Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series.

First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.

Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation.

Telomeres are repetitive DNA sequences that protect the ends of linear chromosomes, and they are maintained by a ribonucleoprotein complex called telomerase. Variants in genes encoding for telomerase components have been associated with a spectrum of disease in the lung, skin, bone marrow, and liver. Mutations in the telomerase reverse transcriptase and telomerase RNA component genes have been observed at a higher prevalence in patients with liver disease compared with the general population; however, the presence of variants in other components of the telomerase complex and their impact on clinical outcomes has not been explored. We evaluated 86 patients with end-stage liver disease for variants in an expanded panel of eight genes, and found that 17 patients (20%) had likely deleterious variants by in silico analysis. Seven unique likely deleterious variants were identified in the regulator of telomere elongation helicase 1 (RTEL1) gene that encodes for a DNA helicase important in telomere maintenance and genomic stability. In gene burden association analysis of their clinical data, the presence of any RTEL1 variant was associated with a 29% lower baseline white blood cell count (95% confidence interval [CI], -7% to -46%; P Value = 0.01) compared with patients without RTEL1 variants, and the presence of any exonic missense RTEL1 variant was associated with a 42% lower baseline platelet count (95% CI, -5% to -65%: P Value = 0.03). The presence of any telomerase variant was associated with an increased number of readmissions within 1 year after transplantation demonstrated by an incident rate ratio (IRR) of 3.15 (95% CI, 1.22 to 8.57). No association with survival was observed. Conclusion: Among patients who underwent liver transplantation, the presence of any exonic missense variant was associated with a longer postoperative length of stay with an IRR of 2.16 (95% CI, 1.31 to 3.68).

Ruxolitinib Rechallenge Can Improve Constitutional Symptoms and Splenomegaly in Patients With Myelofibrosis: A Case Series.

INTRODUCTION: Myelofibrosis (MF) is one of the classic myeloproliferative neoplasms and can occur de novo or following transformation from polycythemia vera (PPV MF) or essential thrombocythemia (PET MF). It can be associated with constitutional symptoms and splenomegaly, both of which can negatively impact quality of life. The only curative option for MF is allogeneic stem cell transplantation. Studies have shown that JAK2 inhibitors such as ruxolitinib are effective in reducing both splenomegaly and symptom burden. Although there is no approved treatment for patients who progress on ruxolitinib, anecdotal evidence suggests patients may respond to a re-challenge of ruxolitinib after drug cessation. PATIENTS AND METHODS: We conducted a multi-institutional, retrospective case series to study patients who were re-challenged with ruxolitinib after inadequate response to or loss of response with an initial treatment course. Thirteen patients were identified. Six patients had primary MF, 3 patients had PPV MF, and 4 patients had PET MF. Ten patients were JAK2-positive, 2 were CALR-positive, and 1 patient had neither mutation. Nine patients received 1 ruxolitinib re-challenge, and 4 received 2 re-challenges. Response was defined as improvement in constitutional symptoms and/or reduction in spleen size. RESULTS: During the primary treatment course with ruxolitinib, there was improvement in constitutional symptoms and reduction in spleen size in 92% and 85% of patients, respectively. Following cessation of ruxolitinib, all patients received a first re-challenge course with improvement in symptoms and splenomegaly in 92% and 69%, respectively. Of the 4 patients who received a second re-challenge course of ruxolitinib, all had improvements in spleen size and constitutional symptoms. Six patients have continued on a first or second ruxolitinib re-challenge course with good response. CONCLUSION: Our study demonstrates that re-exposure to ruxolitinib following a period of treatment cessation in patients with MF can lead to durable responses with regards to both splenomegaly and symptom burden.