Previous reports have shown that acute kidney injury (AKI) is common after hematopoietic stem cell transplantation (HSCT), which is a crucial treatment for patients with hematological disorders. AKI ...could increase mortality and induce adverse effects including the development of chronic kidney disease. The incidence of AKI in association with HSCT reportedly varies significantly because several definitions of AKI have been adopted. Acute kidney disease (AKD) is a new concept that can clinically define both AKI and persistent decreases in glomerular filtration rate (GFR) state. We conducted a retrospective cohort study to determine the incidence of AKD after HSCT.
This study included 108 patients aged between 16 and 70 years undergoing HSCT. In this study, AKD included clinical condition of AKI or subacute decreases in GFR. AKI was defined according to the Kidney Disease: Improving Global Outcomes guidelines based on serum creatinine. However, urine output data were not included to define AKI because the database lacked some of these data. Comparisons were made between groups using the Mann-Whitney U test.
Acute kidney disease occurred in 17 patients (15.7%). There were significant differences between the AKD and non-AKD with respect to ABO-incompatible HSCT (
= 0.001) and incidence of acute graft versus host disease (GVHD) after HSCT (
< 0.001). The 100-day overall survival of patients with AKD and without AKD after HSCT was 70.6% and 79.8%, respectively (
= 0.409).
ABO-incompatible HSCT and acute GVHD after HSCT were risk factors for the incidence of AKD. However, we could not find a significant association between AKD after HSCT and mortality.
Although azacitidine is the first‐line drug for higher‐risk myelodysplastic syndrome (MDS) patients, its efficacy for lower‐risk MDS remains unestablished. Therefore, we conducted a prospective study ...to examine the efficacy and safety of a 5‐day regimen of azacitidine (AZA‐5) for lower‐risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower‐risk MDS based on the French‐American‐British (FAB) classification (44 patients with refractory anemia RA and 7 patients with refractory anemia with ringed sideroblasts RARS) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51‐88). These patients received AZA‐5 (75 mg/m2; once daily for 5 sequential days). The median number of AZA‐5 courses was 8 (range: 1‐57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA‐5 is feasible and effective for lower‐risk MDS patients as well as for higher‐risk MDS patients.
Five‐day regimen of azacitidine for lower‐risk MDS.
BACKGROUND
Cross‐matched platelet (cross‐matched PLT) transfusion is effective for immune‐mediated platelet transfusion refractoriness (PTR), but is more costly and time‐consuming for physical ...cross‐match than using standard PLT units. Recent studies have reported the utility of human leucocyte antigens (HLA) virtual cross‐matched PLT (HLA‐matched PLT) that is defined as HLA‐A/B matched or no antibody against donor‐specific antigen. Here, we evaluated the effect of HLA‐matched PLTs for PTR in post hematopoietic stem cell transplant (HSCT) recipients.
STUDY DESIGN AND METHODS
Our study included a total of 241 PLTs in 16 patients who underwent HSCT at Okayama University Hospital between 2010 and 2017, receiving either HLA‐matched or cross‐matched PLTs. We calculated the 24‐hour corrected count increments (CCI‐24) to evaluate the effect of PLTs. A CCI‐24 ≥ 4500 was considered to be a successful transfusion.
RESULTS
We analyzed 139 cross‐matched PLTs and 102 HLA‐matched PLTs. In the immune‐mediated PTR, the rate of successful transfusion was 60.5% for cross‐matched PLT and 63.4% for HLA‐matched PLT (p = 0.825). On the other hand, the median CCI‐24 for cross‐matched PLT transfusions and HLA‐matched PLT transfusions were 1856 and 5824 (p < 0.001), with a success rate of 28.1 and 54.1% in cases with non‐immune‐mediated PTR, respectively (p = 0.001).
CONCLUSION
The effectiveness of HLA‐matched PLT is not inferior to cross‐matched PLT. This result indicates that physical cross‐match can be omitted in post HSCT PTR.
