ALBERT

Description: Reactivation of varicella-zoster virus (VZV) is a common event in patients undergoing hematopoietic cell trasnplantation (HCT). In post HCT recipients, VZV reactivation can occur frequently as localized zoster and sometimes as disseminated cutaneous lesions resembling varicella with or without visceral involvement, which results in a high mortality rate. The most common complication associated with zoster in healthy individuals is chronic and often debilitating pain called post-herpetic neuralgia (PHN), which can last for several yeas and may reduce quality of life. Although, many previous studies have shown a high incidence of VZV reactivation after HCT, incidence and risk of PHN in HCT recipients have not yet been clarified. To assess the incidence and risk factors associated with PHN after post-HCT VZV infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT in Hokkaido Cooperative Hematology Group (HCHG) between April 2005 and March 2007. HCHG is multicentric clinical study group that includes “all” hematology departments in Hokkaido prefecture, consisting of 26 clinical groups of 19 institutes. VZV infection was defined by the appearance of typical cutaneous vesicular lesions or the detection of VZV antigen. Localized zoster was defined as the presence of vesicular lesions in a dermatomal distribution. Disseminated zoster was defined as a generalized vesicular eruption that is identical to that of varicella. Visceral dissemination was defined as clinical evidence of internal organ involvement in the absence of other identified pathogens that might have accounted for the clinical syndrome. Post-herpetic neuralgia was defined as dermatomal pain that persisted beyond rash healing. Information on pre-transplant therapeutic exposures, HCT procedures and post-transplant health complications was obtained via evaluation form. A total of 418 patients were included in this study. Male/Female ratio was 221/197, median age at HCT was 47 years (range, 0–69 years), autologous HCT/allogeneic HCT/syngeneic HCT ratio was 154/263/1, and median length of follow-up was 344 days (range, 3–1165 days). Seventy-eight patients developed VZV infection after HCT (M/F=36/42; median age, 48 (range, 3–68) years; auto/allo/syngeneic=29/48/1). Sixty-two patients had localized zoster (single dermatome in 53, double dermatome in 9), 12 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster (involvement of GI the tract). All cases were treated by ACV or VACV, and there was no VZV infection-related death. After resolution of VZV infection, VZV infection reoccurred in 5 cases (localized zoster in 4 cases and visceral zoster in 1 case). Cummulative incidences of VZV infecion in allo-HCT and auto-HCT recipients were estimated to be 34% and 22%, respectively, at 2 years after HCT. In autologous HCT, 96.6% of the cases of VZV infection occurred during the first year after HCT, but in allogeneic HCT, only 75.5% of the cases of VZV infection occurred during the first year after HCT. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection (M/F=15/12; median age, 56 (range, 21–64) years; auto/allo=13/14). Although incidences of VZV infection were not different between age groups, the incidence of PHN increased with advance of age (Figure). In HCT recipients, the incidence of PHN increased at a younger age than that in healthy individuals. Multivariate analysis showed that advanced age (P=0.0031; OR=1.09; 95% CI, 1.03 to 1.15) and male gender (P=0.046; OR=3.09; 95% CI, 1.02 to 9.35) were associated with increased risk of PHN. Auto vs allo, CST vs RIST, and onset of VZV infection after HCT were not significant. In allogeneic HCT recipients, existence of GVHD at onset of VZV infection and prophylaxis of GVHD with tacrolimus were associated with increased risk of PHN in univariate analysis, but these factors were not significant in multivariate analysis. This study showed the magnitude of risk of PHN in HCT recipients and revealed advanced age and male gender to be risk factors, suggesting the usefulness of acyclovir as prophylaxis for prolonged periods in these patients. Figure Figure

Description: IL-12 is a cytokine comprised of two disulfide-linked proteins (p35 and p40). The highly coordinated expression of p40 and p35 genes to form IL-12 (also called p70) in the same cell type at the same time is essential for the initiation of effective immuno response. It is known that IL-12 p70 promotes the differentiation of type-1 helper T cells, whereas IL-12 p40 acts as an antagonist of IL-12 p70. Granulocyte-colony stimulating factor (G-CSF) affects the balance in the production of anti-inflammatory cytokines. We had previously examined various cytokine productions (such as IL-4, IL-12, IFN-γ) in Non Hodgkin Lymphoma (NHL) patients. We found that only IL-12 production was associated with the disease status in NHL patients. In the present study, we investigated the plasma IL-12 p40, IL-12 p70 production in patients with B-cell lineage NHL treated with chemotherapy (e.g., CHOP) with or without G-CSF administration. Forty-nine patients were analyzed in this study. Plasma IL-12 p40 and IL-12 p70 were measured separately by enzyme-linked immunosorbent assay (ELISA) before chemotherapy and day 17 after chemotherapy. The survival rates was calculated by the Kaplan-Meier method. Eleven of 49 patients were excluded from this study by the ineligibility. The remaining 38 patients were analyzed in this study. Median age was 61 years old. Clinical stage was I(9), II(10), III(12), IV(7). Eleven patients were received chemotherapy only (C) and 27 patients were received chemotherapy with G-CSF (CG). The patient characteristics in each group were not significantly different. Plasma IL-12 p40 concentration decreased no significantly after chemotherapy than before with G-CSF (median, from 141 pg/ml to 111.1 pg/ml) and without G-CSF (median, from166.9 to 197 pg/ml) (P=0.37). However, median plasma IL-12 p40 concentration decreased significantly after chemotherapy than before chemotherapy with G-CSF (median, from148.4 to 130 pg/ml, P=0.009) and without G-CSF (median, from153.5 to 156.8 pg/ml) (P=0.140) by the classification of each chemotherapy course. Plasma IL-12 p40 concentration in CG group patients with clinical stage III and IV was significantly decreased after chemotherapy than before chemotherapy (median 73.3 pg/ml) compared with C group (0.1 pg/ml)(P=0.006). Plasma IL-12 p70 could not be detected in almost all patients. After chemotherapy, 22 patients showed complete remission (CR), 8 patients showed partial response (PR), 3 patients showed no change (NC), 2 patients showed progressive disease (PD) and 3 patients showed unclear disease status. The overall survival (OS) at 24 months was not significantly differed between both groups(C 64.0% VS GC 89.4%, P=0.67). Interestingly, one of the 2 patients of progressive disease showed high IL-12 p40 concentration in association with disease progression and IL-12 p40 concentration remained high in the other patient. We found that chemotherapy with G-CSF decreased IL-12 p40 production. We did not find the difference in overall survival at the present time, however, a longer administration of G-CSF appears to influence on the survival rate by reducing an immunosuppressive IL-12 p40 production.

Description: Abstract 3704 Introduction: Chronic immune thrombocytopenia (ITP) is an autoimmune disorder characterized by both increased platelet destruction and decreased platelet production. Romiplostim increases platelet counts by binding and activating the thrombopoietin receptor. Romiplostim has been approved for the treatment of adult ITP in the United States, Europe, Canada, and Australia. This study evaluated dosing, efficacy, and safety in a Japanese population of adults with ITP. Methods: This phase 3 study was placebo-controlled, double-blind, and randomized 2:1 (romiplostim:placebo). Patients were eligible for the study if they were Japanese patients with ITP diagnosed at least 6 months before the initial screening, were aged ≥ 20 years, and were H pylori negative or had received at least 1 treatment for H pylori eradication. Patients were stratified by splenectomy status (yes or no). After a 3-week evaluation period, patients were treated for 12 weeks with a weekly subcutaneous injection of either romiplostim or placebo. The starting dose was 3 mcg/kg with dose adjustments to a maximum of 10 mcg/kg to achieve a platelet count within the target range of ≥ 50 to ≤ 200 × 109/L. Patients were monitored posttreatment until their platelet count dropped to ≤ 50 × 109/L or for a maximum of 12 weeks. The primary endpoint was number of weeks with platelet response (platelet count ≥ 50 × 109/L). Results: Thirty-four patients enrolled (22 romiplostim, 12 placebo), 24 (71%) were female, the median (range) age was 55 (44 - 64) years, and the median (range) baseline platelet count was 19 (3 – 32) × 109/L. Patients had received a median of 4 (1 – 19) prior ITP therapies, and 15 (44%) had previously undergone a splenectomy; 23 (68%) patients were receiving concurrent ITP therapy at baseline. All patients completed the study. Romiplostim demonstrated superiority to placebo on weekly platelet response, incidence of increase in platelet count ≥ 20 × 109/L from baseline, change from baseline in mean of last 4 platelet counts during week 2 to week 13, and number of weeks with platelet counts within the target range (Table 1), and 16 (73%) romiplostim patients had platelet counts ≥ 200 × 109/L. Twenty-one (95%) patients in the romiplostim group had a platelet response with a median time of 1 week until first response. Results for weekly platelet response were comparable irrespective of splenectomy status and baseline concurrent ITP therapy. Two (17%) patients in the placebo group achieved a platelet response. In romiplostim-treated patients, posttreatment platelet counts remained 〉 50 × 109/L for 8 weeks in one and for 12 weeks in another. The mean weekly dose of romiplostim for the study was 2.6 mcg/kg compared with the dose range of 3–4 mcg/kg in prior phase 3 studies (Kuter et al. Lancet. 