Allogeneic hematopoietic stem cell transplantation in patients aged 60-79 years in Germany (1998-2018): a registry study.

Incidences of diseases treated with transplantation frequently peak at higher age. The contribution of age to total risk of transplantation has not been estimated amidst an aging society. We compare outcomes of 1,547 patients aged 70-79 years and 9,422 patients aged 60-69 years transplanted 1998-2018 for myeloid, lymphoid and further neoplasia in Germany. To quantify the contribution of population mortality to survival, we derive excess mortality based on a sex-, year- and agematched German population in a multistate model that incorporates relapse and graft-versus-host-disease (GvHD). Overall survival, relapse-free survival (RFS) and GvHD-free-relapse-free survival (GRFS) is inferior in patients aged 70-79 years, compared to patients aged 60-69 years, with 36% (95% Confidence Interval [CI]: 34-39%) versus 43% (41-44%), 32% (30- 35%) versus 36% (35-37%) and 23% (21-26%) versus 27% (26-28%) three years post-transplant (P<0.001). Cumulative incidences of relapse at three years are 27% (25-30%) for patients aged 70-79 versus 29% (29-30%) (60-69 years) (P=0.71), yet the difference in non-relapse mortality (NRM) (40% [38-43%] vs. 35% [34-36%] in patients aged 70-79 vs. 60-69 years) (P<0.001) translates into survival differences. Median OS of patients surviving >1 year relapse-free is 6.7 (median, 95% CI: 4.5-9.4, 70-79 years) versus 9 (8.4-10.1, 60-69 years) years since landmark. Three years after RFS of one year, excess NRM is 14% (95% CI: 12-18%) in patients aged 70-79 versus 12% [11-13%] in patients aged 60-69, while population NRM is 7% (6-7%) versus 3% (3-3%). Mortality for reasons other than relapse, GvHD, or age is as high as 27% (24-29%) and 22% (22-23%) four years after transplantation. In conclusion, survival amongst older patients is adequate after allogeneic stem cell transplantation.

Natural course of AIDS following HIV-2 infection.

In a 21-year-old female, AIDS following infection with HIV-2 was diagnosed alongside an HIV-associated high-grade B cell lymphoma. Treatment of HIV-2 with dolutegravir, emtricitabine, and tenofovir resulted in viral suppression and slow recovery of CD4 cell counts. Treatment of lymphoma caused significant adverse effects but led to complete remission. The patient denied sexual activity and intravenous drug abuse. The patient had been born to an HIV-2-positive mother but appropriate perinatal testing based on national guidelines had remained negative. This case recapitulates the natural course of HIV-2 infection.

Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial.

Azacitidine (Aza) combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide (Lena) to act synergistically with Aza/DLI to improve outcome. We, therefore, prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia. Patients were scheduled for eight cycles Aza (75 mg/m2 day 1-7), Lena (2.5 or 5 mg, days 1-21) and up to three DLI with increasing T-cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of myelodysplastic syndromes (n=24), acute myeloid leukemia (n=23) or chronic myelomonocytic leukemia (n=3) received a median of seven (range, 1-8) cycles including 14 patients with 2.5 mg and 36 with 5 mg Lena daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lena dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade 2-4 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lena can be safely added to Aza/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse (clinicaltrials gov. Identifier: NCT02472691).

Detection of human herpesvirus 6 DNA and chromosomal integration after allogeneic hematopoietic stem cell transplantation: A retrospective single center analysis.

INTRODUCTION: Human herpesvirus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant morbidity and mortality. METHODS: The epidemiology of HHV-6 infections and their impact on outcome after allo-HSCT were retrospectively analyzed in 689 adult allo-HSCT recipients (January 2015-December 2018). Chromosomal integration of HHV-6 (ciHHV-6) in the donor was retrospectively investigated to critically evaluate antiviral treatment strategies. RESULTS: HHV-6 DNA in any specimen was found in 89 patients. HHV-6 infections (encephalitis (one), gastroenteritis (44), dermatitis (two), hepatitis (one), or pneumonitis (five)) were diagnosed in 53/689 patients (7.7%). Elevated levels of HHV-6 DNA were found in 38 patients (5.5%). ciHHV-6, analyzed in patients with HHV-6 viral loads ≥104  copies/ml, was identified in four patients (10/38 patients; 10.5%). Two of those displayed copy numbers of HHV-6 ranging from ≥2 × 105 to 2.5 × 106  copies/ml (HHV-6A). Here, ciHHV-6 was integrated into donor and not into the patients' cells. In this series of allo-HSCT recipients, 10.5% of patients with blood viral loads of HHV-6 showed ciHHV-6. CONCLUSION: Screening of the donor for ciHHV-6 before initiation of antiviral therapy is recommended.

