Successful Allogeneic Stem Cell Transplantation Research Articles

Successful Allogeneic Alternative Donor Hematopoietic Stem Cell Transplantation in High-Risk Patients with Severe Sickle Cell Disease

Successful Allogeneic Alternative Donor Hematopoietic Stem Cell Transplantation in High-Risk Patients with Severe Sickle Cell Disease

Deciphering bone marrow engraftment after allogeneic stem cell transplantation in humans using single-cell analyses.

BACKGROUNDDonor cell engraftment is a prerequisite of successful allogeneic hematopoietic stem cell transplantation. Based on peripheral blood analyses, it is characterized by early myeloid recovery and T and B cell lymphopenia. However, cellular networks associated with bone marrow engraftment of allogeneic human cells have been poorly described.METHODSMass cytometry and CITE-Seq analyses were performed on bone marrow cells 3 months after transplantation in patients with acute myelogenous leukemia.RESULTSMass cytometric analyses in 26 patients and 20 healthy controls disclosed profound alterations in myeloid and B cell progenitors, with a shift toward terminal myeloid differentiation and decreased B cell progenitors. Unsupervised analysis separated recipients into 2 groups, one of them being driven by previous graft-versus-host disease (R2 patients). We then used single-cell CITE-Seq to decipher engraftment, which resolved 36 clusters, encompassing all bone marrow cellular components. Hematopoiesis in transplant recipients was sustained by committed myeloid and erythroid progenitors in a setting of monocyte-, NK cell-, and T cell-mediated inflammation. Gene expression revealed major pathways in transplant recipients, namely, TNF-α signaling via NF-κB and the IFN-γ response. The hallmark of allograft rejection was consistently found in clusters from transplant recipients, especially in R2 recipients.CONCLUSIONBone marrow cell engraftment of allogeneic donor cells is characterized by a state of emergency hematopoiesis in the setting of an allogeneic response driving inflammation.FUNDINGThis study was supported by the French National Cancer Institute (Institut National du Cancer; PLBIO19-239) and by an unrestricted research grant by Alexion Pharmaceuticals.

WITHDRAWN: Host SPHK1 deficiency ameliorates acute graft-versus-host disease by attenuating ER stress-induced gastrointestinal injury

Graft-versus-host disease (GVHD) remains a major obstacle in successful allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that inhibiting sphingosine kinase 1 (SPHK1), an enzyme that phosphorylates sphingosine to bioactive sphingosine-1-phosphate (S1P), effectively ameliorates acute GVHD (aGVHD). The absence of SPHK1 in the host exerts a beneficial effect on maintaining gut homeostasis by limiting intestinal epithelial cell (IEC) injury, thus reducing gut permeability and preventing bacterial translocation, which in turn decreases the activation of antigen-presenting cells and T cell infiltration. Persistent ER stress is observed during GVHD in the gastrointestinal tract and contributes to IEC injury. SPHK1 deficiency attenuates IEC damage by alleviating ER stress, a process that can be reversed by supplementation with exogenous S1P. FTY720, an S1P receptor antagonist, significantly inhibits ER stress-induced IEC injury. Additionally, host SPHK1 deficiency helps in shaping the gut microbiota by diminishing the presence of MHC II inducer-associated bacteria, such as Lactobacillus murinus, and increasing the abundance of the IFN-γ suppressor Akkermansia muciniphila. This leads to decreased MHC II expression in IECs, contributing to an overall reduction in aGVHD severity. Together, our data reveal a pathogenic role of host SPHK1 in gastrointestinal injury during aGVHD.

Treatment Patterns and Clinical Outcomes of Patients with Moderate to Severe Acute Graft-Versus-Host Disease: A Multicenter Chart Review Study.

