Regulatory T Cells in Allogeneic Stem Cell Transplantation

Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their “first-in-man” clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation

Novel Strategies for Immunotherapy in Multiple Myeloma: Previous Experience and Future Directions

Multiple myeloma (MM) is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation is a relatively effective treatment, but residual malignant sites may cause relapse. Allogeneic transplantation may result in durable responses due to antitumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. Cellular immunotherapy using specific antigen-presenting cells (APCs), to overcome aspects of immune incompetence in MM patients, has received great attention, and numerous clinical trials have evaluated the potential for dendritic cell (DC) vaccines as a novel immunotherapeutic approach. This paper will summarize the data investigating aspects of immunity concerning MM, immunotherapy for patients with MM, and strategies, on the way, to target the plasma cell more selectively. We also include the MM antigens and their specific antibodies that are of potential use for MM humoral immunotherapy, because they have demonstrated the most promising preclinical results

Sensitive Replicate Real-Time Quantitative PCR of BCR-ABL Shows Deep Molecular Responses in Long-Term Post–Allogeneic Stem Cell Transplantation Chronic Myeloid Leukemia Patients

n/

Second hematopoietic stem cell transplantation as salvage therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after a first transplantation

Second allogeneic hematopoietic stem-cell transplantation (HSCT2) is a therapeutic option for patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) relapsing after a first transplant (HSCT1). However, patients allocated to HSCT2 may be a selected group with better prognosis and the added efficacy of HSCT2 is not well established. We retrospectively analyzed 407 consecutive patients with relapsed AML/MDS after HSCT1. Sixty-two patients had HSCT2 (15%) and 345 did not. The 2-year cumulative incidence rates of non-relapse mortality and relapse after HSCT2 were 26% (95% confidence interval [95% CI]: 17-39%) and 50% (95% CI: 39-65%), respectively. The 5-year overall survival rates were 25% (95% CI: 14-36%) and 7% (95% CI: 4-10%) in the HSCT2 and no-HSCT2 groups, respectively. Multivariate analysis identified female gender (hazard ratio [HR]=0.31, P=0.001), short remission duration after HSCT1 (HR=2.31, P=0.05), acute graft-versus-host disease after HSCT1 (HR=2.27, P=0.035), HSCT2 from a haplo-identical donor (HR=13.4, P=0.001) or matched unrelated donor (HR=4.53, P=0.007) and relapse after HSCT1 in earlier years (HR=2.46, P=0.02) as factors predicting overall survival after HSCT2. Multivariate analysis of all patients including HSCT2 as a timedependent variable identified relapse within 6 months after HSCT1 (HR=2.32, P<0.001), acute graft-versus-host disease before relapse (HR=1.47, P=0.005), myeloablative conditioning in HSCT1 (HR=0.67, P=0.011), female gender (HR=0.71, P=0.007), relapse in earlier years (HR=1.33, P=0.031) and not having HSCT2 (HR=1.66, P=0.010) as predictive of overall survival after relapse. In conclusion, HSCT2 is associated with longer survival compared to non-transplant treatments and may be the preferred approach in a subset of patients with relapsed AML/MDS after HSCT1

The Role of Donor Selection for a Second Allogeneic Stem Cell Transplantation in Patients with AML Relapsing after a First Transplant; A Study on Behalf of the Acute Leukemia Working Party of EBMT

