Bone marrow GvHD after allogeneic hematopoietic stem cell transplantation

The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT. The complex balance between immunosuppressive and cell-depleting treatments, GvHD and immune reconstitution, as well as the desirable graft-versus-tumor (GvT) effect remains a great challenge for clinicians

Impact of early remission by induction therapy on allogeneic stem cell transplantation for acute myeloid leukemia with an intermediate risk karyotype in first complete remission

For patients with acute myeloid leukemia (AML) early achievement of remission during induction treatment is an important predictor for long-term outcome irrespective of the type of consolidation therapy employed. Here, we retrospectively examined the prognostic impact of early remission (ER) versus delayed remission (DR) in a cohort of 132 AML patients with an intermediate risk karyotype undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). In contrast to patients showing DR, patients achieving ER had a significantly higher 3-year overall survival (OS) and disease-free survival (DFS) of 76% versus 54% (p=0.03) and 76% versus 53% (p=0.03). Likewise, three years after alloSCT the cumulative incidence of relapse (CI-R) was significantly lower in the ER subgroup as compared to patients achieving DR, i.e. 10% versus 35% (p=0.004), whereas non-relapse mortality (NRM) did not differ significantly. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, p=0.002) and a higher CI-R (HR 3.55, p=0.002). Taken together, these data may indicate that the rapid achievement of remission predicts a favorable outcome in patients with intermediate risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be fully overcome by alloSCT

Editorial: Modulation of human immune parameters by anticancer therapies

Contains fulltext : 229590.pdf (publisher's version ) (Open Access

Rabbit antithymocyte globulin induces rapid expansion of effector memory CD8 T cells without accelerating acute graft versus host disease

Rabbit antithymocyte globulin (Thymoglobulin(®)) is commonly used as graft-versus-host disease (GvHD) prophylaxis. Since we found similar total CD8 T cell numbers in patients with and without Thymoglobulin(®) therapy within the first six months after allogeneic hematopoietic stem cell transplantation, we have analyzed the reconstitution of the CD8 T cell compartment in detail. After T cell-depletion, higher and more sustained proliferative capacity of memory CD8 T cells resulted in their rapid expansion, whereas the fraction of naive CD8 T cells decreased. Importantly, this shift towards effector memory CD8 T cells did not accelerate the incidence of GvHD

Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation

BACKGROUND: After hematopoietic stem cell transplantation (HSCT) T- and B-cell reconstitution from primary lymphoid organs are a prerequisite for an effective early lymphocyte reconstitution and a long-term survival for adult patients suffering from acute leukemia. Here, we asked whether quantification of T cell receptor excision circle, (TREC) and kappa-deleting recombination excision circle (KREC) before and within six month after allogeneic HSCT could be used to measure the thymic and bone marrow outputs in such patients. METHODS: We used a duplex real time PCR assay to quantify the absolute copy counts of TREC and KREC, and correlated the data with absolute cell counts of CD3+CD4+ T-cell and CD19+ B-cell subsets determined by flow cytometry, respectively. RESULTS: By comparing two recently proposed naive T cell subsets, CD31+ naive and CD31- naive T cells, we found a better correlation for the CD31+ subset with TREC level post alloHSCT, in line with the assumption that it contained T cells recently derived from the thymus, indicating that TREC levels reflected real thymic de novo production. Transitional as well as naive B cells highly correlated with KREC levels, which suggested an association of KREC levels with ongoing bone marrow B cell output. CD45RO+ memory T cells and CD27+ memory B cells were significantly less correlated with TREC and KREC recovery, respectively. CONCLUSION: We conclude that simultaneous TREC/ KREC quantification is as a suitable and practicable method to monitor thymic and bone marrow output post alloHSCT in adult patients diagnosed with acute leukemia

Acute left ventricular insufficiency in a Burkitt Lymphoma patient with myocardial involvement and extensive local tumor cell lysis: a case report