Acute graft-versus-host disease (aGVHD) remains a barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT) outcomes. Contemporary comprehensive analyses of real-world clinical outcomes among patients who develop aGVHD post-HSCT are needed to better understand the unmet needs of this patient population. This multicenter, retrospective chart review describes treatment patterns and clinical outcomes among patients (≥18 years old) from Finland, Sweden, and France who developed grades II-IV aGVHD after their first HSCT (January 2016-June 2017). From 13 participating centers, 151 patients were included. The median (Q1, Q3) age at HSCT was 56 (45, 62) years old. One line of aGVHD treatment was received by 47.7%, and the most common first-line treatment was methylprednisolone (alone or in a combination regimen, 74.2%; monotherapy, 25.8%). Among patients treated with methylprednisolone, 79.5% achieved a complete or partial response. The median (Q1, Q3) number of treatment lines was 2.0 (1.0, 3.0). The median (Q1, Q3) time to obtain an aGVHD diagnosis from transplant was 29.5 (21.0, 44.0) days, and 14.5 (7.0, 34.0) days to achieve the best response for 110 evaluable patients. At 6 and 12 months, 53.6% and 49.0%, respectively, achieved a complete response. Chronic GVHD occurred in 37.7% of patients, and aGVHD reoccurred in 26.5%. Following aGVHD diagnosis, mortality rates were 30.0% at 6 months and 37.3% at 12 months. Findings from this study demonstrate a continuing unmet need for new therapies that control aGVHD and improve mortality.

AML-521 The Randomized Phase III SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) Trial: Successful Allogeneic Hematopoietic Stem Cell Transplantation Using Treatment With Iomab-B-Led Regimen for Patients With Active, Relapsed or Refractory AML With Failed Targeted Therapies

AML-521 The Randomized Phase III SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) Trial: Successful Allogeneic Hematopoietic Stem Cell Transplantation Using Treatment With Iomab-B-Led Regimen for Patients With Active, Relapsed or Refractory AML With Failed Targeted Therapies

POSTER: AML-521 The Randomized Phase III SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) Trial: Successful Allogeneic Hematopoietic Stem Cell Transplantation Using Treatment With Iomab-B-Led Regimen for Patients With Active, Relapsed or Refractory AML With Failed Targeted Therapies

POSTER: AML-521 The Randomized Phase III SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) Trial: Successful Allogeneic Hematopoietic Stem Cell Transplantation Using Treatment With Iomab-B-Led Regimen for Patients With Active, Relapsed or Refractory AML With Failed Targeted Therapies

Successful allogeneic hematopoietic stem cell transplantation in a patient with type I CD36 deficiency: a case study and literature review.

CD36-deficient individuals may produce anti-CD36 antibodies through antigenic exposure to CD36, in situations including blood transfusions. Therefore, allogeneic hematopoietic stem cell transplantation (HSCT) from CD36-positive donors to CD36-negative patients remains a challenge. A 64-year-old man with acute myeloid leukemia became refractory to platelet transfusions during chemotherapy. Anti-CD36 antibodies without anti-HLA antibodies were detected in serum, and the absence of CD36 expression on platelets and monocytes confirmed type I CD36 deficiency. The patient achieved complete remission, and received maintenance therapy with CD36-negative platelet transfusions. However, he relapsed soon afterward, and thus underwent peripheral blood stem cell transplantation (PBSCT) from a CD36-positive unrelated donor. The anti-CD36 antibody titer had decreased before the transplant, and the PBSCT-course was uneventful. The patient has been well without any complications associated with CD36 status mismatch. The few reports of allogeneic HSCT in patients with CD36 deficiency have suggested that anti-CD36 antibodies could be involved in several post-transplant complications, such as delayed platelet recovery, transfusion refractoriness, and transfusion-related acute lung injury. Our present case confirmed that stem cell transplantation from CD36-positive donors to negative patients is feasible, when it includes careful prior assessment of anti-CD36 antibody titers and interventions to attenuate them.

Successful allogeneic hematopoietic stem cell transplantation for myelodysplastic neoplasms complicated with secondary pulmonary alveolar proteinosis and Behçet's disease harboring GATA2 mutation.

