Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.

Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.

Dendritic Cell Recovery Impacts Outcomes after Umbilical Cord Blood and Sibling Donor Transplantation for Hematologic Malignancies.

Dendritic cells (DCs) orchestrate immune responses after allogeneic hematopoietic cell transplantation (HCT). We studied the association of donor myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) recovery in the landmark analysis of umbilical cord blood (UCB) and matched related donor (RD) HCT. Eighty patients (42 UCB and 38 RD recipients) with a day 100 blood sample were included in the analysis. Median age was 51 years (range, 20 to 71). Most patients had acute leukemia (50%) or lymphoma (23%) and received reduced-intensity conditioning (75%). After transplantation, UCB recipients had higher DC counts than RD recipients reaching normal levels at day 100 after transplantation (UCB median 4.7 cells/µL versus RD median 1.7 cells/µL). UCB recipients with high day 100 pDCs levels (≥ median) had 2-fold lower risk of relapse compared with those with pDClow (14% versus 28%, P = .29) and a trend to improved 1-year survival in multivariate analysis with hazard ratio of .22 (95% confidence interval, .04 to 1.05; P = .057). Cytomegalovirus (CMV) reactivation had adverse impact on DC reconstitution at day 100 in both UCB and RD groups and almost exclusively affected the mDC subset (CMV reactivation: mDC 3.2 cells/µL versus no CMV reactivation: 7.8 cells/µL; P = .004). Collectively, these data suggest that high levels of circulating pDCs at day 100 after UCB transplantation confer a survival advantage at 1 year.

Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection.

The optimal treatment of pituitary carcinomas (PC) is unknown. Treatment includes surgical resection, radiation, and more recently, temozolomide (TMZ). Pituitary adenomas have relatively high expression of vascular endothelial growth factor; therefore, bevacizumab, an antiangiogenic agent, has been used in a small number of aggressive or malignant pituitary tumors after recurrence. However, it has not been administered concurrently with other chemotherapeutic agents or combined with radiation therapy in PC. We present a 63-year-old man with an adrenocorticotropic hormone (ACTH)-secreting PC, causing visual loss. It was resected transsphenoidally. There were several notable factors placing the patient at high risk for recurrence including distant metastasis in the form of a pulmonary nodule. Morphologically, his tumor was a pituitary neoplasm with malignant histopathologic features. It had abundant mitotic figures and zones of necrosis. Six weeks post-surgery, the patient started concurrent chemoradiation, using combination therapy with TMZ and bevacizumab. TMZ was continued for 12 cycles in the adjuvant setting. The ACTH was effective as a serum-based tumor marker and normalized during treatment. The patient is alive, five years after diagnosis, with no recurrence to date. This is the first case of pituitary carcinoma treated successfully with concurrent chemoradiation therapy that combined TMZ and bevacizumab with a long-term follow up.

Risk factors for and pre-medications to prevent cetuximab-induced infusion reactions in patients with squamous cell carcinoma of the head and neck.

OBJECTIVES: Cetuximab, a chimeric monoclonal antibody, is the only targeted therapy approved for squamous cell carcinoma of the head and neck (SCCHN). Infusion reactions (IRs) occur in 6-18% of patients pre-medicated with diphenhydramine. Evidence for clinical risk factors for IRs is limited and the benefit of additional pre-medication to prevent IRs is unclear. MATERIALS AND METHODS: A retrospective, single institution study of 243 SCCHN patients treated with cetuximab to evaluate potential risk factors for IRs and to assess the efficacy of additional pre-medications (nebulized albuterol and intravenous (IV) corticosteroids and/or H2-blockers) to decrease the risk of IR. RESULTS: IR (grades 1-4) and high grade (grades 3-4 only) IR occurred in 47 (19.3%) and 16 (6.6%) patients, respectively. Multivariate analysis identified Caucasian race (OR7.11, p=0.003), medication allergy (OR3.74, p=0.002), and blood eosinophils >3% (OR2.75, p=0.01) independently increased the risk of IR; Caucasian race (OR5.57, p=0.007) and medication allergy (OR4.10, p=0.0007) increased the risk of high grade IR. IR (grades 1-4) and high grade IR occurred in 31.8% and 22.7% pre-medicated with diphenhydramine alone. Univariate analysis identified albuterol, famotidine, and corticosteroids decreased the risk of high grade IR. Furthermore, there was a significant difference between the possible combinations of the pre-medications and the risk of high grade IR by Fisher Exact test (p=0.003) whereby the combination of albuterol, famotidine and corticosteroids was effective in preventing high grade IR. Thirty (64%) of the 47 patients who developed an IR were re-challenged and did not experience a recurrence of an IR. CONCLUSION: These data may be used to identify patients at higher risk for cetuximab-induced IR who may be advised to not receive cetuximab or who may benefit from additional pre-medications to decrease the risk of a high grade IR.

Epoprostenol-induced hypersplenism in portopulmonary hypertension.

Portopulmonary hypertension (POPH) is a not infrequent but serious complication of liver cirrhosis. Continuous intravenous epoprostenol infusion is a treatment option for this condition. Progressive splenomegaly with pancytopenia (hypersplenism) is associated with epoprostenol use in POPH. After recognizing a case of epoprostenol-induced hypersplenism that resolved upon stopping the drug, the authors retrospectively reviewed all patients treated with epoprostenol at the center for both POPH and pulmonary hypertension due to other causes. Five of 11 patients with POPH developed hypersplenism secondary to epoprostenol. In 1 patient, and possibly in a second, the hypersplenism resolved upon discontinuation of epoprostenol. None of 9 patients with pulmonary hypertension due to other causes developed splenomegaly. This report confirms hypersplenism as a complication of epoprostenol therapy for POPH. Furthermore, the authors demonstrate for the first time that hypersplenism may be reversed by stopping the medication and propose a mechanism for this phenomenon.