Thrombotic microangiopathy in untreated myeloma patients receiving carfilzomib, cyclophosphamide and dexamethasone on the CARDAMON study.

Proteasome inhibitors have been associated with thrombotic microangiopathy (TMA) - a group of disorders characterised by occlusive microvascular thrombosis causing microangiopathic haemolytic anaemia, thrombocytopenia and end-organ damage. To date, carfilzomib-associated TMA has predominantly been described in relapsed/refractory myeloma patients. We report eight patients with newly diagnosed myeloma who experienced TMA events while receiving carfilzomib on the phase II CARDAMON trial. The first three occurred during maintenance single-agent carfilzomib, two occurred at induction with carfilzomib given with cyclophosphamide and dexamethasone (KCd) and three occurred during KCd consolidation. At TMA presentation 6/8 were hypertensive; 7/8 had acute kidney injury and in three, renal impairment persisted after resolution of TMA in other respects. The mechanism of carfilzomib-associated TMA remains unclear, though patients with known hypertension seem particularly susceptible. Given the first three cases occurred during maintenance after a longer than five-week treatment break, a protocol amendment was instituted with: aggressive hypertension management, carfilzomib step-up dosing (20 mg/m2 on day 1) at start of maintenance before dose escalation to 56 mg/m2 maximum, and adding 10 mg dexamethasone as premedication to maintenance carfilzomib infusions. No further TMA events occurred during maintenance following this amendment and the TMA incidence reduced from 4·2 to 1·6 per 1 000 patient cycles.

Current views of haemolytic streptococcal pathogenesis.

PURPOSE OF REVIEW: Increasing disease caused by beta-haemolytic streptococci indicates the need for improved understanding of pathogenesis. RECENT FINDINGS: Streptococcus pyogenes, or group A Streptococcus (GAS), causes significant disease worldwide. The closely related Streptococcus dysgalactiae subspecies equisimilis (SDSE) is increasingly recognized as causing a similar disease spectrum. Whole-genome sequencing applied to the study of outbreaks may reveal factors that contribute to pathogenesis and changes in epidemiology. The role of quorum sensing in biofilm formation, and interspecies communication with other streptococci, is discussed. GAS has evolved multiple mechanisms to evade the humoral arm of innate immunity, including complement, which is well known in protecting the host from bacteria, and the coagulation-fibrinolytic system, which is increasingly recognized as an innate immune effector. SUMMARY: Molecular biology has enhanced our understanding of the intricate balance of host-pathogen interactions that result in clearance or establishment of invasive streptococcal infection. Although the skin and oropharynx remain the usual ecological niche of GAS and SDSE, occasionally the bacteria find themselves within deeper tissues and blood. Recent research has armed us with better knowledge of bacterial adaptations to this alternative environment. However, the challenge is to translate this knowledge into clinical practice, through the development of novel therapeutic options and ultimately a vaccine against GAS.

Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).