Myelodysplastic neoplasms (MDS) are defined by cytopenia and morphologic dysplasia originating from clonal hematopoiesis. They are also frequently complicated with diseases caused by immune dysfunction, such as Behçet's disease (BD) and secondary pulmonary alveolar proteinosis (sPAP). MDS with both BD and sPAP is extremely rare, and their prognosis is poor. In addition, haploinsufficiency of the hematopoietic transcription factor gene GATA2 is recognized as a cause of familial MDS and is frequently complicated by sPAP. Herein, we report a case of MDS combined with both BD and sPAP in association with GATA2 deficiency in a Japanese woman. Because she developed progressive leukopenia and macrocytic anemia during BD treatment at the age of 61, she underwent a bone-marrow examination and was diagnosed with MDS. She subsequently developed sPAP. At the age of 63, she underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since allo-HSCT, she has maintained complete remission of MDS as well as the symptoms of BD and sPAP. Furthermore, we performed whole exome sequencing and identified the GATA2 Ala164Thr germline mutation. These findings suggest that patients with MDS, BD and sPAP should be considered for early allo-HSCT.

Successful Allogeneic Stem Cell Transplantation with Ruxolitinib Maintenance Therapy for CSF3R T618I Mutant Chronic Neutrophilic Leukemia

Successful Allogeneic Stem Cell Transplantation with Ruxolitinib Maintenance Therapy for CSF3R T618I Mutant Chronic Neutrophilic Leukemia

Lower dose of ATG combined with basiliximab for haploidentical hematopoietic stem cell transplantation is associated with effective control of GVHD and less CMV viremia.

Currently, the graft-versus-host disease (GVHD) prophylaxis consists of an immunosuppressive therapy mainly based on antithymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). GVHD remains a major complication and limitation to successful allogeneic haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We modified the ATG-based GVHD prophylaxis with the addition of basiliximab in the setting of haplo-HSCT and attempted to explore the appropriate dosages. We conducted a retrospective analysis of 239 patients with intermediate- or high-risk hematologic malignancies who received haplo-HSCT with unmanipulated peripheral blood stem cells combined or not with bone marrow. All patients received the same GVHD prophylaxis consisting of the combination of methotrexate, cyclosporine or tacrolimus, mycofenolate-mofetil, and basiliximab with different doses of ATG (5-9mg/kg). With a median time of 11 days (range, 7-40 days), the rate of neutrophil engraftment was 96.65%. The 100-day cumulative incidences (CIs) of grade II-IV and III-IV aGVHD were 15.8 ± 2.5% and 5.0 ± 1.5%, while the 2-year CIs of total cGVHD and extensive cGVHD were 9.8 ± 2.2% and 4.1 ± 1.5%, respectively. The 3-year CIs of treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) were 14.6 ± 2.6%, 28.1 ± 3.4%, 60.9 ± 3.4%, 57.3 ± 3.4%, respectively. Furthermore, the impact of the reduction of the ATG dose to 6 mg/kg or less in combination with basiliximab on GVHD prevention and transplant outcomes among patients was analyzed. Compared to higher dose of ATG(>6mg/kg), lower dose of ATG (≤6mg/kg) was associated with a significant reduced risk of CMV viremia (52.38% vs 79.35%, P<0.001), while the incidences of aGVHD and cGVHD were similar between the two dose levels. No significant effect was found with regard to the risk of relapse, TRM, and OS. ATG combined with basiliximab could prevent GVHD efficiently and safely. The optimal scheme of using this combined regimen of ATG and basiliximab is that administration of lower dose ATG (≤6mg/kg), which seems to be more appropriate for balancing infection control and GVHD prophylaxis.

Extracorporeal photopheresis (ECP) improves overall survival in the treatment of steroid refractory acute graft-versus-host disease (SR aGvHD).