Myeloproliferative neoplasms (MPNs), including polycythemia vera and essential thrombocythemia, are frequently associated with thrombotic complications. Prevention of thrombotic events is thus a ...primary aim of the current treatment for these disorders. Although it is known that microparticles (MPs), which are small vesicles released from cell membranes and circulate in the blood, directly contribute to thrombosis via their procoagulant activity, potential associations between plasma levels of MPs and the risk of thrombotic events in MPNs have not been reported. In the present study, we characterized plasma levels of MPs and assessed their potential association with the occurrence of thrombotic events in 59 patients with MPNs. Plasma levels of procoagulant MPs expressing tissue factor (TF+ MPs) were significantly higher in patients suffering thrombotic events than in patients without such events (median/μl plasma: 33.8 vs 47.2,
p
= 0.02). Among patients who developed thrombotic events, irrespective of patients’ blood counts, TF+ MP were significantly higher in patients without cytoreductive therapy than in those receiving cytoreductive therapy (101.2 vs. 42.5,
p
< 0.001). These results suggest that elevated levels of TF+ MP may be considered as a novel surrogate marker for thrombotic events in MPN patients. Further studies are needed to clarify the mechanism involved.
Cilostazol is an anti-platelet drug that reversibly inhibits phosphodiesterase III (PDE-III), which is ubiquitously expressed in platelets and various tissues. PDE-III converts cyclic adenosine ...monophosphate (cAMP) to 5'-AMP and up-regulates the intracellular concentration of cAMP, a potent inhibitor of platelet aggregation. Unlike other anti-platelet drugs, cilostazol is unique because patients receiving this drug do not have a significantly prolonged bleeding time, but the reasons for this difference are still unknown. In this study, we have examined how cilostazol inhibits platelet thrombus formation using anti-coagulated normal whole blood in which the platelets were labeled with a fluorescent dye in comparison with the anti-GPIIb/IIIa agent, tirofiban. We used an in vitro assay to examine mural platelet thrombus growth on a collagen surface under a high-shear rate flow in the absence of ADAMTS13 activity. These experimental conditions mimic the blood flow in patients with thrombotic thrombocytopenic purpura. Using this model, we clearly determined that cilostazol down-regulates the height of mural platelet thrombi formed on a collagen surface in a dose-dependent manner, without affecting the surface coverage. The concentration of cilostazol used in this study was relatively high (60–120μM) compared to clinically relevant concentrations (1–3μM), which may be due to the in vivo synergistic effects of PDE-III present in other tissues aside from platelets. Cilostazol does not affect the initial formation of platelet thrombi, but does inhibit the height of thrombi. These results showed a sharp contrast to tirofiban, and address why cilostazol does not significantly prolong bleeding time, despite its strong anti-platelet activity.
We describe the results of a prospective trial of the discontinuation of second-line dasatinib treatment in chronic myeloid leukemia patients who maintained a deep molecular response for > 1 year. ...The treatment-free remission rate at 36 months was 44.4%. High natural killer cell counts before discontinuation correlated significantly with successful therapy discontinuation.
We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective.
The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed.
The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation.
These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.
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Background: The patients with severe aortic-valve stenosis (AS) are often complicated with bleeding episodes. The association between AS and gastrointestinal bleeding due to angiodysplasia is ...reported as Heyde’s syndrome, which is categorized as one of the acquired von Willebrand disease (AVWD) in cardiovascular disorders. An international survey has shown that Type 2A is the common subtype of AVWD in the patients with AS. AVWD Type 2A is characterized by impaired platelet-dependent VWF function caused by marked decrease or absence of the most hemostatically active HMW-VWFM. In the patients with AS, a significant correlation between the increased high shear stress and loss of HMW-VWFM in vivo. Further, the absence of HMW-VWFM and bleeding tendency are normalized after valve replacement. These results suggest that enhanced proteolysis of von Willebrand factor (VWF) as it passes through the stenotic valve may induce the loss of HMW-VWFM because high shear stress can induce structure changes in VWF, which is sensitive form to the VWF cleaving protease, termed ADAMTS13. Here, we performed investigation of plasma levels of VWF antigen (VWF:Ag), ADAMTS13 activity (ADAMTS13:AC), and platelet thrombus formation in the patients with AS by valve replacement to confirm the pathophysiological mechanism of this rare disease.
