Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: final analysis of KEYNOTE-170.

Previous analyses of the phase 2 KEYNOTE-170 (NCT02576990) study demonstrated effective antitumor activity and acceptable safety of pembrolizumab 200 mg given every 3 weeks for up to 35 cycles (∼2 years) in patients with relapsed/refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) whose disease progressed after or who were ineligible for autologous stem cell transplantation. The end points included objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR) according to the investigator per 2007 Response Criteria; overall survival (OS); and safety. In this final analysis, median duration of follow-up was 48.7 months (range, 41.2-56.2). The ORR was 41.5% (complete response, 20.8%; partial response, 20.8%). The median DOR was not reached; no patients who achieved a complete response progressed at the data cutoff. The median PFS was 4.3 months; the 4-year PFS rate was 33.0%. The median OS was 22.3 months; the 4-year OS rate was 45.3%. At the data cutoff, 30 patients (56.6%) had any-grade treatment-related adverse events (AEs); the most common were neutropenia, asthenia, and hypothyroidism. Grade 3/4 treatment-related AEs occurred in 22.6% of the patients; no grade 5 AEs occurred. After 4 years of follow-up, pembrolizumab continued to provide durable responses, with promising trends for long-term survival and acceptable safety in R/R PMBCL.

Glofitamab in relapsed/refractory diffuse large B-cell lymphoma: Real-world data.

Glofitamab is a CD3xCD20 bi-specific antibody with two fragments directed to the CD20 antigen and a single CD3-binding fragment. Encouraging response and survival rates were recently reported in a pivotal phase II expansion trial conducted in patients with relapsed/refractory (R/R) B-cell lymphoma. However, the real-world data of patients of all ages with no strict selection criteria are still lacking. Herein, this retrospective study aimed to evaluate the outcomes of diffuse large B-cell lymphoma (DLBCL) patients who received glofitamab via compassionate use in Turkey. Forty-three patients from 20 centers who received at least one dose of the treatment were included in this study. The median age was 54 years. The median number of previous therapies was 4, and 23 patients were refractory to first-line treatment. Twenty patients had previously undergone autologous stem cell transplantation. The median follow-up time was 5.7 months. In efficacy-evaluable patients, 21% and 16% of them achieved complete response and partial response, respectively. The median response duration was 6.3 months. The median progression-free survival (PFS) and overall survival (OS) was 3.3 and 8.8 months, respectively. None of the treatment-responsive patients progressed during the study period, and their estimated 1-year PFS and OS rate was 83%. The most frequently reported toxicity was hematological toxicity. Sixteen patients survived, while 27 died at the time of the analysis. The most common cause of death was disease progression. One patient died of cytokine release syndrome during the first cycle after receiving the first dose of glofitamab. Meanwhile, two patients died due to glofitamab-related febrile neutropenia. This is the largest real-world study on the effectiveness and toxicity of glofitamab treatment in R/R DLBCL patients. The median OS of 9 months seems promising in this heavily pretreated group. The toxicity related mortality rates were the primary concerns in this study.

Posttransplant cyclophosphamide-based anti-graft-vs-host disease prophylaxis in patients with acute lymphoblastic leukemia treated in complete remission with allogeneic hematopoietic cell transplantation from human leukocyte antigen-mismatched unrelated donors versus haploidentical donors: A study on behalf of the ALWP of the EBMT.