Steroid refractory acute graft-versus-host disease (SR aGvHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) has been used to treat SR aGvHD effectively and with low treatment related toxicity. In this study, we retrospectively analyzed the outcomes of 103 Steroid Refractory aGvHD (SR aGvHD) patients to identify factors associated with improved outcomes including the use of ECP. A total of 79 patients received ECP as part of their SR aGVHD treatment compared to 24 patients who did not. Both groups had similar aGVHD grade and maximum organ stage at onset of aGVHD and treatment initiation. Patients in the group that received ECP had better OS (p = 0.01), DFS (p = 0.008), lower relapse (p = 0.05) and similar NRM compared to the group that did not receive ECP. Patients that received ECP treatment also had shorter hospital stays in the first 180 days after onset of SR aGvHD (20 vs. 38 days, p = 0.03). Multivariable analysis for OS indicated patient CMV status (CMV+ versus CMV-, HR 2.34, CI 1.16-4.69), regimen intensity (Myelo vs. non-Myeloablative, HR 0.39, CI 0.20-0.75), and the use of ECP (ECP vs. no ECP, HR 0.39, CI 0.20-0.75) were associated with OS. In summary, the use of ECP in the treatment of SR aGvHD results in improved overall survival secondary to lower relapse rates compared to other therapeutic modalities that do not incorporate ECP.

Abstract 11714: High-Output Heart Failure in Multiple Myeloma: Novel Approach to a Challenging Diagnosis

High-output heart failure (HOHF) is a rare complication of multiple myeloma and is believed to be related to arteriovenous shunting in osseous myeloma lesions. Timely diagnosis is crucial, as these patients respond best to aggressive treatment of the underlying malignancy. In this case, a 51-year-old man with multiple myeloma complicated by extensive osseous disease was admitted from oncology clinic for several weeks of worsening dyspnea, early satiety, and bilateral leg swelling. His exam was notable for signs of volume overload, and the BNP was elevated to 1444 pg/ml. An echocardiogram showed new right ventricular dysfunction. After the patient failed to respond to escalating doses of intravenous diuretics, right heart catheterization was performed and revealed elevated biventricular filling pressures with evidence of high cardiac output (Fick CO 17.1 LPM, Fick CI 7.9 LPM/m 2 ). In a novel diagnostic approach, 5.1 mCi of technetium-99m-labeled macroaggregated albumin was injected into the aorta at the time of left heart catheterization and then whole body planar images were obtained in anterior and posterior projections. The scan revealed evidence of lower extremity arteriovenous shunting with a proportion of 6% (Fig. 1). He was started on lenalidomide and pulse-dose dexamethasone with improvement in diuretic response and resolution of heart failure symptoms. A follow-up echocardiogram showed normalization of right ventricular size and function. He eventually underwent successful allogeneic stem cell transplant during the admission. Although Tc-99m MAA is routinely used in the diagnosis of hepatopulmonary syndrome, this is, to our knowledge, the first report of its use to investigate myeloma-related HOHF in the clinical setting. This technique was previously utilized successfully to experimentally correlate between shunting values and cardiac indices. It may be of use in a wider population of patients with HOHF in whom occult shunting is suspected.

Successful allogeneic hematopoietic stem cell transplantation in a patient with acute myeloid leukemia and preexisting pulmonary nocardiosis.

Successful allogeneic hematopoietic stem cell transplantation in a patient with acute myeloid leukemia and preexisting pulmonary nocardiosis.

Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD (IRENE-G study) \u2013 design and rational of a randomized controlled trial