Post-Transplantation Multicolored Flow Cytometry-Minimal Residual Disease Status on Day 100 Predicts Outcomes for Patients With Refractory Acute Myeloid Leukemia.

Patients with relapsed/refractory acute myeloid leukemia (AML) have a dismal prognosis. Allogeneic stem cell transplantation (allo-SCT) provides a curative approach; however, the overall survival (OS) remains low (20% to 40%). In this setting, although some effective approaches have been evaluated in recent years, the management of such patients still remains challenging. In this study we evaluated the predictive role of post-transplant day 100 minimal residual disease (MRD) detection for post-transplantation outcomes for patients with refractory AML. Fifty-six adult patients with refractory AML (median age 58, range 20-76; male, 61%) who underwent allo-SCT were included in this retrospective monocentric study. Twenty-nine patients (52%) received fludarabine, amsacrine, and cytarabine (FLAMSA)-based conditioning. MRD was assessed using multicolored flow cytometry (MFC) according to European Leukemia Net guidelines ("different from normal" and leukemia-associated phenotype). The sensitivity of the method was 10-4 to 10-5. The median marrow blast count at allo-SCT was 25% (range 6% to 91%). At day 100 after transplantation, 40 patients (71%) experienced MFC-MRD negativity, and 16 patients (29%) were MRD positive. All included patients survived at least 100 days after transplantation without relapse. Univariate and multivariate analysis based on Kaplan-Meier and Cox proportional hazards method were performed. The median follow-up was 16 months (range 3 to 66). The post-transplantation day 100 MRD-negative patients instead received 2 allografts (27% versus 6%, P = .08). In multivariate analysis, day 100 MRD status (negative versus positive) (OS: 0.23 [0.1 to 0.54], P =0.001; relapses: 0.20 [0.1 to 0.49], P = .0005) and FLAMSA versus other regimens (0.34 [0.1 to 0.83], P = .018; relapses: 0.43 [0.17 to 1.1], P = .07) independently impacted post-transplantation survival. We suggest that post-transplantation day 100 MFC-MRD detection plays predictive role in refractory AML patients and may help to define possible candidates for early post-transplantation interventions aiming to decrease the relapse risk and improve survival.

Comparison of immune reconstitution between anti-T-lymphocyte globulin and posttransplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation.

Anti-T-cell lymphocyte globulin (ATLG) and posttransplant cyclophosphamide (PTCy) are now widely used strategies to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Data comparing immune reconstitution (IR) between ATLG and PTCy is scarce. This retrospective study conducted at the University Medical Center Hamburg-Eppendorf (UKE) compares PTCy (n=123) and ATLG (n=476) after myeloablative allogeneic peripheral blood stem cell transplant. Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100 and 180 posttransplant. Incidence of infections, viral reactivations, GVHD and relapse were collected. Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. day 10, P<0.001) with a high incidence of infection before day+100 in the PTCy arm but a higher Epstein-Barr virus reactivation in the ATLG arm and comparable cytomegalovirus reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was seen more often after PTCy (44% vs. 38%, P=0.005). ATLG resulted in a faster reconstitution of CD8+ T, NK, NKT and gdT cells while CD4 T cells and B cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B cells. Non-relapse mortality relapse incidence, disease-free survival, and overall survival did not differ significantly between both arms. Even though differences in IR were related to a decreased incidence of infection and moderate/severe cGVHD in the ATLG group they had no impact on any of the other long-term outcomes. However, it remains undetermined which regimen is better as GVHD prophylaxis.

Time-dependent analysis of adoptive immunotherapy following sequential FLAMSA-reduced intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with high-risk myeloid neoplasia.

Prophylactic donor lymphocyte infusions (DLI) are part of the sequential FLAMSA-reduced intensity conditioning (RIC) regimen to cure high risk myeloid neoplasia with allogeneic hematopoietic stem cell transplantation (HSCT). Although DLI themselves carry significant risks, their prophylactic use has not been analyzed in a time-dependent manner. One hundred and fourteen patients underwent FLAMSA-RIC HSCT between 2013 and 2020. Next to Kaplan-Meier estimation of overall, disease-free, and graft-versus-host relapse-free survival (OS, DFS, GRFS), cumulative incidences of relapse and death in remission were calculated in a competing risk model. Additionally, the contribution of prophylactic and preemptive DLI as time-dependent covariates was assessed using a time-varying model toward DFS (Simon-Makuch method, Mantel-Byar test). At 2 years, OS was 45.2% [95% CI 36.7-55.7%], DFS 31.8% [95% CI 24-42.2%] and GRFS 11.3 [95% CI 6.5-19.8]. Neither prophylactic nor preemptive DLI showed a significant influence on DFS when considered time-dependent covariates (Mantel-Byar, p = .3). This was further corroborated in competing risk analysis with DLI as time-dependent covariates. Both prophylactic and preemptive DLI miss significance in their impact on survival within a high-risk cohort in a time-varying model. Controlled trials to address the impact of postgrafting immunotherapy approaches are needed.

