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Introduction: Chimeric antigen receptor positive T cell (CAR-T cell) treatment became standard therapy for relapsed or refractory hematologic malignancies, such as non-Hodgkin's lymphoma and multiple myeloma. Owing to the rapidly progressing field of CAR-T cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between centers in the prevention, diagnosis, and management of short- and long-term complications. Methods: To capture the current CAR-T cell management among German centers to determine the medical need and specific areas for future clinical research, the DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie; German Working Group for Hematopoietic Stem Cell Transplantation and Cellular Therapy) performed a survey among 26 German CAR-T cell centers. Results: We received answers from 17 centers (65%). The survey documents the relevance of evidence in the CAR-T cell field with a homogeneity of practice in areas with existing clinical evidence. In contrast, in areas with no – or low quality – clinical evidence, we identified significant variety in management in between the centers: management of cytokine release syndrome, immune effector cell-related neurotoxicity syndrome, IgG substitution, autologous stem cell backups, anti-infective prophylaxis, and vaccinations. Conclusion: The results indicate the urgent need for better harmonization of supportive care in CAR-T cell therapies including clinical research to improve clinical outcome. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for hematologic malignancies but relapse remains the most common cause of death. Infusion of donor lymphocytes (DLIs) can induce remission and prolong survival by exerting graft-vs.-leukemia (GVL) effects. However, sufficient tumor control cannot be established in all patients and occurrence of graft-vs.-host disease (GVHD) prevents further dose escalation. Previous data indicate that invariant natural killer T (iNKT) cells promote anti-tumor immunity without exacerbating GVHD. In the present study we investigated lysis of leukemic blasts through iNKT cells from donor-derived lymphocytes for leukemia control and found that iNKT cells constitute about 0.12% of cryopreserved donor T cells. Therefore, we established a 2-week cell culture protocol allowing for a robust expansion of iNKT cells from cryopreserved DLIs (DLI-iNKTs) that can be used for further preclinical and clinical applications. Such DLI-iNKTs efficiently lysed leukemia cell lines and primary patient AML blasts ex vivo in a dose- and CD1d-dependent manner. Furthermore, expression of CD1d on target cells was required to release proinflammatory cytokines and proapoptotic effector molecules. Our results suggest that iNKT cells from donor-derived lymphocytes are involved in anti-tumor immunity after allo-HCT and therefore may reduce the risk of relapse and improve progression-free and overall survival. [ABSTRACT FROM AUTHOR]

Summary: Donor lymphocyte infusion (DLI) is an effective method to establish full donor chimerism or to prevent and treat relapse after allogeneic haematopoietic cell transplantation (allo‐HCT). Usually, DLIs are collected from naïve donors as steady‐state lymphocytes. When donor lymphocytes are collected during stem cell apheresis, donors are pre‐treated with granulocyte colony‐stimulating factor (G‐CSF). However, the impact of G‐CSF stimulation and the resulting composition of DLIs on beneficial anti‐leukaemic responses and survival remain elusive. Therefore, we performed a retrospective analysis to evaluate the role of G‐CSF‐DLIs: 44 patients received either steady‐state DLIs or G‐CSF‐DLIs to prevent and treat relapse or establish full donor chimerism after allo‐HCT. The G‐CSF‐DLI patient cohort showed an improved conversion to full donor chimerism and a lower cumulative incidence of relapse or disease progression without a significantly increased cumulative incidence of graft‐versus‐host disease (GVHD). CD34+ cells, monocytic myeloid‐derived suppressor cells and monocytes as well as donor age and the subsequent occurrence of chronic GVHD were identified as risk factors that significantly improve overall survival after DLI administration. In conclusion, our data suggest that administration of G‐CSF‐DLIs results in graft‐versus‐leukaemia effects without exacerbating GVHD, therefore, improving survival after DLIs. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) represents the major nonrelapse complication of allogeneic hematopoietic cell transplantation. Although rare, the CNS and the eye can be affected. In this study, manifestation in the retina as part of the CNS and T-cell epitopes recognized by the allogeneic T cells were evaluated. In 2 of 6 patients with posttransplantation retina diseases and 6 of 22 patients without ocular symptoms, antigen-specific T-cell responses against retinaspecific epitopes were observed. No genetic differences between donor and recipient could be identified indicating T-cell activation against self-antigens (graft versus self). Transplantation of a preexisting immunity and cross-reactivity with ubiquitous epitopes was excluded in family donors and healthy individuals. In summary, an immunological reaction against retina cells represents a mechanism of graft-versus-host interaction following hematopoietic cell transplantation. [ABSTRACT FROM AUTHOR]

