Steroid-refractory Graft-versus-host Disease Research Articles

Etanercept with extracorporeal photopheresis (ECP) for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation.

7543 Background: Acute graft versus host disease (aGVHD) is a well-described complication of allogeneic stem cell transplantation (allo-SCT). Complete response to steroids is achieved in 40-50% of cases, with steroid refractory GVHD requiring second line therapy. Currently, there is no accepted standard of care in this setting. In our study, we assessed the safety and efficacy of etanercept with ECP for steroid refractory aGVHD in a single center tertiary care hospital. Methods: Thirty adult patients who underwent peripheral blood allo-SCT and developed steroid-refractory aGVHD between January 2010 - July 2019 were retrospectively analyzed. Patients were planned to receive etanercept 25 mg subcutaneously twice weekly for at least 4 weeks. Safety was assessed by estimating infection related mortality. For efficacy, we analyzed the change in grade of aGVHD using the Wilcoxon signed-rank test. Results: Median age at the time of allo-SCT was 57.6 years and the most common indication for transplant was Myelodysplastic syndrome. Median time from allo-SCT to steroid initiation was 39.5 days (range 14-183 days). Median time from steroid initiation to etanercept was 6 days, with 7.5 median number of etanercept doses received. A total of 25 patients (83.3%) received ECP. As depicted in the table, there was a significant improvement in severity of aGVHD after etanercept therapy compared to that before its initiation. Overall response rate was 83.3%, while overall mortality was 86.7%. Median overall survival for responders was 306 days (range 59-2005 days) and for non-responders was 181 days (range 89-261 days). Death attributed to infection alone occurred in 28% (n=7), infection along with GVHD in 28% (n=7) and infection with relapsed disease in 1 patient. Active infection within 6 months of transplant occurred in 93.3% patients. Conclusions: The use of Etanercept with ECP resulted in improvement of steroid refractory aGVHD following allo-SCT, with responses noted in the majority of patients. High rates of infection related mortality were also noted and remain a cause of concern. [Table: see text]

Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial

AbstractPatients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.

A phase i study to evaluate the safety of wharton's jelly mesenchymal stem cells for the treatment of de novo high risk or steroid refractory acute Graft Versus Host Disease (aGVHD)

Background & Aim Allogeneic hematopoietic stem cell transplantation used to manage hematologic malignancies, is frequently complicated by graft versus host disease (GvHD) leading to poor outcomes with increased non-relapse morbidity and mortality. Traditional immunosuppressive therapy has many side effects, thus, necessitating alternative therapies to treat GvHD. Based on their immunomodulation and immunosuppression properties, mesenchymal stem cells (MSCs) are being explored to treat acute GvHD. Currently, there are no cellular products approved in the United States to treat steroid refractory aGvHD. MSCTC-0010, manufactured at the Midwest Stem Cell Therapy Center's GMP facility, is an investigational product consisting of tissue-derived allogeneic, Wharton's Jelly MSCs. We investigated MSCTC-0010 for the treatment of de novo high-risk acute or steroid refractory GvHD in a Phase I, safety clinical trial (IND#17672). The MSCTC-0010 is manufactured by explantation, ex-vivo culture and expansion, and cryopreservation and is tested for identity, potency, sterility, and stability. Methods, Results & Conclusion Method MSCTC-0010 was delivered intravenously twice at a dose of 2 × 106cells/kg in the first cohort and 10 × 106cells/kg in the second cohort on day 0 and 7. GvHD was graded by organ (skin, liver, and gastrointestinal) involvement. The primary endpoint was to evaluate the safety of MSCTC-0010 in patients who experienced a treatment related adverse event. The secondary endpoints include achievement of complete response of aGvHD by day 42 and improvement of GvHD in 1 or more organs involved. Samples were drawn at regular intervals to explore biomarkers that correlate with biological response. Results The study enrolled 10 patients (ages 18-75). Safety of the MSCTC-0010 was demonstrated as there was no infusion related toxicity and no increased incidence of infections. The study showed aGvHD response in 7 of the 10 patients at day 28 (refer to table). A biomarker panel consisting of Reg 3-α and ST-2 was analyzed. Analysis of these two biomarkers showed a reduction from day 0 to day 42. Subjects who received the higher dose of MSCTC-0010 had a statistically significant decline in the Reg-3 α levels on day 7, 14, 21, and 28. The drop in levels correlated with the clinical response. ST-2 levels showed a significant decrease on day 28 and 42. Conclusion This Phase 1 trial with MSCTC-0010 successfully met its primary endpoint of safety. Treatment with MSCTC-0010 shows promise in patients with high risk aGvHD.

