Lymphocyte numbers need to be quite tightly regulated. It is generally assumed that lymphocyte production and lifespan increase homeostatically when lymphocyte numbers are low and, vice versa, return ...to normal once cell numbers have normalized. This widely accepted concept is largely based on experiments in mice, but is hardly investigated in vivo in humans. Here we quantified lymphocyte production and loss rates in vivo in patients 0.5-1 year after their autologous hematopoietic stem cell transplantation (autoHSCT). We indeed found that the production rates of most T- and B-cell subsets in autoHSCT-patients were two to eight times higher than in healthy controls, but went hand in hand with a threefold to ninefold increase in cell loss rates. Both rates also did not normalize when cell numbers did. This shows that increased lymphocyte production and loss rates occur even long after autoHSCT and can persist in the face of apparently normal cell numbers.
The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) ...as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL.
In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation.
Unadjusted overall survival was 54% (95% confidence interval CI, 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001).
Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM.
Immune checkpoint inhibition (ICI) can induce durable responses in patients with advanced malignancies. Three cases of hematological neoplasia following ICI for solid tumors have been reported to ...date. We present five patients treated at our tertiary referral center between 2017 and 2021 who developed chronic myeloid leukemia (two patients), acute myeloid leukemia, myelodysplastic syndrome and chronic eosinophilic leukemia during or after anti-PD-1-based treatment. Molecular analyses were performed on pre-ICI samples to identify baseline variants in myeloid genes. We hypothesize that PD-1 blockade might accelerate progression to overt myeloid malignancies and discuss potential underlying mechanisms.
Background
We recently reported results of the prospective, open‐label HOVON‐100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first‐line treatment with or without ...clofarabine (CLO). No improvement of event‐free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity.
Aim
In order to investigate the effects of CLO in more depth, two multi‐state models were developed to identify why CLO did not show a long‐term survival benefit despite more MRD‐negativity.
Methods
The first model evaluated the effect of CLO on going off‐protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment‐related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models.
Results
Overall, patients receiving CLO went off‐protocol more frequently than control patients (35/168 21% vs. 18/166 11%, p = 0.019; HR 2.00 1.13–3.52, p = 0.02), especially during maintenance (13/44 30% vs. 6/56 11%; HR 2.85 95%CI 1.08–7.50, p = 0.035). Going off‐protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD‐negativity compared with control patients (HR MRD‐negativity: 1.35 0.95–1.91, p = 0.10), which did not translate into a significant survival benefit.
Conclusion
We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.
We developed two multi‐state models to identify in more depth why clofarabine (CLO) did not show a long‐term survival benefit despite more MRD‐negativity, as recently reported in the HOVON‐100 trial. Patients receiving CLO went off‐protocol (indicated by the left figures) more frequently than control patients (HR 2.00 1.13–3.52, p = 0.02)—especially during maintenance (HR 2.85 95%CI 1.08–7.50, p = 0.035)—and showed a trend towards an increased rate of MRD‐negativity (indicated by the right figures) (HR 1.35 0.95–1.91, p = 0.10); however, neither transition significantly affected subsequent survival estimates. We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.
Background Enterococcus faecium has rapidly emerged as a nosocomial pathogen worldwide, and the majority of these isolates belong to clonal complex-17 (CC17). In Europe, CC17 isolates are usually ...ampicillin-resistant, but most are still vancomycin-sensitive. We aimed to study ampicillin-resistant E. faecium (ARE) epidemiology in our hospital. Methods In a 3 month study, 210 of 358 admissions (59%) to haematology and gastroenterology/nephrology were screened for rectal ARE colonization on admission (<48 h) and 148 of 210 (70%) also at discharge (<72 h). In a second (3 month) study, environmental swabs from eight predetermined sites were obtained from ARE-colonized haematology patients once weekly. All ARE isolates were genotyped by multiple-locus variable-number tandem repeat analysis (MLVA). Results ARE admission prevalence was 10% and 16% and acquisition rates were 39% and 15% in haematology and gastroenterology/nephrology, respectively. Carriage on admission was associated with previous admission <1 year (OR 5.0, 95% CI 1.8–14.0) and acquisition with β-lactam (OR 2.7, 95% CI 1.1–6.7) and quinolone use (OR 3.1, 95% CI 1.1–8.2). Five of the 57 (9%) colonized patients developed invasive ARE infections. Genotyping revealed 12 genotypes (all CC17) with two MLVA types responsible for 94% of acquisitions. In 18 of the 19 colonized patients, the environment was contaminated with ARE. Sites most often contaminated were the toilet seat (43%), over-bed table (34%) and television remote control (28%). Conclusions CC17 ARE epidemiology is characterized by high admission (10% to 16%), acquisition (15% to 39%) and environmental contamination (22%) rates, resulting from cross-transmission, readmission and antibiotic pressure. A multifaceted infection control approach will be needed to curtail further spread.
