ADAMTS 13 levels and von Willebrand Factor (vWF) collagen activity in Dengue fever: AVID Study

OBJECTIVE: To estimate the levels of ADAMTS 13 levels and vWF activity in adults with dengue fever at presentation and compare it to disease severity. METHODS: This is a prospective observational study conducted in the Departments of Medicine, Medical ICU and Accident and Emergency Medicine at Christian Medical Hospital, Vellore, India from May 2016 to July 2017. Consecutive adult patients with acute febrile illness and thrombocytopenia of less than 1lac/cu mm who also fulfilled the other inclusion and exclusion criteriae were recruited. Sample for ADAMTS 13 and vWF:CBA was collected on day 1 and patients were followed till death, discharge or convalescence. We analysed factors affecting dengue severity by univariate analysis and used logistic regression on these significant factors for multivariate analysis. RESULTS: A total of 62 patients (40 males and 22 females) were recruited. Fifteen patients had non-severe dengue with no warning signs, 36 had non-severe dengue with warning signs and 11 had severe dengue. We clubbed the latter two severity grades into “more severe dengue” and the former as “less severe dengue” for outcome analysis. Though ADAMTS 13 levels did not correlate with disease severity, higher levels of ADAMTS 13 meant lesser transfusion requirement. On multivariate analysis higher SOFA scores on Day 1 was associated with dengue severity. CONCLUSION: The AVID study aimed to look at the role of ADAMTS 13 and its association with severity of dengue infection. We also aimed to look at the association of ADAMTS 13 and transfusion requirement; the difference in their levels in pregnant women with dengue amongst other previously studied parameters. It is the first study in adult dengue patients measuring ADAMTS 13 levels and analyzing its association with disease severity. We also aimed to analyse SOFA score and its correlation to ADAMTS 13 levels in dengue. In our study low levels of ADAMTS 13 were associated with increased transfusion requirement, but not to dengue severity either by W.H.O. grading or by SOFA score. SOFA score on Day 1 showed significant association to W.H.O. grading of dengue severity on multivariate analysis. We used dichotomous outcome variables by clubbing non severe dengue with warning signs and severe dengue into one pool of “more severe dengue” and non sever dengue with no warning sign as “less severe dengue.’ Though we had only 6 pregnant patients, ADAMTS 13 levels were not significant different in them compared to the non-pregnant women. Pregnancy per se did not negatively affect dengue severity. Deficiency of ADAMTS 13 is only one of the many mechanisms implicated in thrombocytopenia of dengue and its possible role in propagating dengue pathogenesis. Its role though appears biologically plausible, needs to be studied in further details to implicate it strongly in dengue. Treatment decisions and transfusion practices will change once a causal relationship between the two is strongly established

Chromosomal Instability in Chronic Myeloid Leukemia: Mechanistic Insights and Effects

The most recent two decades have seen tremendous progress in the understanding and treatment of chronic myeloid leukemia, a disease defined by the characteristic Philadelphia chromosome and the ensuing BCR::ABL fusion protein. However, the biology of the disease extends beyond the Philadelphia chromosome into a nebulous arena of chromosomal and genetic instability, which makes it a genetically heterogeneous disease. The BCR::ABL oncoprotein creates a fertile backdrop for oxidative damage to the DNA, along with impairment of genetic surveillance and the favoring of imprecise error-prone DNA repair pathways. These factors lead to growing chromosomal instability, manifested as additional chromosomal abnormalities along with other genetic aberrations. This worsens with disease progression to accelerated and blast phase, and modulates responses to tyrosine kinase inhibitors. Treatment options that target the genetic aberrations that mitigate chromosome instability might be a potential area for research in patients with advanced phase CML

Sorafenib induced Hand Foot Skin Rash in FLT3 ITD mutated Acute Myeloid leukemia- A case report and review of literature

Sorafenib is a novel small molecule multiple kinase inhibitor which has been used for metastatic renal cancer, hepatocellular cancer. Sorafenib induced skin rash has been discussed as a side effect in trials in both FLT3 wild type and mutated acute myeloid leukemia (AML) as monotherapy or as combination with other chemotherapeutic agents . We describe a patient with FLT 3 ITD mutated AML who was started on adjunctive Sorafenib therapy. Skin reactions manifested as NCI Grade III palmoplantar erythrodysesthesia (PPE), requiring drug discontinuation. Several pathogenic mechanisms have been implicated in Sorafenib induced skin reactions, but none has been conclusively proven. While treatment options are varied for early stage skin reactions, drug discontinuation remains the only possible therapy presently for severe grade skin reaction

Management of chronic myeloid leukemia in 2023 – common ground and common sense

Abstract With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results