BACKGROUND: Both mismatched unrelated donor (MMUD) and haploidentical (haplo) transplantation are valid options in patients with high-risk acute lymphoblastic leukemia (ALL) lacking a matched donor. METHODS: The study compared the outcomes of adult patients with ALL in complete remission (CR) who underwent 9/10 MMUD versus haplo transplantation with posttransplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis in 2010-2020. RESULTS: The study included 781 patients (MMUD, 103; haplo, 678). The median age was 40 (19-73) and 38 (18-75) years, respectively (p = .51). The most frequent immunosuppression agents added to PTCy were mycophenolate mofetil (MMF)/cyclosporine A and MMF/tacrolimus. In vivo T-cell depletion (anti-thymocyte globulin) was administered to 21% and 8% of the transplants, respectively (p < .0001). Neutrophil (absolute neutrophil count >0.5 × 109 /L) recovery was achieved in 97.1% versus 96.7% versus (p = 1) in MMUD and haplo, respectively. Nonrelapse mortality and relapse incidence were not significantly different between MMUD and haplo, hazard ratio (HR) = 1.45 (95% confidence interval [CI], 0.81-2.62; p = .21) and HR = 0.81 (95% CI, 0.52-1.28, p = .38), respectively. HRs for leukemia-free survival, overall survival, and GVHD-free, relapse-free survival were respectively, HR = 1.05 (95% CI, 0.73-1.50, p = .8), HR = 1.17 (95% CI, 0.77-1.76, p = .46), and HR = 1.07 (95% CI, 0.78-1.46, p = .7) for haplo compared to MMUD. Acute (a)GVHD grade 2-4 was significantly higher with haplo, HR = 1.73 (95% CI, 1.08-2.76, p = .023), whereas aGVHD grade 3-4 and chronic GVHD did not differ significantly between the two transplant groups. CONCLUSION: Outcomes of MMUD and haplo transplants with PTCy-based GVHD prophylaxis for ALL patients in CR are similar, apart from a higher incidence of aGVHD with haplo transplants.

An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q): Gain of 16p13.3.

Deletion 13q [del(13q)] is a favorable prognostic marker if it is detected as a sole abnormality in chronic lymphocytic leukemia (CLL). However the clinical courses of cases with isolated del(13q) are quite heterogeneous. In our study, we investigated copy number variations (CNVs), loss of heterozygosity (LOH), and the size of del(13q) in 30 CLL patients with isolated del(13q). We used CGH+SNP microarrays in order to understand the cause of this clinical heterogeneity. We detected del(13q) in 28/30 CLL cases. The size of the deletion varied from 0.34 to 28.81 Mb, and there was no clinical effect of the deletion size. We found new prognostic markers, especially the gain of 16p13.3. These markers have statistically significant associations with short time to first treatment and advanced disease stage. Detecting both CNVs and LOH at the same time is an advantageous feature of aCGH+SNP. However, it is very challenging for the array analysis to detect mosaic anomalies. Therefore, it is very important to confirm the results by FISH. In our study, we detected approximately 9% mosaic del(13q) by microarray. In addition, the gain of 16p13.3 may affect the disease prognosis in CLL. However, additional studies with more patients are needed to confirm these results.

Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia.

Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P<0.001), peripheral blood graft source (P=<0.001) and transplanted at an earlier time-period (median year of HCT 2011 vs. 2015). The 100-day grade II-IV and III-IV acute-GVHD was similar between ATG and PTCy, as was 2-year chronic-GVHD. On multivariate analysis (MVA), leukemia-free survival (LFS) and overall survival (OS) was better with PTCy compared to ATG prophylaxis. Relapse incidence (RI) was lower in the PTCy group (P=0.03), while non-relapse mortality (NRM) was not different. Advanced disease and lower performance score were associated with poorer LFS and OS and advanced disease with inferior GVHD-free/relapse-free survival (GRFS). Peripheral grafts were associated with higher GVHD compared to bone marrow grafts. In ALL patients undergoing unmanipulated haplo-HCT, PTCy for GVHD prevention resulted in lower RI and improved LFS and OS compared to ATG.

Role of Therapeutic Plasma Exchange in Guillain-Barre Syndrome after Allogeneic Hematopoietic Stem Cell Transplant: Report of Two Cases.