A Prospective Phase I/II Clinical Study Evaluating the Clinical and Immune Responses of Repeated MSCs Infusions in Steroid-Refractory Chronic GVHD Patients

A Prospective Phase I/II Clinical Study Evaluating the Clinical and Immune Responses of Repeated MSCs Infusions in Steroid-Refractory Chronic GVHD Patients

Large-scale preparations of small extracellular vesicles from conditioned media of mesenchymal stromal cells modulate therapeutic impacts on a newly established Graft-versus-Host-Disease model in batch dependent manners

Background & Aim Extracellular vesicles (EVs) harvested from supernatants of humane adult bone marrow-derived mesenchymal stem/stromal cells (MSCs) can suppress acute inflammatory cues in a variety of different diseases, including Graft-versus-Host Disease (GvHD) and ischemic stroke. Furthermore, they can promote regeneration of affected tissues. Following a successful clinical treatment attempt of a steroid refractory GvHD patient, we intend to optimize MSC-EV production strategies for further clinical applications. As we observed functional differences of independent MSC-EV preparations in vitro, we aimed to adopt an in vivo GvHD model for the more advanced functional testing of different MSC-EV preparations. Methods, Results & Conclusion To this end we set up a bone marrow transplantation mouse model in which endogenous bone marrow was myeloablated by ionizing irradiation (IIR). GvHD was induced by the transplantation of major histocompatibility mismatched allogeneic spleen-derived murine T cells. If not treated otherwise, myeloablated mice developed severe GvHD symptoms. The GvHD symptoms were effectively suppressed, when MSC-EV preparations were applied at 3 consecutive days, which exerted immune modulatory effects in a mixed-lymphocyte reaction assay. MSC-EV preparations lacking in vitro immune modulating activities, however, hardly improved the symptoms of the GvHD mice. Thus, our results demonstrate that not all MSC-EV preparations harvested from adult bone marrow-derived MSCs contain the same therapeutic potential. Thus, successful transplantation of MSC-EVs into the clinics requires a platform allowing identification of MSC-EV preparations with sufficient therapeutic, most probably immune modulating activities.

Failure to Prevent Severe Graft-Versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Chronic Granulomatous Disease.

Haploidentical related donor (HRD) transplantation was performed in 7 recipients with chronic granulomatous disease (CGD) who had no matched-related or unrelated donor. Peripheral blood cell (PBC) products were used with a conditioning regimen consisting of low-dose cyclophosphamide, fludarabine, total body irradiation, and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of high-dose post-transplant cyclophosphamide and sirolimus. Recipients were ages 14-26years, and 3 had severe infections active at transplant. All 7 recipients achieved full engraftment with complete donor chimerism early in the post-transplant period. Acute GVHD occurred in all cases and was grade 3 or steroid refractory in 3. Two patients with steroid-refractory GVHD died. Three patients with severe infectious complications active at transplant, 1 Nocardia pneumonia and 2 extensive invasive fungal infections), survived and were cured of their infection at last follow-up. Bacterial disease occurred post-transplant in all recipients, and viral infections/reactivation were common, including 4 cases of BK virus-associated hemorrhagic cystitis. Seven patients with CGD achieved rapid and full-donor engraftment from HRDs utilizing PBCs and a conditioning regimen with PTCy and sirolimus GVHD prophylaxis. However, the incidence of grade 3 and steroid-refractory GVHD was high and led to 2 deaths. Patients with active infections at transplant had successful transplant courses and were cured of their disease. Although there was an initial success with this regimen, the cumulative experience does not support its use in CGD due to an unacceptable rate of severe GVHD.

Anti-Apoptotic Molecule BCL2 Is a Therapeutic Target in Steroid-Refractory Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is the leading cause of mortality after hematopoietic stem cell transplantation and primarily affects barrier organs such as the skin. One-third of cases are refractory to steroid treatment resulting in poor outcomes and the need for novel therapies. Longitudinal analysis of T-cell transcriptomes in patients before the appearance of GVHD symptoms revealed the upregulation of anti-apoptotic regulator B-cell lymphoma 2 (BCL2) at GVHD initiation. To determine the potential of BCL2 inhibition in active GVHD, we analyzed tissues of 88 patients with acute or chronic GVHD. BCL2 RNA was elevated in multiple organs affected by GVHD and expression correlated with transplant-related mortality and steroid-refractory GVHD. BCL2-expressing lymphocytes were present in skin lesions and peripheral blood of patients with acute and chronic GVHD. Inhibition of BCL2 increased the CD4 to CD8 ratio in allogeneic T cells invitro and induced apoptosis of T cells from patients with steroid-pretreated chronic GVHD exvivo. In addition, the higher ratio of regulatory to nonregulatory T cells upon blockage of BCL2 could add to the anti-inflammatory effect of BCL2 blockage. Collectively, our results highlight BCL2 as an important factor for GVHD development and introduce BCL2 inhibition as previously unreported and urgently needed targeted therapy in the treatment of steroid-refractory GVHD.

