA with clinically significant PNH clones. Here we retrospectively reviewed three pediatric patients with SAA with PNH clones treated with IST, eltrombopag and eculizumab and their unique clinical courses. Two out of three patients had high PNH clone size and were started on eculizumab prior to IST with improvement in transfusion intervals. Of the two, one had decrease in PNH clone size after IST but the other patient's clone size continued to increase despite two courses of IST. Finally, the third patient had a minor PNH clone and was not started on eculizumab prior to IST. He remained asymptomatic for over a year until he developed symptomatic PNH with large clone size and aplastic bone marrow. His clone size continued to increase with no improvement in transfusion frequency despite being started on eculizumab. However, steroids were started based on anecdotal literature and his transfusion frequency decreased subsequently. All three patients are in the process of going through matched unrelated donor stem cell transplants. Several studies have reported the presence of a minor PNH clone at the time of AA diagnosis was associated a favorable response to IST. In this case series, the patient with the smallest PNH clone size at the time of diagnosis of SAA had the best response to IST compared to the other two patients who had larger PNH clone populations. These findings suggest that even though minor PNH population may lead to better response to IST compared to absence of the clone, the correlation between clone size and prognosis is unclear. Further study with larger sample size is needed to investigate this relationship. However, regardless of the population size, all three patients were able to prolong transfusion intervals using eculizumab without significant side effects. As the adoption of eltrombopag with standard IST is evolving with ongoing study, the efficacy of incorporating eculizumab to decrease transfusion frequency in patients with PNH-clone in addition to eltrombopag/IST regimen should be further investigated. Disclosures No relevant conflicts of interest to declare.

Outcomes of Allogeneic Stem Cell Transplantation with Individualized Dosing of Antithymocyte Globulin

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. However, relapse disease and graft-versus-host disease (GVHD) remain to be the main obstacle for a successful HCT. Thus, adequate immune suppression to minimize the risk of high-grade GVHD while not over suppression of donor immunity to allow graft versus tumor effect is crucial. Matched unrelated donor transplant has a higher rate of GVHD as compared to matched sibling donor transplant due to minor histocompatibility mismatch. Rabbit antithymocyte globulin (ATG), a polyclonal antibody produced by immunizing rabbits with human thymocytes, has been utilized as prophylaxis against GVHD. ATG dosing by weight has been the standard. Recent pharmacokinetic (PK) studies revealed that ATG levels and clearance vary significantly among patients receiving weight-based dosing of ATG. Recipient lymphocyte count before receiving ATG has been described as a modulator of both ATG PK and clinical outcomes after ATG-conditioned HCT. The Parachute-Study utilizing an individualized ATG dosing approach has shown more rapid immune reconstitution without affecting the incidence of acute GVHD and graft failure. In this study, we are comparing the outcomes of individualized dosing of ATG versus weight-based dosing. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case-control cohort study in July 2018 when individualized dosing of ATG was initiated, and continues as a historically controlled non-randomized prospective clinical study investigating individualized versus weight-based dosing of ATG. Subjects over 18 years of age who are undergoing matched unrelated donor (MUD) stem cell transplant, with myeloablative or reduced-intensity conditioning, peripheral blood or bone marrow stem cell source, for myeloid or lymphoid malignancies were included in the study. We excluded subjects with HLA mismatch or sibling donors. Individualized dosing was based on the previously validated PK model with cumulative doses varying between 2 to 10 mg/kg, based on weight, recipient lymphocyte counts before the first dose of ATG, and stem cell source, starting day -9; while the standard weight-based dosing of ATG is 4 mg/kg divided into 3 days pre-transplant. The study endpoints are to evaluate the difference between treatment groups on (1) GVHD and its severity; (2) relapse-free survival (RFS) and (3) overall survival (OS). Univariate logistic regression analysis was used to evaluate the probabilities of GVHD in both treatment arms. Multivariable analysis was done to adjust for all covariates between study arms using adjusted logistic. OS and RFS were computed using the Kaplan-Meier curves. Results: The study included 38 subjects undergoing MUD HCT for myeloid or lymphoid malignancies. Subjects included are in 2 cohorts, 19 subjects in the intervention arm using individualized targeted ATG (tATG group), and 19 subjects in the matched control arm using weight-based dosing ATG (ATG group). In a univariate unadjusted logistic regression analysis, the risk of developing GVHD is numerically higher in the ATG group than in the tATG group (OR=1.339, p=0.70). However, the proportion of acute GVHD is significantly higher in the tATG group than the ATG group (73.68% vs 31.58%, p=0.022). Also, the proportion of higher grade acute GVHD is significantly higher in the tATG group than the ATG group (31.58% vs 0%, p=0.020). RFS is longer in the tATG group than the ATG group, tending statistical significance (p=0.063). However, there is no difference in OS between study arms (p=0.645). [Figures 1 and 2] In a multivariable-adjusted logistic regression, adjusting for age at HCT, diagnosis, disease status at HCT, prior lines of therapy, and stem cell source, no confounder was found to be significantly associated with GVHD. Conclusion: Individualized targeted dosing of ATG (tATG), based on weight, recipient lymphocyte counts and stem cell source, increases the risk of acute GVHD when compared to standard fixed-dosing method, however, it improves RFS, implying possibly better immune reconstitution providing improved graft versus leukemia effect. Disclosures No relevant conflicts of interest to declare.

Carfilzomib combined with cyclosporine and methotrexate for the prevention of graft-versus-host disease after allogeneic stem-cell transplantation from unrelated donors

Acute graft-versus-host disease (aGVHD) is the major treatment-related complication after stem-cell transplantation (SCT) from unrelated donors. The proteasome-inhibitor bortezomib was added to GVHD prevention regimens with initial promise. However, two randomized studies failed to show efficacy. We explored the addition of carfilzomib, s second-generation proteasome inhibitor (20 mg/m2, intravenously on days +1 and +2) to cyclosporine/methotrexate backbone in 26 patients after SCT from unrelated donors. We compared outcomes to historical group of 100 patients given cyclosporine/methotrexate alone. Median follow-up was 34 months. There was no difference between the groups in engraftment or toxicities. The cumulative incidence of aGVHD grade II-IV, 6 months post transplant was 11% (95% CI, 4-32) and 39% (95% CI, 30-50), respectively (P = 0.01). The cumulative incidence of chronic GVHD, 2 years post transplant, was 49% (95% CI, 32-75) and 41% (95% CI, 33-52), respectively (P = 0.98). Three-year non-relapse mortality was 11% (95% CI, 4-33) and 18% (95% CI, 12-27, P = 0.45) while 3-year relapse rates were 8% (95% CI, 2-29) and 26% (95% CI, 18-36), respectively (P = 0.06). Three-year survival was 81% (95%CI, 66-96) and 56% (95% CI, 46-66), respectively (P = 0.05). In conclusion, carfilzomib with cyclosporine/methotrexate is safe, may reduce aGVHD, and possibly improve survival after unrelated donor SCT. These initial observations merit further study in larger comparative studies. ClinicalTrial.gov NCT01991301.