BackgroundGraft-versus-host disease (GvHD) remains a major complication and limitation to successful allogeneic hematopoietic stem cell transplantation. Treatment of GvHD is challenging due to its heterogeneous nature of presentation, with steroids remaining the established first-line treatment. Long-term doses of systemic corticosteroids have many well-known side-effects including muscle atrophy. Despite the fact that reports in non-cancer clinical populations treated with glucocorticoids demonstrated that resistance training can reverse atrophy and weakness, no RCT has evaluated the potential of resistance training on preventing the disease- and treatment-induced loss of skeletal muscle mass and function in GvHD patients yet. In this context, ensuring adequate nutrition is important as protein deprivation may accelerate the wasting process. As GvHD patients are commonly found to be malnourished, nutritional medical care should be considered when investigating the effect of exercise in GvHD patients. Therefore, the aim of the present “Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD” – Study (IRENE-G) is to evaluate the effects of resistance exercise in combination with nutritional endorsement on physical, nutritional and patient-reported outcomes in GvHD patients.MethodsIRENE-G is a 24-week prospective interventional RCT. One hundred twelve participants will be randomly allocated (1:1) to one of two arms: resistance exercise and nutritional optimization (experimental) vs. nutritional optimization only (control). Participants in the experimental group will engage in a supervised, progressive moderate-to-high intensity resistance training that is consistent with exercise guidelines for cancer patients, while additionally receiving nutritional support/therapy. Subjects of the control group solely receive nutritional support/therapy based on individual needs. Participants will be assessed at baseline, at 8, 16, 24 weeks for physical performance and various physiological, nutritional and patient-reported outcomes. Follow-up will be 6 months after intervention completion.DiscussionTo our knowledge, this will be the first RCT to assess and compare the effects of a resistance intervention supplemented by nutritional support/therapy against nutritional support only on various health-related outcomes in GvHD patients. The study will contribute to our understanding of the value of exercise and nutritional endorsement in counteracting the negative consequences of GvHD and its treatment.Trial registrationClinicalTrials.gov: NCT05111834. Registered 8 November 2021 – Retrospectively registered.

Multicenter Phase II Study to Evaluate Therapeutic Efficacy of Imatinib Mesylate in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease

BackgroundGraft-versus-host disease (GVHD), where T- and B-cells derived from the graft attack host, is still a vital hurdle to overcome for successful allogeneic stem cell transplantation (allo-SCT). In particular, chronic GVHD (cGVHD) occurs approximately 30-70% of the patients and it is the most relevant cause of non-relapse morbidity (NRM) after allo-SCT. This multicenter, phase II study evaluated the safety and efficacy of imatinib mesylate in patients with steroid-resistant cGVHD. In addition, we scored the quality of life of the enrolled patients using Short Form Health Survey Questionnaire (SF-36).Patients and methodsA total of 36 patients who diagnosed with steroid-refractory cGVHD participated in this study and treated with imatinib from March 2013 to February 2019. Enrolled patients received 100mg of imatinib daily for 2 weeks. Every 2 weeks, imatinib dosage was increased up to 400 mg/day if the patients did not have any grade 3-4 adverse event. Patients who showed stable disease (SD), partial remission (PR) and complete remission (CR) in the 3-month response evaluation continued the imatinib up to 6 months. Treatment response was evaluated every 2 weeks for 6 months according to the NIH global scoring system. Survival outcomes of the enrolled patients were followed up to 2 years. Quality of life was also evaluated using SF-36 at 1, 3, and 6 months after starting imatinib treatment.Response of cGVHD was evaluated based on the NIH response criteria by scoring each involved organ sites with four-point scale (0-3). CR was defined as resolution of all reversible manifestations related to cGVHD. Partial response (PR) of cGVHD was defined clinical score reduction of at least one point in one or more affected organs. Disease progression or treatment failure was defined as increased score at least one point in one or more organs or occurrence of any new symptoms or signs of c GVHD. Failure-free survival (FFS) and overall survival (OS) were calculated from the day of starting imatinib.ResultMedian age was 47.5 years (23-63). Majority of the patients were diagnosed with acute leukemia (75%) and myelodysplastic syndrome (16.9%), and underwent allo-SCT in CR disease status (69.5%). Twenty-five (69.4%) patients experienced acute GVHD. Most of the patients presented overlap symptoms. Skin GVHD was identified in 23 (63.9%) patients. Lung, mouth, and eye involvement were found in 16 (44.4%), 14 (38.9%), and 14 (38.9%) patients, respectively. All of the enrolled patients had been treated with steroid due to moderate (55.6%), and severe (44.4%) grade cGVHD.Overall, median duration of imatinib therapy was 5.4 months and no severe adverse effect over grade 3 was reported. The last therapeutic mean dosage of imatinib was 305.6 mg/day. Three patients (8.3%) achieved CR, and 18 (50%) and 12 patients (33.3%) were reported as PR and SD. Treatment failure was identified in three patients (8.3%). Overall response rate (ORR) of imatinib was 58.3% and 25 patients (69.4%) could reduce the steroid. According to the each involved organ site, ORR of the gastrointestinal (GI) and liver cGHVD were 70.5% and 66.7%, while skin and lung were 34.8% and 25.0%, respectively. The efficacy of imatinib was better in GI, liver, and mouth than skin and lung in the current clinical study. With the median follow-up duration of 28.5 months, two-year FFS and OS rate were 76% and 88.5%. Responders to the imatinib therapy showed a superior tendency in OS than non-responders (p = 0.066). In the patients-reported QOL evaluation with SF-36, both physical and mental component score were improved. Particularly, a factor representing emotional well-being was significantly improved (p = 0.002).ConclusionThis multicenter clinical study showed that imatinib is an effective option not only for skin GVHD but also for GI and liver involvement. Moreover, QOL of the patients tended to improve during imatinib treatment with steroid dose reduction. [Display omitted] DisclosuresLee: Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board; Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees.