BACKGROUND: Guillain-Barre Syndrome (GBS) is an acute inflammatory polyneuropathy characterized with rapid, progressive, ascending, and symmetrical weakness and areflexia. It is supposed to be an autoimmune disease related with production of antibodies by T lymphocytes activated against antigenic proteins of the peripheral nerves. Guillain-Barre Syndrome occurring after hematopoietic stem cell transplant (HSCT) has been associated with viral infections or toxic effects of chemotherapy. METHODS: We report two GBS cases after HSCT treated successfully by means of therapeutic plasma exchange. RESULTS: In a total of 257 patients, 2 cases (0.8%) were diagnosed with GBS following HSCT. Allogeneic HSCT was performed and complete remission was achieved. Diagnosis of GBS was established on the 45th and 69th days with respect to clinical, cerebrospinal fluid, and electromyography findings. Patients did not respond to treatment consisting of intravenous immunoglobulins (IVIG) (1 g/kg/day) for 2 days and methylprednisolone (1 g/kg/day). Mechanical ventilation was indicated in one patient due to the involvement of respiratory muscles. Therapeutic plasma exchange resulted in complete recovery in both cases. CONCLUSIONS: Guillain-Barre Syndrome is a rare but serious complication, which may occur after HSCT. Increased awareness and early diagnosis are crucial in the management of GBS. First line treatment consists of IVIG and steroids and therapeutic plasma exchange must be considered without delay in refractory cases.

Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for T Cell Acute Lymphoblastic Leukemia: A Report from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients without an HLA-identical donor, haploidentical (haplo-) HCT is becoming the leading source of stem cell donation. However, data are scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age, 31 years; range, 18 to 68 years) with T-ALL who underwent haplo-HCT with post-transplantation cyclophosphamide (ptCy) between 2010 and 2017. The median duration of follow-up of living patients was 23 months. The 2-year incidences of relapse and nonrelapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS), and graft-versus-host disease, relapse-free survival (GRFS) were 34%, 42%, and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplantation, being 49% and 55%, respectively, for patients in first complete remission (CR1); 34% and 50%, respectively, for those in second CR (CR2); and 8% and 12%, respectively, for patients with active disease. On multivariate analysis, only disease status was found to affect LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at the time of haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in patients in CR. Despite the limitation of the small sample size, our results were not affected by the type of conditioning, calling into question the need for total body irradiation-based myeloablative conditioning in that setting.

Influence of donor type, stem cell source and conditioning on outcomes after haploidentical transplant for lymphoma - a LWP-EBMT study.

Haploidentical stem cell transplantation (haploSCT) is becoming a major transplant modality for lymphoma. To assess the effects of donor characteristics, stem cell source and conditioning on outcomes, we identified 474 adults with Hodgkin (HL; 240), peripheral T-cell (PTCL; 88), diffuse large B-cell (77), mantle cell (40) or follicular lymphoma (FL; 29), who received haploSCT with post-transplant cyclophosphamide. Median follow-up of alive patients was 32 months. On multivariate analysis, acute graft-versus-host disease (GVHD) grade 2-4 was lower with offspring donors or bone marrow cells, whereas extensive chronic GVHD was higher in partial response at haploSCT or when using sisters, haploidentical donors beyond first degree, or female donors in male patients. Progression-free survival (PFS) was better for FL, HL and PTCL, whereas overall survival (OS) was better for HL and PTCL. Complete remission at haploSCT improved PFS and OS whereas these were negatively affected by cytomegalovirus donor positive/recipient positive status. No other donor characteristics (age, gender, human leucocyte antigen mismatch, ABO incompatibility) affected PFS or OS except use of haploidentical donors beyond first degree, which negatively affected OS. PFS and OS are mostly influenced by disease status and lymphoma subtype, supporting the use of any first degree haploidentical family member as a donor.

Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience.