Natural killer (NK)-cell alloreactivity after allogeneic hematopoietic cell transplantation (HCT) is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and human leukocyte antigen (HLA) class I ligands on recipient cells. We investigated the influence of donor KIR haplotype and KIR-ligand mismatch (MM) on relapse in 57 patients with hematologic malignancies receiving haploidentical HCT after reduced intensity conditioning and graft CD3/CD19 depletion. Of the 57 donors, 17 had KIR haplotype A (29.8 %) and 40 had KIR haplotype B (70.2 %). A KIR-ligand MM was found in 34 of 57 patients (59.6 %). There was no difference between donor KIR haplotypes in non-relapse mortality (NRM, p = 0.200) but had a significantly reduced incidence of relapse for patients with a haplotype B donor ( p = 0.001). In particular, patients in partial remission (PR) benefited more from a haplotype B graft ( p = 0.008) than patients in complete remission (CR, p = 0.297). Evaluating KIR-ligand MM cumulative incidences of relapse ( p = 0.680) or NRM ( p = 0.579), we found no significant difference. In conclusion, in the setting of reduced intensity conditioning (RIC) and CD3/CD19-depleted haploidentical HCT, we could not confirm the positive data with KIR-ligand MM but observed a significant lower risk of relapse with a KIR haplotype B donor. [ABSTRACT FROM AUTHOR]

Patients with primary refractory or relapsed acute myeloid leukemia (AML) have a dismal prognosis. We report a retrospective single center analysis of aplasia-inducing chemotherapy using fludarabine, cytarabine, and amsacrine (FLAMSA) followed by reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (HCT) in 62 consecutive primary refractory or relapsed AML patients. Two-year event-free survival and overall survival (OS) were 26 and 39 %, respectively. Risk stratification according to cytogenetic and molecular genetic markers showed superior survival in patients in the intermediate-1 risk group (2-year OS 70 %) compared to the intermediate-2 risk (2-year OS 34 %, p = 0.03) and adverse risk (2-year OS 38 %, p = 0.06) group. The use of HLA-matched versus HLA-mismatched donors had no significant influence on survival ( p = 0.98). Two-year OS in the elderly subgroup defined by age ≥60 years was 31 % compared to 46 % in the group of younger patients <60 years ( p = 0.19). Cumulative incidence of non-relapse mortality at 2 years adjusted for relapse as competing risk was 20 % for patients <60 years and 26 % for older patients ( p = 0.55). Chronic graft-versus-host disease was associated with a statistically significant superior survival ( p < 0.01). FLAMSA-RIC followed by allogeneic HCT enables long-term disease-free survival in primary refractory or relapsed AML even in the elderly patient population. [ABSTRACT FROM AUTHOR]

The article discusses a study of the outcomes among patients aged 60 years or older after non-myeloablative conditioning and allogeneic hematopoietic cell transplantation (HCT) for advanced hematologic malignancies (AHM). The authors enrolled 372 patients in multicenter, prospective clinical trials of allogeneic HCT for AHM, at 18 centers coordinated through the Fred Hutchinson Cancer Research Center in Seattle, Washington. They calculated the cumulative incidence values for acute and chronic graft-vs-host disease, toxicities, relapse and nonrelapse mortality. They found that there was an association between risks for relapse and worse outcomes.