Ruxolitinib for treatment of steroid-refractory graft-versus-host disease in adults: a systematic review and meta-analysis

ABSTRACT Objectives Authors assessed the impact of ruxolitinib (RUX) on steroid-refractory graft-versus-host disease (SR-GVHD) patients. Methods Studies published before January 2019 were identified by electronic search of MEDLINE, EMBASE, Cochrane Library, Clinical Trials.Gov and Web of Science databases. Results Sixteen cohort studies (414 adults) were included whose methodological quality ranged from poor to good. Pooled outcomes such as the response rates, steroid dose reduction, 1-year overall survival, overall infection, and grade 3 to 4 cytopenia were calculated separately for adults with steroid-refractory acute GVHD (aGVHD) and chronic GVHD (cGVHD). Further, the overall response rates were analyzed according to the affected organ. Adults with aGVHD as well as cGVHD showed high response with RUX, and steroid dose reduction was observed in both cases. Infection rates and cytopenia were important safety concerns for both aGVHD and cGVHD. Conclusion Notwithstanding the need of randomized controlled trials to confirm the effect of RUX on SR-GVHD, response rates among adults with aGVHD and cGVHD seem to be high with the use of RUX as a salvage treatment, particularly in cases with gastrointestinal and cutaneous involvement. However, high rates of myelosuppression and infection remain a cause for concern regardless of aGVHD or cGVHD.

Functional dosing of mesenchymal stromal cell-derived extracellular vesicles for the prevention of acute graft-versus-host-disease.

Graft-vs-host-disease (GvHD) is currently the main complication of allogeneic hematopoietic stem cell transplantation. Mortality and morbidity rates are particularly high, especially in steroid-refractory acute GvHD (aGvHD). Immune regulatory human bone marrow mesenchymal stromal cells (hMB-MSCs) represent a therapeutic approach to address this issue. Unfortunately, their effect is hardly predictable in vivo due to several variables, that is, MSC tissue origin, concentration, dose number, administration route and timing, and inflammatory status of the recipient. Interestingly, human bone marrow MSC-derived extracellular vesicles (hBM-MSC-EVs) display many of the hBM-MSC immunoregulatory properties due to their content in paracrine factors that greatly varies according to the collection method. In this study, we focused on the immunological characterization of hBM-MSC-EVs on their capability of inducing regulatory T-cells (T-regs) both in vitro and in a xenograft mouse model of aGvHD. We correlated these data with the aGvHD incidence and degree following hBM-MSC-EV intravenous administration. Thus, we first quantified the EV immunomodulation in vitro in terms of EV immunomodulatory functional unit (EV-IFU), that is, the lowest concentration of EVs leading in vitro to at least threefold increase of the T-regs compared with controls. Second, we established the EV therapeutic dose in vivo (EV-TD) corresponding to 10-fold the in vitro EV-IFU. According to this approach, we observed a significant improvement of both mouse survival and control of aGvHD onset and progression. This study confirms that EVs may represent an alternative to whole MSCs for aGvHD prevention, once the effective dose is reproducibly identified according to EV-IFU and EV-TD definition.

UM171 Expansion Overcomes Shortcomings of Cord Blood Transplantation While Maintaining Benefits