Risk factors for outcome after allogeneic stem cell transplantation in patients with advanced phase CML.

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n = 96) or accelerated phase (n = 51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in ≥CP2 (n = 70), in AP (n = 40) or in BC (n = 37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD34+ count in the graft, donor age (>36 years) and BC. Cumulative incidence of Non-Relapse Mortality (NRM) was 28% (95% CI 18-38) and of relapse (RI) 43% (95% CI 33-53) at 15 years. PB-HSCT and HSCT after 2008 were favorable prognostic factors for NRM, while family donor and patient age >39 years were independently associated with higher RI. HSCT resulted in long-term OS in patients with advanced CML. OS was improved in non-BC patients, with donors ≤36 years and with higher CD34+ dose in the graft.

Multi-dimensional and longitudinal systems profiling reveals predictive pattern of severe COVID-19.

COVID-19 is a respiratory tract infection that can affect multiple organ systems. Predicting the severity and clinical outcome of individual patients is a major unmet clinical need that remains challenging due to intra- and inter-patient variability. Here, we longitudinally profiled and integrated more than 150 clinical, laboratory, and immunological parameters of 173 patients with mild to fatal COVID-19. Using systems biology, we detected progressive dysregulation of multiple parameters indicative of organ damage that correlated with disease severity, particularly affecting kidneys, hepatobiliary system, and immune landscape. By performing unsupervised clustering and trajectory analysis, we identified T and B cell depletion as early indicators of a complicated disease course. In addition, markers of hepatobiliary damage emerged as robust predictor of lethal outcome in critically ill patients. This allowed us to propose a novel clinical COVID-19 SeveriTy (COST) score that distinguishes complicated disease trajectories and predicts lethal outcome in critically ill patients.

TKI Maintenance After Stem-Cell Transplantation for FLT3-ITD Positive Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis.

This analysis aimed to systematically review and synthesize the existing evidence regarding the outcome of tyrosine kinase inhibitor (TKI) maintenance therapy after allogeneic stem-cell transplantation for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). We searched publicly available databases, references lists of relevant reviews, registered trials, and relevant conference proceedings. A total of 7 studies comprising 680 patients were included. Five studies evaluated sorafenib and 2 studies evaluated midostaurin, compared with control. The incidence of relapse was significantly reduced after TKI therapy, showing an overall pooled risk ratio (RR) of 0.35 (95% confidence interval [CI], 0.23-0.51; P < 0.001), with a marked 65% reduced risk for relapse. The overall pooled RR for relapse-free survival and overall survival showed significantly improved outcome after TKI maintenance therapy, being 0.48 (95% CI, 0.37-0.61; P < 0.001) and 0.48 (95% CI, 0.36-0.64; P < 0.001). The risk for relapse or death from any cause was reduced by 52% using TKI. No difference in outcome was seen for non-relapse mortality, and the risk for chronic or acute graft-vs. -host disease appeared to be increased, at least for sorafenib. In conclusion, post-transplant maintenance therapy with TKI was associated with significantly improved outcome in relapse and survival in patients with FLT3-ITD positive AML.

Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematologic malignancies and solid tumors: 2020 updated guidelines of the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO/DGHO).

Hematologic and oncologic patients with chemo- or immunotherapy-related immunosuppression are at substantial risk for bacterial infections and Pneumocystis jirovecii pneumonia (PcP). As bacterial resistances are increasing worldwide and new research reshapes our understanding of the interactions between the human host and bacterial commensals, administration of antibacterial prophylaxis has become a matter of discussion. This guideline constitutes an update of the 2013 published guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). It gives an overview about current strategies for antibacterial prophylaxis in cancer patients while taking into account the impact of antibacterial prophylaxis on the human microbiome and resistance development. Current literature published from January 2012 to August 2020 was searched and evidence-based recommendations were developed by an expert panel. All recommendations were discussed and approved in a consensus conference of the AGIHO prior to publication. As a result, we present a comprehensive update and extension of our guideline for antibacterial and PcP prophylaxis in cancer patients.

Comparison of clinical characteristics and disease outcome of COVID-19 and seasonal influenza.