Summary: Background: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F). Methods: Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III–IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343. Findings: The number of patients in the ATG-F group who had severe aGVHD grade III–IV or who died within 100 days of transplantation was 12 and 10 (21·4%, 95% CI 13·4–29·3), respectively, compared with 24 and nine (33·7%, 24·3–43·0) patients, respectively, in the control group (adjusted odds ratio 0·59, 95% CI 0·30–1·17; p=0·13). The cumulative incidence of aGVHD grade III–IV was 11·7% (95% CI 6·8–19·8) in the ATG-F group versus 24·5% (17·3–34·7) in the control group (adjusted hazard ratio [HR] 0·50, 95% CI 0·25–1·01; p=0·054), and cumulative incidence of aGVHD grade II–IV was 33·0% (n=34; 95% CI 25·1–43·5) in the ATG-F group versus 51·0% (n=50; 95% CI 42·0–61·9) in the control group (adjusted HR 0·56, 0·36–0·87; p=0·011). The 2-year cumulative incidence of extensive chronic GVHD was 12·2% (n=11; 95% CI 7·0–21·3) versus 42·6% (n=34; 95% CI 33·0–55·0; adjusted HR 0·22, 0·11–0·43; p<0·0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes. Interpretation: The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors. Funding: Fresenius Biotech GmbH. [Copyright &y& Elsevier]

Abstract: Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with CD34-selected stem cells has been complicated by high regimen related toxicities, slow engraftment and delayed immune reconstitution leading to increased treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer, graft facilitating and dendritic cells. RIC was performed with fludarabine (150–200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2) and OKT-3 (5 mg/day, day −5 to +14) and no posttransplant immunosuppression. Twenty nine patients (median age=42 (range, 21–59) years) have been transplanted with this regimen. Diagnosis were AML (n =16), ALL (n =7), NHL (n =3), MM (n =2) and CML (n =1). Patients were “high risk” with refractory disease or relapse after preceding HCT. The CD3/CD19 depleted haploidentical grafts contained a median of 7.6×106 (range, 3.4–17×106) CD34+ cells/kg, 4.4×104 (range, 0.006–44×104) CD3+ T cells/kg and 7.2×107 (range, 0.02–37.3×107) CD56+ cells/kg. Donor–recipient KIR-ligand-mismatch was found in 19 of 29 patients. The regimen was well tolerated with maximum acute toxicity being grade 2–3 mucositis. Because of severe neurotoxicity in 4 patients treated with 200 mg/m2 fludarabine, the dose was reduced to 150 mg/m2. Engraftment was rapid with a median time to >500 granulocytes/μL of 12 (range, 10–21) days, >20,000 platelets/μL of 11 (range, 7–38) days and full donor chimerism after 2–4 weeks in all patients. Incidence of grade II–IV° GVHD was 48% with grade II°=10, III°=2 and IV°=2. One patient, who received the highest T-cell dose, developed lethal grade IV GVHD. TRM in the first 100 days was 6/29 (20%) with deaths due to idiopathic pneumonia syndrome (n =1), mucormycosis (n =1), pneumonia (n =3) or GVHD (n =1). Overall survival is 9/29 patients (31%) with deaths due to infections (n =7), GVHD (n =1) and relapse (n =12) with a median follow-up of 241 days (range, 112–1271). In conclusion, this regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing. [Copyright &y& Elsevier]

Highlights • Major mechanisms of relapse include HLA loss, HLA down-regulation, and expression of coinhibitory ligands. • Combination of donor lymphocyte infusion with immunomodulating agents and tyrosine kinase inhibitors may enhance the graft-versus-leukemia (GVL) effect. • Immune checkpoint inhibitors can induce a significant GVL effect, but toxicity is high. ABSTRACT The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs. [ABSTRACT FROM AUTHOR]