Background Benefits of cord blood (CB) transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, CB use has rapidly declined because of the high rates of infections, severe acute GVHD, and transplant-related mortality (TRM) as well as prolonged hospitalization. We therefore initiated a clinical trial with UM171, a potent agonist of hematopoietic stem cell (HSC) self-renewal, to attempt to solve these limitations and permit transplantation of smaller, better HLA-matched CBs. Methods Expansion culture lasted 7 days and patients received a myeloablative conditioning regimen followed by a single CB transplant including both the expanded CD34+ cells and the lymphocyte-containing CD34- fraction. Results Between 9/16-11/18, 22 adults with mostly high- to very high-risk hematologic malignancies were transplanted. Median transplant co-morbidity index was 2 (0-5). Five patients had already failed an allogeneic transplant, 3 patients had acute leukemia not in remission, and 2 patients had relapsed/refractory aggressive lymphoma. UM171 treatment profoundly changed the cellular composition of the graft, including a 600 and 8000-fold increase in dendritic and mast cell progenitors, respectively. Neutrophil engraftment was prompt with median time to 100 and 500 neutrophils/μL of 9.5 and 18 days, respectively. Patients seemed to derive clinical benefit from achieving 100 neutrophils rapidly translating into early resolution of febrile neutropenia (median day 7) contributing to shorter hospitalization when compared to conventional CB transplants at same institution with larger cell doses and similar time to 500 neutrophil engraftment. Median CD4 counts at 3 and 12 months were 218 and 413/μL, respectively. Incidence of grade 3-4 acute GVHD was low (9%) and there was no steroid refractory GVHD or moderate-severe chronic GVHD. More than 90% of patients were off immunosuppressive therapy by 12 months. One patient died of TRM ( Conclusions A 7-day UM171 expansion CB protocol is feasible and provides clinical benefits beyond engraftment, such as very low TRM. If confirmed, UM171 expansion may overcome the shortcomings of CB transplants while maintaining its benefits of low risk of chronic GVHD and relapse. We have now embarked on a phase 2 trial to confirm if a UM171 modified graft, enriched in dendritic cells, will have a potent antileukemia effect in extremely high-risk patients such as refractory leukemias and high risk mutations (e.g.: p53, EVI-1).

A Case Report of the Benefit of Cannabidiol (Cannabidiol (CBD)-Predominant Medical Cannabis Preparation) in the Management of Refractory Skin Graft Vshost Disease (GVHD)

Cannabis sativa contains numerous cannabinoids, with D9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the primary cannabinoids. Both possess potent anti-inflammatory and immunosuppressive properties, but THC has significant psychoactive properties. Yeshuron's phase 2 study of CBD plus standard GVHD prophylaxis found low rates of grade 2-4 acute(A-) GVHD, and compared with 101 historical controls given standard GVHD prophylaxis, the hazard ratio of developing grades 2-4 A-GVHD was .3 (P =.0002). Kalytera Therapeutics announced a Phase 2a study of CBD for treatment of Grade 3 - 4 A-GVHD, including 9/ 10 responses, of which 7 were complete remission (CR). We report a case of steroid refractory eczematous GVHD successfully treated with a CBD predominant medical cannabis product. A 35 year old woman with T-cell Acute Lymphoblastic Leukemia with CNS involvement in complete remission underwent matched related donor stem cell transplant (SCT) conditioned with Etoposide, TBI 1200 cGy. GvHD prophylaxis was Alemtuzumab, Tacrolimus. A rash developed on day 126 post transplant involving face and scalp and within 1 week involved 100% BSA with itching, facial and orbital swelling, ankle/feet swelling. Skin biopsy revealed an eczematous variant of GvHD known to be very aggressive, difficult to control with immunosuppression , and carries a poor prognosis. Phototherapy and steroid ointment provided initial benefit and regression of rash but it recurred within 6 months. Ruxolitinib provided no benefit. Systemic steroids were restarted at 1mg/kg/ day with minimal benefit. Photopheresis offered only minimal response. Ibrutinib was added. With steroids, photopheresis and ibrutinib she had only marginal response . Numerous infectious complications including soft tissue skin infections required multiple admissions. At 16 months post SCT, she began a medical cannabis product manufactured by VIREO HEALTH, consisting of a high CBD:THC ratio (19:1) oral solution containing CBD 47.5mg/ml and THC 2.5mg/ml. A daily dose of 6 ml provided 285 mg CBD and 15mg THC daily comparable to the 300 mg CBD Kalytera product. Toxicity was sleepiness; thus it was dosed in the evening. There was a definite response within 3 months, allowing discontinuation of ibrutinib and photopheresis. By 2 years post SCT, her GVHD had resolved with only mild itching and flakiness. Her response is sustained 1 year after starting CBD. She remains on 6 ml daily. This adds to the evidence of the anti- inflammatory and immunosuppressive effects of medical cannabis and its activity for the treatment of active GVHD. THC and CBD are anti-inflammatory via CB2 receptors. THC inhibits T-lymphocyte expansion in a murine BMT model. The THC component may have both therapeutic benefit and dose limiting toxicity. Further studies are warranted to explore the role, optimal dose of medical cannabis, in the management of GVHD.