Novel Insights Into the Mechanism of GVHD-Induced Tissue Damage.

Prophylaxis for and treatment of graft-versus-host disease (GVHD) are essential for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) and mainly consist of immunosuppressants such as calcineurin inhibitors. However, profound immunosuppression can lead to tumor relapse and infectious complications, which emphasizes the necessity of developing novel management strategies for GVHD. Emerging evidence has revealed that tissue-specific mechanisms maintaining tissue homeostasis and promoting tissue tolerance to combat GVHD are damaged after allo-SCT, resulting in exacerbation and treatment refractoriness of GVHD. In the gastrointestinal tract, epithelial regeneration derived from intestinal stem cells (ISCs), a microenvironment that maintains healthy gut microbiota, and physical and chemical mucosal barrier functions against pathogens are damaged by conditioning regimens and/or GVHD. The administration of growth factors for cells that maintain intestinal homeostasis, such as interleukin-22 (IL-22) for ISCs, R-spondin 1 (R-Spo1) for ISCs and Paneth cells, and interleukin-25 (IL-25) for goblet cells, mitigates murine GVHD. In this review, we summarize recent advances in the understanding of GVHD-induced tissue damage and emerging strategies for the management of GVHD.

Carfilzomib in Addition to Standard Cyclosporine/Methotrexate Combination Effectively Prevents Acute Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation from Unrelated Donors