Abstract Introduction. Recurrent disease is the major cause of treatment failure after allogeneic stem cell transplantation (SCT) in patients with AML. Second SCT (SCT2) is a valid treatment option in this setting but outcome is relatively poor. Haplo-identical (haplo) SCT is increasingly used over the last decade due to the introduction of non T-depleted methods. Prior studies have shown similar outcome when using the same or different HLA-matched donor for SCT2. However, there is relatively limited data on the use of haplo-donors. Methods and Results. The study included 556 patients with AML relapsing after a first allogeneic SCT (SCT1) given in CR1 from an HLA-matched sibling (sib, n= 294) or a matched unrelated donor (MUD, n=262) and given SCT2 during the years 2006-2016. The median age at SCT2 was 46 years (20-73). 247 patients were in CR2 (44%) and 309 had active leukemia (55%) at the time of SCT2. The conditioning regimen was myeloablative (MAC, 66%) or reduced-intensity (RIC, 34%) for SCT1, and 41% and 59%, respectively for SCT2. 19% of all patients had acute GVHD grade II-IV and 20% had chronic GVHD after SCT1 and before relapse. Patients were divided into 3 groups based on the donor selected for SCT2; 1) same donor (n=163, sib/sib-112, MUD/MUD-51), 2) different HLA-matched donor (n=305, sib/different sib-44, sib/MUD-93, MUD/ different MUD- 168), 3) haplo-donor (n=88, sib/haplo-45, MUD/haplo-43). All haploSCT were non T-depleted. There were some differences between the 3 groups in the timing of relapse and SCT2. The median time from SCT1 to relapse was similar; 10.6, 12.5 and 9.3 months, respectively (P=0.14). However, the median time from relapse to SCT2 was shorter for the same donor group; 2.8, 3.7 and 3.5 months, respectively (P<0.001) and the median time between SCT1 and SCT2 was longer for the different donor group; 14.3, 17.5 and 13.8 months, respectively (P=0.03). There were no difference between the groups in patient age, gender, disease status at SCT2 or conditioning regimen intensity for SCT1 or SCT2. The 2-year leukemia-free survival (LFS) after SCT2 was 23.5%, 23.7% and 21.8%, respectively (unadjusted P=0.30). Multivariate analysis of factors predicting relapse after SCT2 showed no effect of the second donor type, hazard ratio (HR) 0.96 (P=0.83) and 1.20 (P=0.47) for different matched donor and haplo-donor compared to the same donor, respectively. MUD donor in SCT1, CR2 compared to active disease and chronic GVHD after SCT1 were associated with reduced relapse risk after SCT2, HR 0.70 (P=0.02), 0.60 (P=0.001) and 0.66 (P=0.03), respectively. Age, gender, conditioning regimen used for SCT1 or SCT2 and time to first relapse or to SCT2 did not predict relapse rate after SCT2. The second donor type did predict for non-relapse mortality (NRM) after SCT2; HR 1.26 (P=0.41) and 2.18 (P=0.02) for different matched donor and haplo-donor compared to same donor, respectively. Advanced age and MAC in SCT1 also predicted for NRM, HR 1.40 (P<0.001) and 0.61 (P=0.04), respectively. The second donor also predicted for LFS after SCT2; HR 1.05 (P=0.77) and 1.55 (P=0.03), respectively. Advanced age and SCT2 in CR2 also predicted for LFS; HR 1.11 (P=0.06) and 0.66 (P=0.002), respectively. In all, there were no differences between same or different matched donors in SCT2 outcomes, but haploSCT2 was associated with higher NRM and lower LFS. Significant interaction was detected between second donor type and conditioning for SCT1. The inferior outcome after SCT2 with a haplo-donor was limited to patients given MAC in SCT1. In this setting it was associated with higher relapse and NRM rates and lower LFS, HR 1.86 (P=0.05), 3.40 (P=0.005) and 2.25 (P=0.001), respectively. However, there was no difference in any of these outcomes in patients given RIC in SCT1. Unadjusted analysis showed that in patients with no chronic GVHD after SCT1, haploSCT2 was associated with lower LFS, due to higher NRM. However, LFS was similar in patients with prior chronic GVHD. Multivariate analysis was not feasible due to low patient numbers. Conclusions. Second SCT with the same donor or different matched donor is associated with similar outcomes in patients with relapsed AML after a first SCT. However, SCT2 with a haplo-donor is associated with higher NRM and lower LFS, mostly in patients given MAC in SCT1. Prior chronic GVHD after SCT1 is associated with lower relapse rate after SCT2. The role of prior chronic GVHD in donor selection should be further investigated. Disclosures Finke: Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Gramatzki:Affimed: Research Funding. Stelljes:Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria; MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Stoelzel:Neovii: Speakers Bureau. Mohty:MaaT Pharma: Consultancy, Honoraria

Graft-Versus-Leukemia Effect after Haplo-Identical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with AML- No Association with Graft-Versus-Host Disease (GVHD): A Study on Behalf of the Acute Leukemia Working Party of EBMT.