Experience with Ruxolitinib (Jakafi®) As a Salvage Therapy for Graft-Versus-Host Disease in Children and Young Adults

Ruxolitinib was recently approved as a treatment for steroid refractory acute GVHD (aGVHD) and is used in adults for the treatment of chronic GVHD (cGVHD). As a JAK-1/JAK-2 inhibitor, it reduces T-cell proliferation and trafficking and leads to a potent anti-inflammatory effect. There is limited data of its use in pediatric and adolescent/young adult (AYA) patients. We report our single center experience with ruxolitinib in this population. Data on patients treated with ruxolitinib at Lucile Packard Children's Hospital between 8/1/18 and 8/31/19 were retrospectively analyzed after institutional IRB approval. aGVHD was graded according to the Modified Glucksberg scale, while cGVHD was scored as limited or extensive based on Seattle criteria. Only patients on ruxolitinib for ≥14 days were evaluated for response, which was defined as a reduction by at least one grade in severity of aGVHD. Ability to reduce other GVHD medications, especially steroids, and/or symptomatic improvement was considered a response in cGVHD. 15 patients (median age 18, range: 11-29 years) received ruxolitinib: 5 for aGVHD and 10 for cGVHD. Standard starting dose was 5 mg twice a day. Patients in the aGVHD group were steroid refractory with ≥ Grade III GVHD and had received a median of 3 (range: 2-5) different agents prior to ruxolitinib. Patients received treatment for a median of 46 days (range: 23-332). 4 of 5 patients had a partial response (PR) with one non-responder, for an overall response rate (ORR) of 80%. All patients experienced at least one episode of infection- CMV reactivation (n=2), adenovirus (n=1), viral gastroenteritis (n=1), bacterial infections (n=3) and probable fungal infection (n=1). Dose-limiting cytopenia was the only toxicity observed in 3 patients (60%), requiring dose reduction or discontinuation. 2 patients had TRM, both related to GVHD and infections. 10 patients treated for cGVHD (6 limited, 4 extensive) had received a median of 3 (range: 2-6) different agents prior to ruxolitinib. One patient required early cessation of therapy due to a severe allergic reaction and in another patient ruxolitinib was stopped due to leukemia relapse. Of the eight patients evaluable for response, treatment duration was for a median of 195 days (range: 59-372) with an ORR of 88%. 5 (63%) patients developed infections: CMV reactivation (n=2), respiratory infections (n=4), bacterial infection (n=1). Only one patient required dose reduction due to GI side effects and cytopenias. Ruxolitinib is an effective salvage therapy for severe GVHD. It was well tolerated in our patient population, with myelosuppression as the dose limiting toxicity, especially in aGHVD patients. A high rate of infections was noted during ruxolitinib treatment and concomitant antimicrobial prophylaxis is strongly recommended.

Sustained Immunogenic and Clinical Effects of Low-Dose Interleukin-2 Therapy with an Intermittent Maintenance Method for Refractory Chronic Graft-Versus-Host Disease: Results of Phase1/2a LDIL2-01 Study

Introduction and Objectives Regulatory T cells (Treg) play a central role in the maintenance of immune tolerance. We previously reported that the altered Treg homeostasis in the prolonged lymphopenia after HSCT is one of the major pathogenesis of impaired Treg recovery leading to the onset of chronic GVHD and low-dose IL-2 can restore normal Treg homeostasis by a PD-1-dependent mechanism, resulting in the improvement of clinical GVHD symptoms. In these years, the tolerogenic effects of IL-2 have been tested for various autoimmune diseases by clinical trials. However, the schedules of IL-2 dosing in each trial are different and the optimal strategy to expand Treg is still unclear. Our murine study has shown that daily administration of IL-2 seems to be optimal for the initial expansion of Treg but less frequent dosing within the threshold could be preferable for the following maintenance of expanded Treg. Methods Based on the findings, we conducted a phase1/2a clinical trial of low-dose IL-2 for steroid-refractory chronic GVHD with a distinctive dosing schedule consisting of an initial induction phase (IL-2 dosing everyday for the first 4 weeks) and a subsequent maintenance phase (IL-2 dosing 3 times a week for the following 8 weeks). Patients who obtained clinical benefit by the 3 months could proceed to the extended therapy up to total 12 months. The appropriate single dose of IL-2 was examined by a three-step dose escalation design. Results A total of 12 patients were enrolled. None had progression of chronic GVHD or recurrent hematologic malignancy. Dose-limiting toxicity did not occur even at the maximum dose. All patients were evaluable for response, and 7 had clinically significant responses involving multiple sites. Response was observed most often in the joints (67%). One patient with oral GVHD and another patient with gastrointestinal GVHD achieved complete response. One patient with severe lung GVHD markedly improved pulmonary functional test (%FEV1; from 24.8% to 64.8 %) and activity of daily life (from bedridden to return to work). Treg were preferentially increased in all patients, with a peak median value almost 10 times the baseline value (P Conclusion These results indicate that the sustained efficacy of IL-2 against chronic GVHD does not necessarily require that Treg is maintained at a high level by continuing daily IL-2 administration over the long term. Our data provide important information for reconsidering IL-2 dosing methods from the viewpoint of long-term safety and possible combination with other treatments.