Classical Hodgkin lymphoma (cHL) is considered a curable disease; however, in approximately one-third of the responding patients, the disease relapses following completion of therapy. One of the drugs that have been approved for the treatment of relapsed/refractory cHL is nivolumab, an immune check point inhibitor that shows its effects by blocking the programmed death 1 (PD-1) receptor. In this study, we present a retrospective "real-life" analysis of the usage of nivolumab in patients with relapsed/refractory cHL that have joined the named patient program (NPP) for nivolumab, reflecting 4 years of experience in the treatment of relapsed/refractory cHL. We present a retrospective analysis of 87 patients (median age, 30) that participated in the NPP in 24 different centers, who had relapsed/refractory cHL and were consequently treated with nivolumab. The median follow-up was 29 months, and the median number of previous treatments was 5 (2-11). In this study, the best overall response rate was 70% (CR, 36%; PR, 34%). Twenty-eight of the responding patients underwent subsequent stem cell transplantation (SCT). Among 15 patients receiving allogeneic stem cell transplantation, 9 patients underwent transplantation with objective response, of which 8 of them are currently alive with ongoing response. At the time of analysis, 23 patients remained on nivolumab treatment and the rest discontinued therapy. The main reason for discontinuing nivolumab was disease progression (n = 23). The safety profile was acceptable, with only nine patients requiring cessation of nivolumab due to serious adverse events. The 24-month progression-free and overall survival rates were 58.5% (95% CI, 0.47-0.68) and 78.7% (95% CI, 0.68-0.86), respectively. Eighteen patients died during the follow-up and only one of these was regarded to be treatment-related. With its efficacy and its safety profile, PD-1 blockers became an important treatment option in the heavily pretreated cHL patients.

Impact of total body irradiation- vs chemotherapy-based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia.

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P < .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs 27% (P < .01) and extensive cGVHD incidence was 9% vs 12% (P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI- and 65 (7%) CT-MAC recipients (P = .08). Death from veno-occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2-3.1, P < .01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy.

CD34+ cell dose effects on clinical outcomes after T-cell replete haploidentical allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia using peripheral blood stem cells. A study from the acute leukemia working Party of the European Society for blood and marrow transplantation (EBMT).

Previous observations have reported controversial conclusions regarding cell dose and survival endpoints after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis on 414 adult patients (median age 54 years, range, 18-74 years) with acute myeloid leukemia (AML) in first and second complete remission. They received a T-cell replete allogeneic HSCT from haploidentical donors, using peripheral blood stem cells, between 2006-2018. Median number of infused CD34+ was 6.58 × 106 /kg (range, 2.2-31.2 × 106 /kg). Graft-vs-host disease (GVHD) prophylaxis was post-transplant cyclophosphamide in 293 patients and anti-lymphocyte serum in 121 patients. Conditioning was myeloablative in 179 patients and reduced-intensity in 235 patients. After a median follow-up of 23.3 months (range, 12.1-41.8 months), 2-year overall survival (OS) was 64.5% (95% CI 59.3%-69.7%) with leukemia-free survival (LFS) of 57.3% (95% CI 51.8%-62.7%) and non-relapse mortality (NRM) of 23.3% (95% CI 19%-27.7%). Grades III-IV acute GVHD day+100 incidence was 14.6% while extensive chronic GVHD was 14.4% at 2-years. Thirteen (3.2%) patients experienced graft failure. We found the optimal CD34+/kg threshold defining high (n = 334) vs low cell dose (n = 80) at 4.96 × 106 . Recipients of >4.96 × 106 /kg CD34+ cells experienced less NRM (Hazard ratio [HR] 0.48; 95% CI 0.30-0.76) and prolonged LFS (HR 0.63; 95% CI 0.43-0.91) and OS (HR 0.60; 95% CI 0.40-0.88) compared to those in the lower cell dose cohort. Larger cohort studies are needed to confirm these findings.

Brentuximab vedotin for recurrent Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation: A report from the EBMT Lymphoma Working Party.