Introduction
Chronic Graft Versus Host Disease (cGVHD) has a large impact on morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Therapeutic approaches for cGVHD ...are limited. Affected patients require long-term use of immunosuppressive drugs, mainly corticosteroids combined with a calcineurin inhibitor, which lead to severe side effects. Options for second line therapy are numerous but no consensus on the most favourable choice of agents has been reached. Both monotherapy with rituximab (Cutler, Miklos et al. 2006, Kharfan-Dabaja, Mhaskar et al. 2009, van Dorp, Resemann et al. 2011) and monotherapy with tyrosine kinase inhibition (Magro, Mohty et al. 2009, Olivieri, Locatelli et al. 2009) have shown to be effective in reducing cGVHD symptoms.
Materials and Methods
We performed a prospective study to test whether the sequential therapy of the anti-CD20 antibody rituximab followed by a 6 month treatment period with nilotinib, a tyrosine kinase inhibitor, is a favorable treatment strategy for patients with sclerotic cGVHD (EudraCT nr 2008-004125-42). All patients were evaluated monthly according to NIH cGVHD consensus response criteria working group recommendations from 2005. Serial blood sampling was performed every other month.
Results
We included 29 patients, 5 patients went offstudy (1 with side effects rituximab, 2 with gastro-intestinal side effects nilotinib, 1 patient had progression of M. Hodgkin, 1 patient due to viral encephalitis with cognitive impairment), 24 are available for analysis. Baseline characteristics are depicted in table 1. We observed a response in 71% (2 patients CR, 15 patients PR). Only 1 patient showed progressive disease (PD) and the remaining 6 patients showed stable disease (SD). Moreover, 2 out of 5 patients who suffered from severe ulcerations at the start of the study had a complete resolution of ulcers at the end of the treatment period. Responding patients show a significant decrease in cGVHD affected body surface area (Figure 1) mostly explained by a significant reduction in nonmoveable sclerosis. Patients with a (partial) response also show a clinically relevant decrease in self attributed severity of cGVHD. On a scale of 10 points their self-attributed cGVHD severity decreased in the PD+SD group with a mean of 0,3 points whilst in the PR+CR group there was a mean decrease of 2,4 points. Fifty percent of responding patients could taper >50% of their daily prednisolone dose at the end of the study period. Other immunosuppressive drugs (ciclosporin, MMF) could also be tapered. Rituximab was well tolerated except for 1 patient who showed a neurological syndrome resembling Guillain Barre after 2 infusions and therefor went offstudy. Nilotinib was dosed 300mg b.i.d. however only 9 patients tolerated this dose without side effects. For the remaining patients the dose was decreased to 200mg b.i.d. which was well tolerated for the majority. Most encountered side effects included fatigue, nausea, pain in extremities and prolonged QT-interval on standard ECG monitoring.
Conclusions
The combination of B-cell depletion and tyrosine kinase inhibition provides a new and interesting alternative treatment option for this difficult and heavily pretreated patient category. Approximately 70% of patients achieve a (partial) response with a decrease of sclerosis, an improved quality of life and a significant reduction in the use of corticosteroids. Two patients reached a complete resolution of all cGVHD related symptoms which is seldom achieved. How to prospectively designate which patients will benefit from this treatment strategy is currently under investigation.
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