Pre-Emptive Donor-Derived Innate Immune Cell Add-Back after Haploidentical Hematopoietic Stem Cell Transplantation to Reduce High Rate of Infection, Gvhd, and Non-Relapse Mortality

<h3>Introduction</h3> Post-transplant cyclophosphamide has allowed alloHSCT using haploidentical donors. PTCy is very effective at reducing GVHD-causing T cells, but it has the unwanted effect of eliminating Natural Killer cells. We have developed a new reduced-intensity haploHSCT transplant conditioning regimen based on an a regimen developed for fully-matched donors with lymphoma: bendamustine 130 mg/m2 IV daily, and fludarabine 30 mg/m2 IV daily, for 3 days, +/- rituximab. We made additional modifications designed to improve NK immune recovery: 1.) no mycophenolate, 2.) no routine G-CSF, 3.) early tacrolimus taper starting on day +60, 4.) pre-emptive NK-enriched donor lymphocyte infusion on Day +8. <h3>Objectives</h3> Conduct a prospective clinical trial to evaluate the safety of bendamustine-fludarabine conditioning, PTCy, NK cell add-back, and short course tacrolimus for patients with myeloma or lymphoma undergoing haploHSCT. Assess clinical outcomes over the first year after transplantation. Efficacy Endpoints: Death or engraftment failure at D+30, death or severe chronic extensive GVHD at D+100. Test rate of survival, engraftment, and GVHD. Measure reconstitution of adaptive and innate lymphocyte subsets. Measure NK KIR repertoire recovery and assess for ‘missing self'. <h3>Methods</h3> This is a Phase I, single center, single cohort, open-label, proof-of-concept clinical trial to evaluate the safety of the BFRHaplo regimen (Figure 1) and preemptive CD56-selected DLI following PTCy for adults with myeloma or lymphoma. <h3>Results</h3> We have safety data on six patients (Table 1). Recovery of neutrophils and platelets is prompt. No primary or secondary graft failures have occurred. No patients have developed Grade III-IV or steroid-refractory acute GVHD. No organ toxicities, and no alkylator-alkylator toxicity from bendamustine – PTCy, have been observed. No instances of either veno-occlusive disease or transplant-related thrombotic microangiopathy, and no deaths, serious infections, or re-hospitalizations. One patient relapsed and is alive without GVHD receiving salvage therapy. We used single-step CD56 selection to prepare CD56-enriched donor lymphocyte infusions (Table 2). The one-step CD56 selection method has the attractive property of preserving CD3+/CD56+ cells, including NK/T and gdT. The target cell dose (> 1 million CD56+ cells/kg and < 1 million T cells/kg) was achieved for all patients. <h3>Conclusion</h3> The trial will establish whether BFRHaplo, and the infusion of cytotoxic NK and some T cells (< 1million/kg) without mycophenolate, is safe. Completion of this Phase I trial will lead to double-blind, placebo- controlled studies to assess the efficacy of CD56-selected immune cell add-back after PTCy in reducing the high rate of infection, GVHD, and mortality following haploidentical stem cell transplantation.

The CELLEX is comparable to the UVAR-XTS for the treatment of acute and chronic graft versus host disease (GVHD).

Two extracorporeal photopheresis (ECP) instruments, the CELLEX and the UVARXTS are currently being used "off-label" in the US for treatment of graft versus host disease (GVHD). Our study compared the performance of the two instruments in the setting of acute and chronic GVHD. We retrospectively analyzed the outcomes of patients with steroid refractory or steroid resistant GVHD undergoing ECP at Barnes Jewish Hospital. Multivariate logistic regression was used to evaluate the comparative efficacy of the two instruments with respect to steroid dose reduction (≥50% from baseline) and clinical improvement in GVHD. Chi-square/Fisher exact tests were used to compare the incidence of adverse events, while multivariate Cox regression was employed to assess a potential difference in mortality between the two instrument treatment cohorts. After adjusting for potential confounders, there was no significant difference in the odds of steroid dose reduction (OR = 1.41, 95% confidence interval [CI]: 0.51-3.90, p = 0.50) or clinical improvement (OR 2.0, 95% CI: 0.63-6.41, p = 0.24) between the two instrument treatment cohorts. The frequency of adverse events (CELLEX 45.4%; UVAR XTS 40.5%, p = 0.55) was also comparable between the cohorts. There was no significant difference in mortality of either acute or chronic GVHD patients when treated by the CELLEX as compared to the UVAR-XTS (aHR 0.66, 95% CI: 0.35-1.25, p = 0.20). The efficacy and safety of the two ECP instruments, the CELLEX and the UVAR-XTS, are comparable for the treatment of acute and chronic GVHD.

Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial

AbstractClinical- and biomarker-based tools may identify a lower-risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced-intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus, n = 58; prednisone, n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% confidence interval [CI], 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone ≤0.25 mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs 31.7%; P < .001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2 to 3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life. This trial was registered at www.clinicaltrials.gov as #NCT02806947.

Treatment of graft-versus-host disease

Graft-versus-host disease (GVHD) is one of the most important complications after an allogeneic hematopoietic stem cell transplantation (allo-SCT). The current National Institutes of Health's (NIH) consensus is that clinical manifestations, and not the time to symptomatic onset after transplantation, determine whether the clinical syndrome of GVHD is considered acute or chronic. In the past decade, peripheral blood stem cell transplantation from an unrelated donor can be performed in Japan. Furthermore, poor-risk patients without human leukocyte antigen (HLA)-matched donor can receive allo-SCT from HLA haploidentical donor. Therefore, severe or steroid-refractory GVHD would be increased. Corticosteroid, at a dose of 2 mg/kg, is a standard first-line therapy for acute GVHD. If there is no improvement after the first-line therapy, second-line therapy should be administered immediately. Although anti-thymocyte globulin and mesenchymal stem cells are covered by health insurance in Japan, another treatment options should be determined for steroid-refractory acute GVHD. Furthermore, severe chronic GVHD increases patients' mortality and decreases their quality of life. A number of novel drugs targeting specific biological pathways for GVHD are under development. Currently, more than 60 clinical trials are carried out for the treatment of steroid-refractory GVHD worldwide for drug approval. The accumulation of novel evidence for GVHD treatment is expected to be established.

Clinical Translation of Mesenchymal Stromal Cell Therapy for Graft Versus Host Disease.

Graft versus host disease (GVHD) is a common condition in patients subjected to allogeneic hematopoietic stem cell transplantation (HSCT). The immune cells derived from the grafted stem cells attack recipient’s tissues, including those from the skin, liver, eyes, mouth, lungs, gastrointestinal tract, neuromuscular system, and genitourinary tract, may lead to severe morbidity and mortality. Acute GVHD can occur within few weeks after the allogeneic cells have engrafted in the recipient while chronic GVHD may occur any time after transplant, typically within months. Although treatable by systemic corticosteroid administration, effective responses are not achieved for a significant proportion of patients, a condition associated with poor prognosis. The use of multipotent mesenchymal stromal cells (MSCs) as an alternative to treat steroid-refractory GVHD had improved last decade, but the results are still controversial. Some studies have shown improvement in the life quality of patients after MSCs treatment, while others have found no significant benefits. In addition to variations in trial design, discrepancies in protocols for MSCs isolation, characterization, and ex vivo manipulation, account for inconsistent clinical results. In this review, we discuss the immunomodulatory properties supporting the therapeutic use of MSCs in GVHD and contextualize the main clinical findings of recent trials using these cells. Critical parameters for the clinical translation of MSCs, including consistent production of MSCs according to Good Manufacturing Practices (GMPs) and informative potency assays for product quality control (QC), are addressed.

Ruxolutinib in Steroid Refractory Graft Versus Host Disease (SR-GVHD): Systemic Literature Review

Background: Graft versus host disease (GVHD) is a main cause of morbidity and mortality in patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT). About 30-40% of patients have steroid‐refractory GVHD (SR‐GVHD) after the first‐line use of high doses of corticosteroids with a poor prognosis .Ruxolitinib is a promising treatment for SR-GVHD. However, data regarding optimum dosing, response rates and associated adverse events are scarce. Herein, we provide the first systemic review of literature for the use ruxolutinib in GVHD. Methods: A Medline (PubMed), google scholar, OVID and Cochrane Database of Systematic Reviews search using key words "Ruxolutinib and GVHD", "Ruxolutinib and SR-GVHD" was undertaken in June 2019. Only peer reviewed databases were searched and search was restricted to human studies of acute and chronic GVHD only. Results: 16 publications, as listed in Table 1. Only one was a prospective trial, all others were retrospective studies, case series (5), and case reports (2). Overall response, ranged 45% - 100%, complete response was noted in 5.2% -80% patients. Time to response was variable from 1-12 weeks. Cytopenias and infectious complications were frequently reported with dose reduction or interruptions needed in most studies. Maintained responses were reported in a small proportion after ruxolutinib discontinuation. Conclusion Ruxolutinib has promising efficacy in SR-GVHD , however cytopenias and infectious complications reported frequently mandate close monitoring. Results of ongoing prospective trials could provide answers for optimum dosing and response assessment, and management of related adverse events. Table Disclosures No relevant conflicts of interest to declare.