Background aims. The CliniMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany) was used for depletion of T-cell receptor alpha/beta positive (TCRαβ+) and CD19 positive (CD19+) cells from apheresis products. Methods. Investigators performed 102 separations. Apheresis products with a median 5.8 (minimum to maximum, 1.2-10.4) × 1010 mononuclear cells were used with a median 358 (92-1432) × 106 CD34+ cells. There were 24.8% (6.1-45.7%) median TCRαβ+ cells and 4.4% (1.2-11.7%) median B cells in the apheresis product. Results. After depletion, a median 0.00097% (0.00025-0.0048%) of TCRαβ+ cells could be detected, and B cells, as determined as CD20+ cells, were reduced to 0.0072% (0.0008-0.072%). TCRαβ+ cells were depleted by log 4.7 (3.8-5.5), and B cells were depleted by log 4.1 (3.0-4.7). Recovery of mononuclear cells was 55% (33-77%), and recovery of CD34+ cells was 73% (43-98%). Recovery of CD56+/3− natural killer cells was 80% (35-142%), recovery of TCR gamma/delta positive (TCRγδ+) T cells was 83% (39-173%) and recovery of CD14+ cells was 79% (22-141%). Viability of cells was 98% (93-99%) after separation (all values median). Conclusions. Profound depletion of TCRαβ+ T cells can be achieved with the CliniMACS system. Recovery of CD34+ stem cells is in the same range than after CD34+ enrichment and CD3/CD19 depletion. Transplantation with >4 × 106 CD34+ cells/kg can be performed for every patient with 1-5 × 104 TCRαβ+ cells/kg and about 5-10 × 106 TCRγδ+ cells/kg with two rounds of apheresis. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic hematopoietic cell transplantation (HCT) is the only curative strategy for patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPD). We report the results of 148 patients (median age = 59 years old) with de novo MDS (n = 40), acute myelogenous leukemia (AML) after antecedent MDS/MPD (n = 49), treatment-related MDS (t-MDS) (n = 25), MPD (n = 27), and chronic myelomonocytic leukemia (CMML) (n = 7) who underwent allogeneic HCT using a conditioning regimen of low-dose total body irradiation (TBI) alone (200 cGy) on day 0 (n = 5) or with the addition of fludarabine (Flu) 30 mg/m2/day on days −4 to −2 (n = 143). Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil (MMF). Seventy-five patients (51%) received an allograft from a matched related donor (MRD), and 73 patients (49%) were recipients of unrelated donor (URD) grafts. There was no significant difference in the incidence of acute (gr II-IV) and chronic extensive graft-versus-host disease (aGVHD, cGVHD) between the recipients of related and unrelated donor grafts. By day +28, 75% of patients demonstrated mixed T cell chimerism. Graft rejection was seen in 15% of patients. With a median follow-up of 47 (range: 6-89) months, the 3-year relapse-free survival (RFS) and overall survival (OS) are both 27% for all patients, with a relapse incidence of 41%. The 3-year RFS for the patients with de novo MDS, AML after antecedent MDS/MPD, t-MDS, MPD, and CMML were 22%, 20%, 29%, 37%, and 43%, respectively, and the 3-year OS was 20%, 23%, 27%, 43%, and 43%, respectively. The 3-year nonrelapse mortality (NRM) was 32%. Factors associated with a lower risk of relapse were the development of extensive cGVHD and having a low risk or intermediate-1 risk International Prognostic Score for the de novo MDS patients. Nonmyeloablative HCT confers remissions in patients who otherwise were not eligible for conventional HCT but for whom relapse is the leading cause of treatment failure. [Copyright &y& Elsevier]

Abstract: We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after nonmyeloablative conditioning and were given postgrafting immunosuppression consisting of mycophenolate mofetil (MMF; administered from day 0 until day +40 with taper through day +96) and cyclosporine (CSP; given from day −3 to day +100, with taper through day 180) (historical patients). The incidences of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 52% and 49%, respectively, and the 1-year probabilities of relapse, nonrelapse mortality (NRM), and progression-free survival (PFS) were 26%, 18%, and 56%, respectively. Here, we treated 71 patients with hematologic malignancies (median age 56 years) with unrelated PBSC grafts and investigated whether postgrafting immunosuppression with an extended course of MMF, given at full dosing until day +150 and then tapered through day +180, and a shortened course of CSP, through day +80, would promote tolerance induction and reduce the incidence of GVHD (current patients). We observed 77% grade II-IV aGVHD and 45% extensive cGVHD (P = .03, and P = .43, respectively, in current compared to historical patients). The 1-year probabilities of relapse, NRM, and PFS were 23%, 29%, and 47%, respectively (P = .89, P = .02, and P = .08 compared to the historical patients). We conclude that postgrafting immunosuppression with extended MMF and shortened CSP failed to decrease the incidence of GVHD among unrelated PBSC recipients given nonmyeloablative conditioning. [Copyright &y& Elsevier]