2008;371:395–403). There was a low incidence of rescue medication use in the study (Table 1). The adverse events profile was comparable to that seen in non-Japanese studies. Patients in both treatment groups experienced similar proportions of adverse events (91% romiplostim, 92% placebo). Adverse events with 〉 10% higher frequency in the romiplostim group than placebo group) were (romiplostim, placebo) nasopharyngitis (41%, 17%), headache (32%, 17%), peripheral edema (18%, 0%), back pain (14%, 0%), and pain in extremity (14%, 0%). Significant (≥ grade 3) bleeding events occurred in 1 patient in the romiplostim group (subarachnoid hemorrhage) and 1 patient in the placebo group (subarachnoid hemorrhage, cerebral hemorrhage, and gastrointestinal hemorrhage). There were no adverse events of bone marrow reticulin, thrombosis, or detection of neutralizing antibodies. Conclusion: Romiplostim significantly increased and maintained platelet counts and was well-tolerated in a Japanese ITP population. Disclosures: Tomiyama: Kyowa Hakko Kirin Co.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Kurokawa:Novartis: Consultancy; Shionogi & Co., Ltd.: Consultancy. Wei:Amgen Inc.: Employment, Equity Ownership. Lizambri:Amgen Inc.: Employment, Equity Ownership.

Description: Abstract 3089 Adult T-cell leukemia/lymphoma (ATL) mainly occurs in HTLV-1 endemic areas such as the southwest island in Japan (Kyushu) and Caribbean countries. A recent report showed that the incidence of ATL was increasing in HTLV-I non-endemic areas (1). Although allogeneic stem cell transplantation (allo-SCT) has been considered to be the only curative treatment for ATL (2, 3), there has been no report about the treatment strategy for ATL occurring in HTLV-1 non-endemic area. We therefore conducted a retrospective analysis for all of the patients who developed ATL and received allo-SCT in an HTLV-1 non-endemic area of Japan, Hokkaido (a northernmost island). Clinical data for 56 patients who received allo-SCT were collected from 12 SCT centers in Hokkaido, Japan. The median age of the patients was 57 years (range: 37 – 69 years). Twenty-eight of the patients had acute type and 22 had lymphoma type. Median count of white blood cells and median levels of serum LDH and serum soluble interleukin-2 receptor (sIL-2R) at diagnosis were 10900/mL, 352 IU/L and 11153 mg/dL, respectively. After chemotherapies mainly using CHOP or VCAP–AMP–VECP regimens, twenty-three of the patents received allo-SCT in complete remission (CR), and the other patients received allo-SCT in non-CR (partial remission, n=16; primary refractory, n=9; relapse, n=23). Median levels of serum LDH and sIL-2R before the conditioning regimen were 218 IU/L and 1153 mg/dL, respectively. HCT-CI scoring was available in 42 of the patients, and the scores were 0 in 15 patients, 1 in 10 patients, 2 in 5 patients and more than 3 in 9 patients. Thirty-nine of the patients received bone marrow, 11 of the patients received peripheral blood stem cells and 6 of the patients received cord blood. Thirty of the patients received SCT from HLA-matched siblings, 22 of the patients received SCT from HLA-matched unrelated donors and 14 of the patients received SCT from HLA-mismatched donors. Seventeen patients received myeloablative conditioning and the other 39 patients received reduced-intensity conditioning. Fifty-three (95%) of the patients achieved neutrophil engraftment at median day of 16. Acute graft-versus-host disease (AGVHD) and grade II-IV AGVHD occurred in 40 (75%) and 31 (58%) evaluable patients, respectively, at median onset day of 29. Chronic GVHD (CGVHD) occurred in 24 (38%) evaluable patients at the median onset day of 168. After a median follow-up period of 48 months, 1-year overall survival (OS) and 5-year OS rates were 56.3% and 46.5%, respectively The survival curve reached a plateau at 22 months after SCT. Univariate analysis showed that year in which SCT was performed, male sex, high level of sIL-2R both at diagnosis and at SCT, and disease status (non-CR at SCT) were significant risk factors for overall survival. SIL-2R at SCT (P=0.02) was determined to be a significant risk factor for disease progression and male sex was marginally significant (P=0.06) by univariate analysis. Non-CR at SCT was marginally significant for transplant-related mortality (P=0.07). Worse survival for male patients and patients in non-CR at SCT were confirmed by using multivariate analysis with Cox's regression model [hazard ratio of 3.15 (95% confidence interval: 1.36–7.30) for male patients and hazard ratio of 2.70 (95% confidence interval: 1.01–7.24) for non-CR patients]. This is the first report on ATL patients in a non-endemic area who received allo-SCT, and we think that this report shows very important information for management of ATL patients in non-endemic areas. Disclosures: No relevant conflicts of interest to declare.