Background: Acute graft-versus-host disease (GVHD) remains a major obstacle for successful allogeneic stem cell transplantation (HSCT) from unrelated donors. Novel preventive regimens are thus needed. The proteasom inhibitor bortesomib has immune modulatory effects that were shown to be beneficial in several studies adding a short treatment course to the standard calcineurin/ methotrexate regimen in matched and mismatched unrelated donor transplant. Carfilzomib is a second generation irreversible proteasome inhibitor. It is more selective than bortesomib and was shown to be more effective in relapsed refractory multiple myeloma. However, there is no data on the effect of carfilzomib in GVHD prevention. We explored a novel regimen consisting of 2 doses of carfilzomib at 20 mg/m2, given on days 1 and 2 after HSCT combined with standard anti GVHD prophylaxis regimen of cyclosporine/ methotrexate. The study enrolled patients with acute myeloid leukemia (AML) in remission (CR) or patients with myelodysolastic syndrome (MDS) with less than 10% blasts, given a 10/10 or 9/10 matched unrelated donor transplant with fludarabine-based reduced-intensity or reduced-toxicity conditioning.Patients and Methods: 20 patients, 8 male, 12 female, median age 63 years (range, 30-72) were recruited to the study. Fifteen patients had AML and 5 had MDS. Ten patients were in CR1, 5 in CR2 and 5 were previously untreated at the time of transplantation. The conditioning regimen included fludarabine combined with intravenous busulfan at reduced doses (n=6) or myeloablative doses (n=11) or with treosulfan (n=3). All patients were also given antithymocyte globulin (ATLG ,Grafalon ,Neovii, total dose 15 mg/kg). The donors were all unrelated donors and were 10/10 HLA matched (n=10) or 9/10 matched (n=5). Transplantation outcomes were compared to a historical group of 100 patients with similar patient and transplant characteristics given unrelated donor transplant with a standard anti GVHD cyclosporine/ methotrexate GVHD prevention regimen.Results: Eighteen patients completed the planned two days of carfilzomib on day 1 and 2 post-transplant. One patient had only one dose and one none of the doses due to adverse events that dictated stopping treatment by protocol. The median follow-up is 11 months (range 1-29). All patients engrafted with a median of 15 days (range, 10-31) compared with 14 days (range, 9-23) in the control group (P=0.14). Mucositis grade ≥3 occurred in 60% and 24% of the study patients and historical controls, respectively (P=0.001). There was no difference in the rate of all other grade ≥3 organ toxicities, 20% and 30%, respectively (P=0.36). Acute GVHD grade II-IV occurred in only one patient in the study group, a cumulative incidence of 5% (95%CI, 1-34) compared with 39% (95%CI, 30-50) in the control group (P=0.007). Chronic GVHD occurred in 5 patients in the study group , a cumulative incidence of 58% (95%CI, 30-100) compared with an incidence of 41% in the historical controls (95%CI, 33-52) (P=0.58). Notably, all study pts had mild chronic GVHD while, the incidence of moderate to severe chronic GVHD was 0% and 18% (95%CI, 11-30), respectively (P=0.17). Non-relapse mortality (NRM) occurred in 2 patients on study, one died of acute GVHD and the other of multi-organ failure. The cumulative incidence of NRM was 11% (95%CI, 3-39) and 22% (95%CI, 15-32), in the study and control group, respectively (P=0.68). Finally, only one study patient relapsed, cumulative incidence 8% (95%CI, 1-53), compared to 26% (95%CI, 18-36) in the historical controls (P=0.310). In all, 17/20 study patients are alive with an estimated 2-year survival of 81% (95%CI, 68-100) compared to 56% (95%CI, 46-66) in the control group, respectively (Figure, P=0.31).Conclusions: Carfilzomib in addition to standard cyclosporine/ methotrexate as anti GVHD prophylaxis after unrelated- donor transplant is safe and allows better prevention of acute GVHD without compromising the graft-versus-leukemia effect. The add on of carfilzomib results in favorable outcome. Larger studies with longer follow-up are required to confirm these initial promising results. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PD-1 Is Not a Reliable Marker of Impending Relapse after Allogeneic Stem Cell Transplantation

