ALBERT

Description: Abstract 1878 Introduction: The unbalanced translocation of der(1;7)(q10;p10) is relatively rare in myeloid neoplasms, which was reported at frequencies of 2% in de novo myelodysplastic syndrome (MDS), 0.5% in de novo acute myeloid leukemia (AML) and 3–7% in therapy-related myeloid neoplasms. Although chromosome 7 abnormality is generally considered as a poor prognostic factor in MDS and AML, it is still unclear whether or not this unbalanced translocation has a negative impact on prognosis. In addition, there appears to be some unique clinicopathological features such as male predominance, low blast counts, high hemoglobin level, presence of eosinophilia and a high rate of sole chromosomal abnormality. Methods: We retrospectively analyzed 122 der(1;7)(q10;p10) and -7/del(7q) adult patients with MDS or AML who were diagnosed at our institute between February 1995 and March 2010. According to the French-American-British (FAB) classification, 29 patients had AML (M0, n=5; M1, n=6; M2, n=10; M4, n=3; M5, n=1; M6, n=4) and 93 patients had MDS (RA, n=50; RARS, n=2; RAEB, n=35; RAEB-t, n=3; CMML, n=3). We compared the clinicopathological features and outcome of 33 der(1;7) patients with those of 89 -7/del(7q) patients. Results: The median age was 71 years for the der(1;7) patients and 67 years for -7/del(7q) patients (p=0.29). Male predominance was observed in both patients in the der(1;7) and the -7/del(7q) (p=0.52). The proportion of the sole abnormality in the der(1;7) was significantly higher than that in the -7/del(7q) (58% vs 13%, p

Description: Background: Oral tacrolimus (Tac) was first developed as a twice-daily formulation (Tac BID) and has been widely used in solid organ and allogeneic hematopoietic stem cell transplantation (allo-SCT). Lifelong immunosuppression is required to preserve graft function after solid organ transplantation, and medical nonadherence of transplant recipients has been identified as a major cause of allograft failure. It has been well documented that frequent drug dosing affects patients' adherence. In response to this potential nonadherence problem, a once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed. Results of randomized prospective phase III studies have indicated that Tac QD is well tolerated with similar efficacy and safety profiles as those of Tac BID in recipients after organ transplantation. Although Tac BID has been widely used in allo-SCT recipients, there are no available data on the use of Tac QD in this population. In this study, we compared retrospectively the efficacy of Tac QD versus Tac BID administration. The objective of this study was to investigate whether Tac QD is as effective as Tac BID in the setting of allo-SCT from unrelated donors. Methods: The study cohort included 77 consecutive patients who received allogeneic bone marrow transplantation from unrelated donors for treatment of hematologic malignancies between 2000 and 2014: AML (n=35), ALL (n=15), CML (n=8), MDS (n=12), NHL (n=5), and MPN (n=2). Patients received Tac iv from day -1 with short-term methotrexate (MTX) on days 1, 3, 6, and 11; Tac iv was converted to either Tac QD (n=37) or Tac BID (n=40) when the patients were engrafted and could tolerate oral medication. Doses were modified to maintain a whole-blood trough concentration of 8-12 ng/ml. Tac BID was administrated until Oct 2008, and Tac QD was used from Nov 2008. Kaplan-Meier estimates were used for overall survival (OS), and cumulative incidence estimates were used for acute GVHD, chronic GVHD, and non-relapse mortality (NRM). Results: Median age was 53 years (range: 23-66) for Tac QD cohorts and 39 years (range: 17-56) for Tac BID cohorts. Tac QD patients were older (P