Introduction Allogeneic stem-cell transplantation (SCT) is curative therapy in AML by providing intensive chemotherapy and enhancing a graft-versus-leukemia (GVL) effect. The GVL effect is usually closely associated with GVHD. The use of haploidentical SCT (haploSCT) is rapidly increasing due to the introduction of non-T depleted methods, in particular with post-transplant cyclophosphamide (PTCy), with similar outcomes as following other donor sources. There is no data whether GVL after haploSCT is associated with GVHD as in matched donor SCT. Methods We assessed the impact of acute and chronic GVHD on SCT outcomes following non-T depleted haploSCT with PTCy, by using a series of landmark analyses. Results The study included 605 patients with AML in CR1 (73%) or CR2 (27%) after haploSCT with PTCy, given during the years 2009-2016. The median age was 53 years (18-76). The overall rate of acute GVHD grade II-IV and III-IV was 28.4% and 8.0%, respectively. The rates of chronic GVHD all grades and extensive were 32.7% and 12.3%, respectively. The 2-year leukemia-free survival (LFS) was 59.9%. 509 patients were alive and leukemia-free 100 days after SCT; 366 had no prior acute GVHD at this landmark, 107 had acute GVHD grade II and 36 had grade III-IV. The subsequent relapse rate was 20.3%, 18.3% and 11.9%, respectively (P=0.60). The subsequent non-relapse mortality (NRM) rate was 10.3%, 19.0% and 35.7%, respectively (P Conclusions Acute and chronic GVHD of any grade were not associated with subsequent relapse. Acute GVHD grade III-IV and extensive chronic GVHD were associated with higher NRM and lower LFS. GVL is thus not closely associated with GVHD after non T-depleted haploSCT with PTCy. Future novel strategies for prevention of significant GVHD are warranted

Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P &lt; 0.001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P &lt; 0.001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0.03) and platelets (P = 0.02) and in a lower incidence of acute graft versus host disease (GvHD) grades II-IV (24% vs. 47%, P = 0.06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0.001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12-37%] for ATG vs. 28% (95% CI = 15-55%) for alemtuzumab, P = 0.7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39-75%) vs. 45% (95% CI: 28-73%) and 30% (95% CI: 16-55%) vs. 36% (95% CI: 20-62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2.37; P = 0.05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P &lt; 0.0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma

Allogeneic hematopoietic cell transplantation for patients with TP53 mutant or deleted chronic lymphocytic leukemia : Results of a prospective observational study

Non peer reviewe

Long-term survival and late events after allogeneic stem cell transplantation from HLA-matched siblings for acute myeloid leukemia with myeloablative compared to reduced-intensity conditioning : a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation

Background: Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years) and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods: We analyzed long-term outcomes in a cohort of 1423 AML patients, age >= 50 years, after SCT from HLA-matched siblings, during the years 1997-2005, median follow-up 8.3 years (0.1-17). Results: The 10-year leukemia-free survival (LFS) was 31 % (95CI, 27-35) and 32 % (28-35) after MAC and RIC, respectively (P = 0.57). The 10-year GVHD/relapse-free survival (GRFS), a surrogate for quality of life was 22 % (18-25) and 21 % (18-24), respectively (P = 0.79). The 10-year non-relapse mortality (NRM) was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65-76) and 73 % (67-78) after MAC and RIC, respectively (P = 0.76). Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions: Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.Peer reviewe