While several studies have described the clinical course of patients with coronavirus disease 2019 (COVID-19), direct comparisons with patients with seasonal influenza are scarce. We compared 166 patients with COVID-19 diagnosed between February 27 and June 14, 2020, and 255 patients with seasonal influenza diagnosed during the 2017-18 season at the same hospital to describe common features and differences in clinical characteristics and course of disease. Patients with COVID-19 were younger (median age [IQR], 59 [45-71] vs 66 [52-77]; P < 0001) and had fewer comorbidities at baseline with a lower mean overall age-adjusted Charlson Comorbidity Index (mean [SD], 3.0 [2.6] vs 4.0 [2.7]; P < 0.001) than patients with seasonal influenza. COVID-19 patients had a longer duration of hospitalization (mean [SD], 25.9 days [26.6 days] vs 17.2 days [21.0 days]; P = 0.002), a more frequent need for oxygen therapy (101 [60.8%] vs 103 [40.4%]; P < 0.001) and invasive ventilation (52 [31.3%] vs 32 [12.5%]; P < 0.001) and were more frequently admitted to the intensive care unit (70 [42.2%] vs 51 [20.0%]; P < 0.001) than seasonal influenza patients. Among immunocompromised patients, those in the COVID-19 group had a higher hospital mortality compared to those in the seasonal influenza group (13 [33.3%] vs 8 [11.6%], P = 0.01). In conclusion, we show that COVID-19 patients were younger and had fewer baseline comorbidities than seasonal influenza patients but were at increased risk for severe illness. The high mortality observed in immunocompromised COVID-19 patients emphasizes the importance of protecting these patient groups from SARS-CoV-2 infection.

A prognostic score including mutation profile and clinical features for patients with CMML undergoing stem cell transplantation.

The inclusion of mutation status improved risk stratification for newly diagnosed patients with chronic myelomonocytic leukemia (CMML). Stem cell transplantation is a potentially curative treatment option, and patient selection is critical because of relevant transplant-related morbidity and mortality. We aimed to evaluate the impact of mutation status together with clinical presentations on posttransplant outcome. Our study included 240 patients with a median follow-up of 5.5 years. A significant association with worse survival was identified for the presence of mutations in ASXL1 and/or NRAS. In multivariable analysis, ASXL1- and/or NRAS-mutated genotype (hazard ratio [HR], 1.63), marrow blasts >2% (HR, 1.70), and increasing comorbidity index (continuous HR, 1.16) were independently associated with worse survival. A prognostic score (CMML transplant score) was developed, and the following points were assigned: 4 points for an ASXL1- and/or NRAS-mutated genotype or blasts >2% and 1 point each for an increase of 1 in the comorbidity index. The CMML transplant score (range, 0-20) was predictive of survival and nonrelapse mortality (P < .001 for both). Up to 5 risk groups were identified, showing 5-year survival of 81% for a score of 0 to 1, 49% for a score of 2 to 4, 43% for a score of 5 to 7, 31% for a score of 8 to 10, and 19% for a score >10. The score retained performance after validation (concordance index, 0.68) and good accuracy after calibration. Predictions were superior compared with existing scores designed for the nontransplant setting, which resulted in significant risk reclassification. This CMML transplant score, which incorporated mutation and clinical information, was prognostic in patients specifically undergoing transplantation and may facilitate personalized counseling.

Role of pre-transplant MRD level detected by flow cytometry in recipients of allogeneic stem cell transplantation with AML.

OBJECTIVES AND METHODS: We analyzed the impact of pretransplant MRD level in bone marrow measured by flow cytometry using "different from normal" method on outcomes for 189 AML patients (108 males; median age, 58 (21-80) years). All patients were subdivided into negative (n = 96), "low" (0.1%-0.5%, n = 32), and "high" MRD (>0.5%, n = 61) groups. RESULTS: In multivariate analysis, the hazard ratios for "high" and "low" MRD levels related to MRD negativity were 7.9 (95% CI 3.5-18.1, P < .001) and 5.4 (95% CI 2.1-14, P = .0058) for relapse; 2.3 (95% CI 1.3-4.1, P = .006) and 1.6 (95% CI 0.82-3.3, P = .16) for OS; and 2.8 (95% CI 1.7-4.7, P < .001) and 2.2 (95% CI 1.1-4.2, P = .02) for LFS, respectively. We found no significant impact of "low" MRD level on relapses (0.68, 95% CI 0.33-1.4, P = .30), OS (0.72, 95% CI: 0.36-1.5, P = .36) and LFS (0.79, 95% CI: 0.42-1.5, P = .46) related to "high" MRD group. CONCLUSIONS: Presence of detectable MRD was indicative for a high relapse risk, low LFS and OS. "Low" MRD level showed no significant impact on relapse, LFS and OS related to "high" MRD group.

Long-Term Survival Benefit after Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia.

The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients age ≤70 years at diagnosis who underwent allo-HCT (n = 119) compared with those who did not (n = 142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower risk (CPSS low/intermediate-1) or higher risk (intermediate-2/high) showed significantly improved outcomes after transplantation in higher-risk patients, with a 37% reduced hazard for death. However, although higher CPSS was associated with worse outcomes in the nontransplantation group, the score was of limited utility for post-transplantation risk stratification. This study may provide further support for the potentially beneficial role of allo-HCT in terms of long-term survival in higher-risk patients but also underscores the need for transplantation-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of patients with CMML.