Description: Abstract 3048 Background: In solid organ transplantation, lifelong immunosuppression is required to preserve graft function, and medication nonadherence is a major risk factor for graft failure. Tacrolimus (Tac) was first developed as an oral twice-daily formulation (Tac BID) and has been widely used in hematopoietic stem cell and solid transplantation, but long-term adherence remains a concern. In renal transplant patients, morning dosing is associated with significantly higher adherence than evening dosing. In response to this potential adherence problem, a once-daily modified release formulation (Tac QD) has been developed with a morning dosing regimen that maximizes the potential for adherence. However, several investigators have recently reported a sustained decrease in Tac exposure in kidney transplant recipients after conversion from Tac BID to Tac QD. In this study, we measured Tac exposure after switching from Tac intravenous infusion (Tac iv) to Tac QD and analyzed the pharmacokinetics (PK) of Tac QD to investigate the correlation between area-under-curve (AUC) and trough in patients who received allogeneic hematopoietic stem cell transplantation (HSCT). This is the first report of the PK study of Tac QD in patients who received allogeneic HSCT. Methods: Patients who were 15–65 years of age and received HSCT from unrelated donors were eligible. They received Tac iv 0.03mg/kg by continuous infusion beginning one day before transplantation, and administration was converted to Tac QD at a 1:4 ratio when the patients engrafted and could tolerate oral medication. Doses were modified to maintain whole-blood trough concentration of 8–12 ng/ml. To analyze PK of Tac QD, plasma samples were obtained at baseline and at 0, 1, 2, 3, 6, 12, and 24 hours after the once-daily administration. Plasma concentration of Tac was determined by an ELISA method. Results: A total of 10 patients with hematological malignancies (AML 6, ALL 1, MDS 2, NHL 1) were enrolled in the PK study. Median age was 45 (23–65) years. Five patients received myeloablative preparative regimens, and 5 patients received reduced intensity regimens, and stem cell sources were bone marrow (BM) from HLA-matched unrelated donor (n=4), BM from HLA DRB1 mismatched unrelated donor (n=4), or cord blood (n=2). After conversion from Tac iv to Tac QD, six out of 10 patients (60%) showed a sustained decrease in Tac exposure and required an increase in their Tac QD daily dose. One patient experienced a quick decrease of more than 78% in trough level of Tac QD, and he developed grade II acute GVHD after the conversion. No other patients developed grade II-IV acute GVHD. None of the patients had to discontinue the agent because of adverse effects, and none developed treatment-related mortality within 100 days after HSCT. In PK analysis, median area-under-curve (AUC) was 246 ng·h/ml. There was a strong correlation between AUC and trough level (Figure 1). Obtaining over 240 ng•h/ml of AUC required 7.5 ng/ml of whole-blood trough levels of tacrolimus. Conclusions: Despite initial reports showing the bioequivalence of Tac QD with Tac BID, we found that 60% of patients experienced a sustained decrease in Tac exposure. Therefore, the conversion from Tac iv to Tac QD should be performed under close medical supervision. Our study demonstrated that AUC and trough concentration level curves showed a strong correlation in patients who underwent allogeneic HSCT. The whole-blood trough should be maintained above 7.5ng/ml to provide an adequate level of AUC. If the trough level of Tac QD can be maintained above 7.5 ng/ml, Tac QD can be as effective as Tac iv and stable administration can be maintained for the patients with reduced stress because of the easier administration schedule. Our findings indicate that the use of Tac QD instead of Tac BID for GVHD prophylaxis is beneficial for patients undergoing allogeneic HSCT without moderate toxicities. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4342 (Purpose) We retrospectively analyzed the data regarding patients who received fractionated administration (FR) of gemtuzumab ozogamicin (GO) and standard administration (ST) of GO for the treatment of their refractory and relapsed acute myeloid leukemia in order to review the efficacy and safety of GO in each type of administration. (Method) The patients with relapsed and refractory acute myeloid leukemia (excluding patients with acute promyelocytic leukemia) who were treated with the ST of GO received 2 doses of monotherapy with 9 mg/m2 GO as a 2-hour intravenous (iv) infusion with a 14–28-day interval. The fractionated GO group received 2 doses of GO monotherapy administered as a 2-hour iv infusion of 3 mg/(m2·day) on days 1, 3, and 5 with a 14–28-day interval. (Result) Eleven patients received ST and 9 received FR. The median age of all patients was 66.1 (55–77) years. Overall response rates (CR+CRp) in the ST and FR groups were 27% and 33%, respectively. The adverse events (grade 3–4) in the ST and FR groups were neutropenia (100% vs. 100%), thrombocytopenia (90.9% vs. 88.9%), and hypertransaminasis (18.2% vs. 0%). Grade 3–4 hypertransaminasis was seen only in the ST group. Infusion reactions occurred in 5 patients: 3 in the ST group and 2 in the FR group. The median CD33 positivity of blast cells of patients who received CR or CRp was 90.9% (78.2–99.5%). (Discussion) The response rates of the ST and FR groups were similar. However, the incidence of grade 3–4 hypertransaminasis tended to be higher in the ST group. These data suggest that FR of GO is less toxic than ST. Thus, FR of GO is safer than ST even for Japanese patients with acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Reactivation of HHV-6 and HHV-7 (HHV-6/7) are associated with encephalopathy, skin rush, institutional pneumonia, and cytopenia in patients with hematological malignancies. Our colleges in the department of virology reported that reactivation of saliva HHV-6/7 was measurable in healthy person and non-immunosuppressive patients although reactivation of serum HHV-6/7 was not detected. Hence determination of HHV-6/7 from salvia sample must be more sensitive than from serum sample. Clinical significance of reactivation of HHV-6/7 has not been well-analyzed in multiple myeloma (MM) patients treated with novel agents. Patients and Methods We prospectively analyzed saliva sample from MM patients treated with bortezomib (BOR), lenalidomide (LEN) or thalidomide from May 2013 to January 2016. Saliva sample was harvested on day 1 of each cycles. DNA copy numbers of HHV-6/7 in saliva samples were also measured using real-time PCR. We analyzed factors associated with reactivation of HHV-6/7 in univariate analysis by Fisher's exact test. We evaluated the correlation between HHV-6/7 ratio and M-protein ratio, which was calculated using DNA copy number of HHV-6/7 and M-protein level at each time points, by Pearson's product moment correlation coefficient. The cutoff value of reactivation of HHV-6 and HHV-7 were defined as 1 x103 and 1 x105 copy/mL. High and low corticosteroid (CS) groups were defined depending on daily estimated dose of predonisolone; the cutoff value was 100mg/body. Results One hundred and ninety-one saliva samples were collected from 20 patients. Median age was 69 years. Patients with newly diagnosed and relapsed or refractory MM were 14 and 6. Seventeen patients were treated with bortezomib (BOR) and 7 patients were treated with lenalidomide (LEN). All patients received either dexamethasone or predonisolone. The cumulative incidence of reactivation of HHV-6 and HHV-7 were 78.2% and 65.5%. High CS was related with reactivation of HHV-6 and HHV-7. LEN was related with only reactivation of HHV-7 while BOR did not induce reactivation of HHV-6/7. There was significant reverse correlation between HHV-7 ratio and M-protein ratio (r=-0.34, P