Results from an Expanded Access Program of Anti-CD3/CD7 Immunotoxin Combination (T-Guard®) for the Treatment of Steroid-Refractory Acute Gvhd

Background More effective therapies for treating steroid-refractory acute GVHD (SR-aGVHD) are urgently needed. In our recent phase I/II study, we showed that anti-CD3/anti-CD7 immunotoxin (IT) therapy T-Guard was both safe and well tolerated, and yielded both a high rate of CR and high 6-month OS in high-risk patients (Groth et al. BBMT 2019). Following this study, patients with SR-aGVHD were offered T-Guard via an expanded access treatment program (EAP). Objectives We evaluated patients' outcome after receiving T-Guard for SR-aGVHD. In addition, we examined the relationship between plasma citrulline levels (a biomarker of enterocyte mass) and the response to T-Guard in a subset of patients with SR-aGVHD of the gut, combining 16 patients from the phase I/II trial and 9 patients in the EAP group. Methods An EAP was started after completion of the phase I/II trial. This program was approved by the local ethics committee and the Health and Youth Care Inspectorate of the Dutch government. Adult patients with grade II-IV SR-aGVHD were eligible to receive T-Guard as their second- or third-line treatment for aGVHD. Patients with an uncontrolled infection, signs of moderate-severe chronic GVHD, and/or severe renal impairment were not eligible to receive T-Guard. Eligible patients received four 4-hour i.v. infusions of 4 mg/m2 T-Guard delivered at 48-hour intervals. In addition, plasma citrulline levels were measured at baseline and every 7 days after the start of T-Guard therapy using HPLC with mass spectrometry. A plasma citrulline level &lt;10 µmol/L was considered to indicate severe GI-GVHD. Results From Jan. 2017 through Dec. 2018, 12 patients (8 male, 4 female; median age: 54 yr, range: 20-70 yr) who had received an allogeneic stem cell transplantation for myeloid or lymphoid malignancy were treated with T-Guard. T-Guard was given as the second-line therapy to 10 patients; the remaining 2 patients received T-Guard as the third-line therapy after receiving ruxolitinib (N=1) or cyclosporin-UVB (N=1). The median time between aGVHD onset and the start of T-Guard therapy was 7 days (range: 3-55 days). SR-aGVHD was classified as grade II, III, or IV in 1, 7, and 4 patients, respectively. Nine patients (75%) had GI involvement, and the skin and liver were involved in 6 and 2 cases, respectively. All 12 patients were classified as high-risk in accordance with MacMillan et al. (BJH 2012), and the median albumin level at baseline was 23 g/L (range: 13-32 g/L). By treatment day 28, 9 patients (75%) had achieved a clinical response, with 5 achieving complete remission. After a median follow-up of 16 months, 7 patients were alive; the 6-month and 1-year OS rate was 75% and 58%, respectively, which was significantly higher than historical controls; Figure 1. The cause of death in the other five patients was refractory aGVHD (N=3), relapse AML (N=1), and GVHD after undergoing a second stem cell transplantation for relapse AML (N=1). No significant infusion-related reactions were recorded. As expected, the overall rate of infection was high, but was comparable to other cohorts; 1 and 2 patients developed an EBV or CMV infection, respectively, but these were manageable. The most common potentially treatment-related adverse events were transient worsening of hypoalbuminemia and thrombocytopenia. One patient developed grade 2 vascular leak syndrome, but this was easily managed. One patient developed severe thrombotic microangiopathy with renal insufficiency, but several contributing factors other than the use of T-Guard were present in this patient, including calcineurin toxicity, severe GI-GVHD, and CMV disease. Our preliminary analysis of citrulline levels in 16 patients with GI-GVHD showed that mean baseline levels were extremely low (4.3 µmol/L; range: 2.9-17.9 µmol/L); 28 days after the start of T-guard, citrulline levels had increased significantly in the 9 patients who achieved complete remission; Figure 2. Conclusion Consistent with our recent phase I/II trial, our expanded access program in which 12 patients with high-risk SR-aGVHD received T-guard confirms that this treatment is safe and significantly improves patient outcome. A multicenter phase III study is planned to start in 2019 (BMT-CTN 1802). Disclosures Hooren: Xenikos BV: Employment. van Oosterhout:Xenikos BV: Employment.