Patients and Methods: Ten consecutive patients who underwent aortic valve replacement for AS in Nara Medical University Hospital were enrolled in this study. The severity of AS was judged by the American Heart Association guideline. All patients had no bleeding history and received bovine tissue valves replacement followed by administration of warfarin and/or anti-platelet agents for prevention of thrombosis a week after surgery. We collected a series of blood samples from these patients before and day1, 8, 15, 22 after valve replacement. Excluding one patient who developed critical cardiac failure just after valve replacement, 9 patients were eventually evaluated by analyses of VWF:Ag, VWF multimers, ADAMTS13:AC, and mural thrombus formation using flow chamber system. VWF:Ag was measured by sandwich ELISA using a rabbit anti-human VWF polyclonal antiserum. Analysis of VWF multimers was performed according to the method of Ruggeri and Zimmerman. ADAMTS13:AC was measured by a chromogenic ADAMTS13-act-ELISA. Platelet thrombus formation was evaluated by thrombus generation under a high shear stress in a parallel plate flow chamber system. Briefly, whole blood anti-coagulated with argatroban was incubated with the fluorescent dye DiOC6 (1uM), and these samples containing DiOC6 -labeled platelets were perfused for 7 min over a type I collagen-coated glass surface under a high shear rate (1500 s-1). The DiOC6 fluorescence corresponding to the platelets was examined at an excitation wavelength of 488 nm with a barrier filter at 500 nm. The percentage of the area covered by adhering platelets (surface coverage) and each thrombus volume were evaluated.
Results: Plasma levels of VWF:Ag before surgery were 78.1 % (median) and those on day 1, 8, 15, 22 after surgery were 130, 224, 155, and 134 %, respectively (Fig 1). Conversely, these levels of ADAMTS13:AC were 50.5, 35.5, 25.5, 25.1, and 30.3 %, respectively (Fig 2). The ratio of VWF:Ag/ADAMTS13:AC at before and day 1, 8, 15, 22 after surgery were 1.6, 4.5, 8.1, 6.1, and 4.1, respectively. In VWF multimer analysis, we found the obvious defect of HMW-VWFM in 7 of 9 patients before surgery, who were diagnosed with severe AS. The remaining two patients had moderate AS with the slight defect of HMW-VWFM. These defects were improved within 14 days after surgery. In platelet thrombus formation, the amount of thrombus volumes significantly increased at day 8, 15, and 22 after compared with before surgery (Fig 3).
Conclusion: The dramatic recovery of platelet thrombus formation was observed in the patients with AS by valve replacement. The rapid increment of VWF and normalization of VWFM pattern, together with reduction of ADAMTS13 after valve replacement suggested heightened proteolysis of VWF by ADAMTS13 under high shear stress would be a major cause of this unique bleeding complication. The highest ratio of VWF:Ag/ADAMTS13:AC at day 8 after surgery might imply the necessity of blockade of heightened VWF function with anti-platelet agents.
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Matsumoto:Alfresa Pharma Corporation: Patents & Royalties. Fujimura:Alfresa Pharma Corporation: Patents & Royalties.
The three drugs combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) is highly active regimen for the treatment of the patients with multiple myeloma (MM). However, twice-weekly ...schedule of bortezomib and high dose dexamethasone has been shown to cause significant toxicities, including peripheral neuropathy (PN) and thrombotic events. Once-weekly bortezomib induction therapy with reduced dosage of dexamethasone (modified-CyBorD) has shown less toxicity with high response rate equal to original regimen (Reeder, CB et al. Leukemia 2009). However, it was found more than half of the patients still developed bortezomib induced PN (BiPN) in this modification. Thus it was still concerned adverse event for the transplant ineligible patients, especially frail elderly patients because it often caused interruption or withdrawal of the treatments, resulting in fewer efficacies. Under these circumstances, we have studied the reduced-dosage of CyBorD regimen (reduced-CyBorD) in the treatment of transplant ineligible patients with MM to assess response and toxicity.