INTRODUCTIONPost-transplant relapse is a major obstacle to successful allogeneic stem cell transplantation (allo-SCT) in hematologic malignancies. Failure to maintain an effective graft versus leukemia effect (GVL) is one mechanism responsible for post-transplant relapse. There is recent interest in PD-1 and other T cell exhaustion markers as therapeutic targets in cancer immunotherapy, however PD-1 inhibitors might induce graft versus host disease (GVHD) after allo-SCT. Therefore, understanding PD-1 kinetics in allo-SCT is needed before using check point inhibitors to prevent or treat relapse. Here we evaluated the relationship between leukemia relapse and the kinetics of T-cell exhaustion markers during the early post-transplant period. We further analyzed the functions of leukemia associated antigen (LAA) specific T-cells from relapsed subjects and sought for the mechanism of post-transplant relapse at a single cell level. METHODSEighty-five patients with various hematologic malignancies received ex-vivo T-cell depleted HLA matched related sibling allo-SCT at a single center between 2006 and 2015. All subjects were treated with a myeloablative conditioning regimen of cyclophosphamide, fludarabine, and total body irradiation with GVHD prophylaxis of low-dose cyclosporine for 21 days. Peripheral blood mononuclear cells (PBMCs) were collected from donors and recipients at 30, 60, and 100 days following transplant and at relapse to characterize regulatory T cells and T cell exhaustion markers by flow cytometry. Samples from six relapsed subjects with acute leukemias were evaluated for 5LAAs (WT1, PRAME, NY-ESO1, MAGEA3, AURAK) by RT-PCR and LAA specific T-cells by Elispot and flow cytometry. LAA specific T cells in one subject were further analyzed for single cell RNAseq. RESULTSAt a median follow up of 3.4 years, 35 patients had relapsed with a 5-year cumulative relapse incidence of 44% at a median time of 226 days. Post-relapse survival was poor among subjects relapsing before 180 days post allo-SCT (median post-relapse survival 126 days vs. 329 days for patients relapsing after 180 days; P=0.004). In the early post-transplant period, PD-1 expression in CD4 and CD8 T-cells was significantly and comparably elevated in both relapsed and non-relapsed cohorts as compared to donors. No association was observed between relapse incidence and pattern of PD-1 expression. In contrast, Helios+Tregs frequency was significantly higher in the relapsed cohort at day 30 (Figure 1). Among six relapsed subjects, at least one LAA was detected in PBMCs before and after relapse. LAA specific T-cells were observed in four subjects, however all samples eventually expressed new LAA different from the ones targeted by their own LAA specific T-cells suggesting immunological escape of leukemic blasts. Of note, LAA specific T-cells were predominantly enriched in the PD-1 negative fraction (Figure 2). Single cell analysis in one patient revealed a distinct cluster with the other exhaustion marker, LAG3 in PRAME specific T-cells in comparison to CMV specific T-cells. CONCLUSIONOur findings contradict the prevailing view that PD-1+ T cell exhaustion is a prominent feature of leukemic relapse after SCT. We found that PD-1 was overexpressed in T-cells during the early post-transplant period in all patients and PD-1 expression patterns did not identify patients destined to relapse. Furthermore, the leukemia antigen specific T-cells did not overexpress PD-1, instead single cell analysis revealed LAG3 overexpression in one patient at relapse. These findings do not support PD-1 is the predominate marker for leukemia specific T cell exhaustion in relapsing patients but point to other exhaustion markers or suppressor Treg cells as causes of relapse. Further studies are required to identify predictive biomarkers for check point inhibitors in hematologic malignancies and the patterns of LAA expression in residual disease following allo-SCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Demographic and Clinical Donor Characteristics as Predictors of Total Nucleated Cell Concentrations in Harvested Marrow Products

Successful allogeneic hematopoietic stem cell transplantation (alloHSCT) relies significantly on adequate allograft cell composition to achieve sustained engraftment, and a minimum of 2×108 total nucleated cells (TNCs) per kilogram of recipient body weight has been identified as the prerequisite cell dose for successful engraftment of marrow-derived products. To meet this minimum requirement, marrow harvest volumes are estimated based on anticipated TNC concentrations of 18.3×106/mL. However, there is considerable variability in marrow TNC concentrations. Thus, an algorithm that incorporates baseline donor characteristics to predict TNC concentrations could optimize outcomes for both donors and recipients. For this study, donor baseline characteristics and corresponding unstimulated marrow products harvested between 2004 and 2017 at a single large-volume donor center were collected. Multivariable analysis was used to identify significant predictors of TNC concentration. Two models-ordinary least squares (OLS) and least absolute shrinkage and selection operator (LASSO) regression-were compared for their fitness to the data and their utility in predicting TNCs. Donors with higher body mass index, younger age, male sex, white race/ethnicity, smaller harvest volumes, lower preharvest hematocrit, higher preharvest platelet count, and higher preharvest WBC count predicted significantly higher TNC concentrations in marrow products. When comparing predictive models that incorporate these characteristics, the cross-validated LASSO and bootstrapped OLS provided the best fit. We now supply these formulas to be validated in other datasets before clinical use. TNC concentration in marrow products can be predicted using donor characteristics, most of which are readily available during the donor clinical assessment. The ability to predict marrow allograft TNC concentrations can optimize collection volumes during a harvest.

Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients.

Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.