BACKGROUND: The treatment of patients with Hodgkin lymphoma (HL) who develop disease progression after undergoing allogeneic stem cell transplantation (allo-SCT) remains challenging. METHODS: The authors assessed outcomes in 184 adult patients with HL who developed disease recurrence or progression after a matched related or unrelated allo-SCT at European Society for Blood and Marrow Transplantation-participating centers between 2010 and 2014. RESULTS: Eighty patients who received brentuximab vedotin (BV) salvage therapy were compared with 104 patients who did not. Patients in the BV group were younger (median age of 30 years vs 34 years) and were more likely to receive pretransplant BV (65% vs 46%) or posttransplant donor lymphocyte infusion (66% vs 33%). The 2 groups otherwise were comparable. Patients in the BV group received a median of 6 doses of posttransplant BV, resulting in a complete remission rate of 29%, a partial response rate of 45%, and a stable disease rate of 26%. Response to BV after allo-SCT did not appear to be affected by receipt of pretransplant BV. Despite a longer median follow-up for surviving patients in the BV group (33 months vs 23 months; P<.001), approximately 34% of the original BV cohort were alive and in CR at the time of last follow-up versus 18% in the group that did not receive BV (P=.003). The use of BV before donor lymphocyte infusion was found to be associated with the highest probability of being alive and in CR (40%) at the time of last follow-up. Salvage BV appeared to have no effect on chronic graft-versus-host disease or 1-year overall survival from the time of disease recurrence after allo-SCT (76% vs 67%). CONCLUSIONS: BV is a safe and effective salvage therapy for patients with HL who develop disease recurrence or progression after undergoing allo-SCT, even after prior exposure to BV.

Cytokine Profile, Apoptosis, Glucocorticoid Receptor, and P-glycoprotein Expression Before and After Megadose Methylprednisolone Treatment in Children With Acute Immune Thrombocytopenia.

OBJECTIVE: Immune thrombocytopenia (ITP) is an autoimmune disease, and it has become evident that T lymphocytes play an important role in the pathogenesis of ITP. We investigated the role of T helper (Th) intracellular IL-2, IL-4, IL-6, IFN-γ, and T lymphocyte apoptosis in the pathogenesis of acute ITP and the effect of glucocorticoid treatment on cytokine profile. We investigated also P-glycoprotein (P-gp) and glucocorticoid receptor (GCR) expression as a possible mechanism for glucocorticoid resistance. MATERIAL AND METHODS: The study includes 20 children with acute ITP having a platelet count <20,000/mm and 20 healthy children as a control group. Patients with acute ITP were treated with megadose methylprednisolone (MDMP) (MDMP in the dose of 30 mg/kg/d between day 1 and 3 and 20 mg/kg/d between day 4 and 7). Th intracellular IL2, IL-4, IL-6, and IFN-γ percentages, T-cell P-gp expression, T-cell and monocyte GCR expression, and T-cell apoptosis were evaluated before and after treatment in acute ITP patients and in the control group. RESULTS: Acute ITP patients had significantly higher Th IL-2, IL-4, IL-6, and IFN-γ percentages compared with the control group (P<0.05). Th IL-2 and IFN-γ percentages were significantly lowered with MDMP treatment (P<0.05). IFN-γ/IL-4 ratio was also lowered with the MDMP treatment (P<0.05). T-lymphocyte P-gp expression and T lymphocyte and monocyte GCR expression were all similar between acute ITP pretreatment and control groups (P>0.05). T-lymphocyte P-gp expression was higher in the posttreatment group than in the pretreatment group (P<0.05). Both T lymphocyte and monocyte GCR expression percentages were not different in the pretreatment and posttreatment groups (P>0.05). Early apoptosis in T lymphocytes was significantly lower in the pretreatment acute ITP group than in the control group (P<0.05). Necrotic apoptosis in T lymphocytes was significantly increased with MDMP treatment (P<0.05). CONCLUSIONS: Th1 and Th2 cytokine profile is observed in acute ITP pathogenesis, and MDMP treatment causes Th1 to Th2 cytokine profile shift and induction of T-lymphocyte apoptosis. There is a need to have a greater number of resistant cases in order to better evaluate the P-gp and GCR expression in glucocorticoid resistance in acute ITP.

Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide.

BACKGROUND: Incidence of graft-versus-host disease (GVHD) in haploidentical bone marrow (BM) transplants using posttransplantion cyclophosphamide (PT-Cy) is low, whereas GVHD using mobilized peripheral blood stem cells (PBSC) ranges between 30% and 40%. METHODS: To evaluate the effect of stem cell source in haploidentical transplantation with PT-Cy, we analyzed 451 patients transplanted for acute myeloid leukemia or acute lymphoblastic leukemia reported to the European Society for Blood and Marrow Transplantation. RESULTS: BM was used in 260 patients, and PBSC were used in 191 patients. The median follow-up was 21 months. Engraftment was lower in BM (92% vs 95%, P < 0.001). BM was associated with a lower incidence of stage II-IV and stage III-IV acute GVHD (21% vs 38%, P ≤ .01; and 4% vs 14%, P < .01, respectively). No difference in chronic GVHD, relapse, or nonrelapse mortality were found for PBSC or BM. The 2-year overall survival (OS) was 55% versus 56% (P = .57) and leukemia-free survival (LFS) was 49% versus 54% (P = .74) for BM and PBSC, respectively. On multivariate analysis, PBSC were associated with an increased risk of stage II-IV (hazard ratio [HR], 2.1; P < .001) and stage III-IV acute GVHD (HR, 3.8; P < .001). For LFS and OS, reduced intensity conditioning was the only factor associated with treatment failure (LFS: HR, 1.40; P = .04) and relapse (HR, 1.62; P = .02). CONCLUSION: In patients with acute leukemia in first or second remission receiving haploidentical transplantation with PT-Cy, the use of PBSC increases the risk of acute GVHD, whereas survival outcomes are comparable. Cancer 2018;124:1428-37. © 2018 American Cancer Society.

Donor age determines outcome in acute leukemia patients over 40 undergoing haploidentical hematopoietic cell transplantation.

Haploidentical hematopoietic cell transplantation (haplo-HCT) is being increasingly used in acute leukemia patients as an alternative transplant modality when matched sibling or matched unrelated donors are unavailable. As several potential haploidentical relative donors are typically available for a given patient, optimizing donor selection to improve clinical outcome is crucial. The impact of donor age and kinship on the outcome of acute leukemia patients is not clearly established in this setting. Using the multinational registry of the acute leukemia working party of the European society for blood and marrow transplantation we retrospective analyzed the clinical outcome of 1270 acute myeloid leukemia and acute lymphoblastic leukemia patients who underwent haplo-HCT between 2005 and 2015. Patients over the age of 40 were significantly affected by increasing donor age resulting in higher non-relapse mortality (NRM) [Hazard ratio (HR)=1.86, confidence interval (CI) 95%, 1.18-2.94; P = .007], inferior leukemia-free survival (LFS) (HR = 1.59, CI 95%, 1.13-2.24; P = .007), and overall survival (OS) (HR = 1.74, CI 95%, 1.22-2.47; P = .002) when donors were over the age of 40. Additionally, kinship was found to be prognostically significant as patients transplanted from children donors over the age of 35 experienced an increased rate of NRM (HR = 1.82, CI 95%, 1.13-2.9; P = .01), inferior LFS (HR = 1.5, CI 95%, 1.05-2.13; P = .03), and OS (HR = 1.5, CI 95%, 1.04-2.15; P = .03). For patients younger than 40 years, donor age and kinship were mostly not clinically impactful. Our data establish donor age and kinship as significant determinants of outcome following haplo-HCT for acute leukemia patients.

Haploidentical stem cell transplantation-bone marrow vs peripheral blood.