The protocol consisted of bortezomib given intravenously at a dose of 1.3 mg/m2 once a week on days 1, 8, 15, cyclophosphamide orally at a dose of 50 mg daily on days 1-21, and dexamethasone orally or intravenously at a dose of 20 mg daily on days 1,2,8,9,15,16 in 4-week cycles. Total of 32 patients, including 20 newly diagnosed and 12 refractory, were treated with reduced-CyBorD and evaluated its efficacy and safety.
The median age was 72 years (range from 62 to 88). 14 patients were more than 75 year-old (44 %). 15 patients were female. According ISS, 4 patients were classified in stage I, 10 were in II, and 18 were in III. The overall response (ORR) was 90.6 % with 43.8 % of CR/nCR (6 CR, 8 nCR, 7 VGPR and 8 PR). Hematological adverse events were anemia (18.8%; G1/2 n=7), neutropenia (37.5%; G1/2 n=10, G3/4 n=2), lymphocytopenia (43.8%; G1/2 n=10, G3/4 n=4), thrombocytopenia (12.5%; G1/2 n=1, G3/4 n=3). Non-hematological adverse events were pneumonia (12.5%; G2 n=2, G3 n=2), VZV infection (15.6%; G1/2 n=5), cerebral infarction (3.1%; G2 n=1). Importantly, only 6 patients (18.8%) developed grade 1 PN, and no patient reduced or discontinued bortezomib due to PN. The overall survival (OS) at 1, 2, and 3 years were 81, 63.1, and 45.9 %, respectively. In this study, neither inferior response nor poor survivals were significantly observed between over 75 year-old patients group (n=14) and under 75 year-old group (n=18) (ORR; 100 vs 83.4 %, CR/nCR; 42.9 vs 44.4 %, 1-year PFS 54.6 vs 50 %, and 3-year OS 29.8 vs 55 %).
Reduced-CyBorD with three times once-weekly bortezomib retained high efficacy seen in standard and modified CyBorD previously reported (ORR; 90.6 vs 88 and 93 %, CR/nCR; 43.8 vs 39 and 43 %). These results showed that our regimen has less toxicity, especially BiPN (18.8 %) compared with those previous regimens (64 % and 57 %), resulting in no discontinuation nor reduction of bortezomib. Furthermore, over 75 year-old patients group did not showed inferior outcomes in comparison with under 75 year-old patients group. Our results suggested that reduced-CyBorD might be suitable for the transplant ineligible patients, especially elderly frail patients (over 75 year-old) with MM.
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No relevant conflicts of interest to declare.
Abstract A 68-year-old woman was admitted to the regional hospital because of hemolytic anemia, thrombocytopenia, and neurological abnormalities including unconsciousness. One week before admission, ...she suffered from diarrhea and subsequently passed out and hit her face on the ground. She was suspected of having TTP and was transferred to our hospital. We performed the assays of ADAMTS13 activity and anti-ADAMTS13 antibody titers, and confirmed the diagnosis of acquired idiopathic TTP with total deficiency of ADAMTS13 activity with its inhibitor. She was initially treated with plasma exchange combined with corticosteroids, however, we were forced to substitute plasma exchange with fresh frozen plasma infusion due to procedure-associated complications. The infusion of fresh frozen plasma was known as less effective and more likely to boost inhibitor titers compared to plasma exchange. In this circumstance, we could successfully switch the plasma therapy under close monitoring of ADAMTS13 activity and anti-ADAMTS13 antibody titers which precisely revealed the disease status of TTP in our patient, and eventually she achieved complete remission with normal level of ADAMTS13 activity and no inhibitor. Our experience suggested that the measurement of ADAMTS13 activity and inhibitor titer might be valuable not only for making the diagnosis but also for guiding treatment decisions by precise evaluating of disease status in patients with the acquired form of TTP.
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