BACKGROUND: Burkitt lymphoma (BL) is a rare disease with the sporadic variant accounting for less than 1% of adult non-Hodgkin lymphomas. BL usually presents with an abdominal bulk, but extranodal disease affecting the bone marrow and central nervous system is common. Cardiac manifestations, however, are exceedingly rare, with less than 30 cases reported in the literature. CASE PRESENTATION: We report on a 54-year-old male patient with a six week-long history of paranasal sinus swelling, fatigue and dyspnea on exertion. Stage IV sporadic BL with extensive lymphonodal and cardiovascular involvement was diagnosed. Manifestations included supra- and infradiaphragmatic lymphadenopathy as well as infiltration of the aortic root, the pericardium, the right atrium and the right ventricle. EBV-reactivation was detected, which is uncommon in the sporadic subtype. After initial full-dose chemotherapy with very good BL control, the patient developed acute, but fully reversible cardiac insufficiency. Myocardial lymphoma involvement receded completely during the following two therapy cycles, while cardiac function periodically deteriorated shortly after chemotherapy administration and quickly recovered thereafter. Interestingly, the decline in cardiac function lessened with decreasing myocardial lymphoma manifestation. Once the cardiovascular BL infiltration was resolved, cardiac function remained stable throughout further treatment. Following seven cycles of chemotherapy and mediastinal radiation, the patient is now in continued complete remission. CONCLUSIONS: Although rare, cardiac involvement in BL can quickly become life-threatening due to rapid lymphoma doubling time and should therefore be considered at initial diagnosis. This case suggests an association between myocardial infiltration, chemotherapy associated tumor cell lysis and transient deterioration of cardiac function until the damage caused by the underlying lymphoma could be restored. While additional studies are needed to further elucidate the mechanisms of acute cardiac insufficiency due to lymphoma lysis in the infiltrated structures, prompt BL control and full recovery of the patient supports courageous treatment start despite extensive cardiovascular involvement

Long-term observation of the frequency of secondary colorectal cancer and other malignancies in tyrosine kinase inhibitor treated chronic myeloid leukemia patients and controls

In this analysis, we examined the risk of secondary malignancies for tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients. We also collected data on specific risk factors for colorectal cancer. Ninety-one patients with CML and 76 controls were included and in total 4 (4.4%) secondary malignancies were found in patients and 8 (10.5%) in controls. The risk for secondary malignancies was not significantly elevated for CML patients (p = 0.141). Two (2.2%) CML patients developed colorectal cancer compared to 4 (5.3%) in the reference group. A higher risk for CML patients for colorectal cancer could not be found (p = 0.414)

Simultaneous genetic ablation of PD-1, LAG-3, and TIM-3 in CD8 T cells delays tumor growth and improves survival outcome

Immune checkpoint inhibitors (ICI) represented a step forward in improving the outcome of patients with various refractory solid tumors and several therapeutic regimens incorporating ICI have already been approved for a variety of tumor entities. However, besides remarkable long-term responses, checkpoint inhibition can trigger severe immune-related adverse events in some patients. In order to improve safety of ICI as well as T cell therapy, we tested the feasibility of combining T cell-based immunotherapy with genetic disruption of checkpoint molecule expression. Therefore, we generated H-Y and ovalbumin antigen-specific CD8(+) T cells with abolished PD-1, LAG-3, and TIM-3 expression through CRISPR/Cas9 technology. CD8(+) T cells, subjected to PD-1, LAG-3, and TIM-3 genetic editing, showed a strong reduction in immune checkpoint molecule expression after in vitro activation, while no relevant reduction in responsiveness to in vitro stimulation was observed. At the same time, in B16-OVA tumor model, transferred genetically edited OT-1 CD8(+) T cells promoted longer survival compared to control T cells and showed enhanced expansion without associated toxicity. Our study supports the notion that antigen-specific adoptive T cell therapy with concomitant genetic disruption of multiple checkpoint inhibitory receptors could represent an effective antitumor immunotherapy approach with improved tolerability profile

Long-term in vitro expansion ensures increased yield of central memory T cells as perspective for manufacturing challenges

Adoptive T cell therapy (ATT) has revolutionized the treatment of cancer patients. A sufficient number of functional T cells is indispensable for ATT efficacy; however, several ATT dropouts have been reported due to T cell expansion failure or lack of T cell persistence in vivo. With the aim of providing ATT also to those patients experiencing insufficient T cell manufacturing via standard protocol, we evaluated if minimally manipulative prolongation of in vitro expansion (long-term (LT) >3 weeks with IL-7 and IL-15 cytokines) could result in enhanced T cell yield with preserved T cell functionality. The extended expansion resulted in a 39-fold increase of murine CD8(+) T central memory cells (Tcm). LT expanded CD8(+) and CD4(+) Tcm cells retained a gene expression profile related to Tcm and T memory stem cells (Tscm). In vivo transfer of LT expanded Tcm revealed persistence and anti-tumor capacity. We confirmed our in vitro findings on human T cells, on healthy donors and diffuse large B cell lymphoma patients, undergoing salvage therapy. Our study demonstrates the feasibility of an extended T cell expansion as a practicable alternative for patients with insufficient numbers of T cells after the standard manufacturing process thereby increasing ATT accessibility