Hematopoietic stem cells may be obtained by collection of bone marrow, mobilization and collection of peripheral blood stem cells or umbilical cord blood. Transplantation of peripheral blood hematopoietic cells has increased due to faster engraftment and practicability in both the related, unrelated or haploidentical setting. We reviewed the question of which stem cell source - bone marrow (BM) or peripheral blood (PBSC) - is the most suitable for individuals undergoing haploidentical stem cell transplantation. BM or PBSC could be safely used as allograft sources for haploidentical transplantation with good outcomes and acceptable rates of GVHD and graft failure. Prospective randomized studies are needed to evaluate the effect of PB vs BM in haploidentical settings.

Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients: Intercontinental Prospective Study of the Infectious Diseases Working Party of the European Bone Marrow Transplantation Group.

BACKGROUND: This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). METHODS: GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas ß-lactams (noncarbapenems), carbapenems, and multidrug resistance. RESULTS: Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and ß-lactam/ß-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on ß-lactam/ß-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. CONCLUSIONS: Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. CLINICAL TRIALS REGISTRATION: NCT02257931.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma-related bone disease in patients who had a partial response or better after frontline high-dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35-day cycles of bortezomib 1·6 mg/m2 intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent-to-treat population included 104 patients (51 bortezomib, 53 observation). There were no meaningful differences in the primary endpoint of change from baseline to end of treatment in bone mineral density (BMD). End-of-treatment rates (bortezomib versus observation) of complete response/stringent complete response were 22% vs. 11% (P = 0·19), very good partial response or better of 80% vs. 68% (P = 0·17), and progressive disease of 8% vs. 23% (P = 0·06); median progression-free survival was 44·9 months vs. 21·8 months (P = 0·22). Adverse events observed ≥15% more frequently with bortezomib versus observation were diarrhoea (37% vs. 0), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0) and vomiting (16% vs. 0). Compared with observation, bortezomib appeared to have little impact on bone metabolism/health, but was associated with trends for improved myeloma response and survival.

Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant.

Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3-4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09-2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04-2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03-2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98-2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia.

Impact of ABO incompatibility on patients' outcome after haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia - a report from the Acute Leukemia Working Party of the EBMT.

A significant proportion of hematopoietic stem cell transplants are performed with ABO-mismatched donors. The impact of ABO mismatch on outcome following transplantation remains controversial and there are no published data regarding the impact of ABO mismatch in acute myeloid leukemia patients receiving haploidentical transplants. Using the European Blood and Marrow Transplant Acute Leukemia Working Group registry we identified 837 patients who underwent haploidentical transplantation. Comparative analysis was performed between patients who received ABO-matched versus ABO-mismatched haploidentical transplants for common clinical outcome variables. Our cohort consisted of 522 ABO-matched patients and 315 ABO-mismatched patients including 150 with minor, 127 with major, and 38 with bi-directional ABO mismatching. There were no significant differences between ABO matched and mismatched patients in terms of baseline disease and clinical characteristics. Major ABO mismatching was associated with inferior day 100 engraftment rate whereas multivariate analysis showed that bi-directional mismatching was associated with increased risk of grade II-IV acute graft-versus-host disease [hazard ratio (HR) 2.387; 95% confidence interval (CI): 1.22-4.66; P=0.01). Non-relapse mortality, relapse incidence, leukemia-free survival, overall survival, and chronic graft-versus-host disease rates were comparable between ABO-matched and -mismatched patients. Focused analysis on stem cell source showed that patients with minor mismatching transplanted with bone marrow grafts experienced increased grade II-IV acute graft-versus-host disease rates (HR 2.03; 95% CI: 1.00-4.10; P=0.04). Patients with major ABO mismatching and bone marrow grafts had decreased survival (HR=1.82; CI 95%: 1.048 - 3.18; P=0.033). In conclusion, ABO incompatibility has a marginal but significant clinical effect in acute myeloid leukemia patients undergoing haploidentical transplantation.