Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience.

Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity.

Specific abnormalities versus number of abnormalities and cytogenetic scoring systems for outcome prediction after allogeneic hematopoietic SCT for myelodysplastic syndromes.

Newer cytogenetic scoring systems for myelodysplastic syndromes (MDSs), like cytogenetic stratification of the revised international prognostic scoring system (IPSS-R) or monosomal karyotype, may also improve outcome prediction after hematopoietic SCT (HCT). We compared the prognostic value of specific cytogenetic abnormalities, IPSS-R karyotype and monosomal karyotype for HCT outcome in 98 patients with MDS and AML post MDS. Higher-risk IPSS-R karyotype, 3q21q26 and transformation to AML before HCT were associated with increased cumulative incidence of relapse (CIR), whereas OS was adversely influenced by del 5q/-5, abnormalities of chromosomes 11 and 17 and cytogenetic IPSS-R very poor category. Karyotype with ⩽2 abnormalities and no abnormalities of chromosomes 3, 5, 7, 11 and 17 was an independent prognostic factor of lower CIR (hazard ratio (HR)=0.2, P=0.01) and longer OS (HR=0.5, P=0.03). In conclusion, some specific cytogenetic abnormalities and high cytogenetic complexity, as reflected by IPSS-R very poor karyotype, rather than monosomal karyotype, were associated with higher CIR and shorter OS after HCT. Conversely, results were encouraging in patients lacking those abnormalities, who may be very good candidates for HCT.

GVHD-associated chronic kidney disease after allogeneic haematopoietic cell transplantation.

Chronic kidney disease (CKD) has been related to allogeneic haematopoietic cell transplantation (HCT) as a late effect caused by a variety of factors. We retrospectively evaluated the development of CKD in 230 patients, aged 34 (5-65) years, who had undergone allogeneic HCT for haematological disease, using sibling or unrelated donors and myeloablative or reduced conditioning regimens. Pre-HCT glomerular filtration rate (GFR) was within normal limits (108±28 mL/min/1.73 m(2)) in patients who did not develop CKD and 95±24 mL/min/1.73 m(2) in those with CKD postHCT, while the GFR 12 months post transplant declined to 104±26 and 69±19 mL/min/1.73 m(2), respectively. CKD incidence was 20.4%, with a median time of development of 6 (3-18) months post transplant. On multivariate analysis, risk factors for CKD were the presence of chronic GVHD (cGVHD; P=0.001), unrelated donor transplantation (P=0.008), post-transplant event of acute kidney injury (AKI) (P=0.002) and older age (P=0.002). In long-term survivors stable significant predictors for CKD were older age at transplantation, cGVHD and AKI. CKD did not influence non-relapse mortality. In our study, cGVHD emerges as an important cause of kidney injury in HCT survivors, regardless of administration of nephrotoxic agents.

Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation.

Mesenchymal stromal cells (MSCs) are explored as a novel treatment for a variety of medical conditions. Their fate after infusion is unclear, and long-term safety regarding malignant transformation and ectopic tissue formation has not been addressed in patients. We examined autopsy material from 18 patients who had received human leukocyte antigen (HLA)-mismatched MSCs, and 108 tissue samples from 15 patients were examined by PCR. No signs of ectopic tissue formation or malignant tumors of MSC-donor origin were found on macroscopic or histological examination. MSC donor DNA was detected in one or several tissues including lungs, lymph nodes, and intestine in eight patients at levels from 1/100 to <1/1,000. Detection of MSC donor DNA was negatively correlated with time from infusion to sample collection, as DNA was detected from nine of 13 MSC infusions given within 50 days before sampling but from only two of eight infusions given earlier. There was no correlation between MSC engraftment and treatment response. We conclude that MSCs appear to mediate their function through a "hit and run" mechanism. The lack of sustained engraftment limits the long-term risks of MSC therapy.

Therapy-related myelodysplastic syndrome with monosomy 5 and 7 following successful therapy for acute promyelocytic leukemia with anthracyclines.

Myelodysplastic syndrome (MDS) in patients treated for acute promyelocytic leukemia (APL) is a rare event. We describe a patient with APL who developed MDS 40 months after entering complete remission (CR). Karyotypic analysis revealed monosomy 5 and 7, which are cytogenetic changes usually occurring after the use of alkylating agents. The patient had received only anthracyclines as potential leukemogenic drugs. A review of the literature on t-AML/MDS occurring after successful therapy for APL showed three similar cases. These observations suggest that anthracyclines may cause t-AML/MDS similar to that induced by alkylating agents.