Description: Typical acute promyelocytic leukemia (APL) is associated with expression of the PML/RARα fusion protein resulting from chromosomal translocation t(15;17) and responsiveness to treatment with all-trans retinoic acid (ATRA). A few population of APL is associated with variant chromosomal translocations, t(11;17), t(5;17) and t(17;17). PLZF/RARα is the chimeric fusion protein resulting from the chromosomal translocation, t(11;17)(q23;q21). APL cells with PLZF/RARα have been reported to be unresponsive to ATRA-induced terminal differentiation clinically and experimentally. The molecular basis of unresponsiveness in PLZF/RARα-derived APL cells against ATRA explained by a rigid interaction between BTB/POZ domain of PLZF and a transcriptional co-repressor, N-CoR. PLZF/RARα contains BTB/POZ domain in its N-terminus. BTB/POZ domain is developmentally conserved among various species, and recently several BTB/POZ-containing molecules have been reported to function as substrate-specific adaptors for Cul3-based E3 ubiquitin ligase. Here we examined the possibility that PLZF/RARα functions as an E3 ligase. We performed the series of transient transfection analysis. By immunoprecipitation assay, PLZF/RARα associated with Cul3, and PLZF/RARα also associated with RXRα. PLZF/RARα accelerated an ubiquitin-dependent degradation of RXRα, and resulted in the decreased expression of RXRα. This degradation of RXRα was dependent on the expression level of PLZF/RARα. On the contrary, co-expression of dominant negative form of Cul3 with PLZF/RARα resulted in the restored expression of RXRα. When we expressed PML/RARα, PLZF or PLZF/RARαΔBTB, the accelerated degradation of RXRα was not observed. In RARα-responsive luciferase assay, PLZF/RARα repressed ATRA response. Consistent with the result that PLZF/RARαΔBTB did not down-regulate the expression of RXRα, PLZF/RARαΔBTB did not repress ATRA response. In addition, the transduction of recombinant RXRα molecule into PLZF/RARα expressing cells partially restored ATRA-responsiveness. Collectively, we suggest that ATRA resistance in PLZF/RARα-positive cells is explained by the novel function of PLZF/RARα molecule.

Description: Appearance of anti-hepatitis B surface antigen antibody (anti-HBs) and clearance of hepatitis B virus (HBV) from serum usually indicates resolution of hepatitis in patients infected with HBV. However, in most patients in whom HBV has been eliminated from serum, HBV DNA is still detectable in the liver using polymerase chain reaction. Reactivation of this dormant HBV in the liver is known as reverse seroconversion (RS). Previously, we reported that HBV-RS after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was a frequent late-onset complication that can be predicted by careful monitoring of progressive disappearance of anti-HBs. RS hepatitis after allo-HSCT is thought to be a phenomenon caused by naive donor immunity after loss of recipient-oriented immunity against HBV. We speculated that vaccination could prevent reactivation of HBV in allo-HSCT recipients. Safety and efficacy of recombinant HBV vaccine in allo-HSCT recipients have already been confirmed. We studied HBV serological markers in 23 patients with anti-HBs and/or anti-HBc before allo-HSCT who were followed for more than 1 year. Patients’ characters are following; Age at HSCT 22 to 65 (median, 38) years; M:F ratio 14:9; Hematological disorders CML 6, AML 1, ALL 4, MDS 4, SAA 2, NHL 4, MM 1 and CAEBV 1; Serological markers anti-HBc(+) and anti-HBs(+) 17, anti-HBc(+) and anti-HBs(−) 3, anti-HBc(−) and anti-HBs(+) 3. No patients had a prior history of vaccination or HBV-specific immunoglobulin usage. All patients were negative for hepatitis B surface antigen (HBsAg) and were considered to have previous HBV infection. The follow-up period varied from 12 to 116 (median, 36) months. Eighteen patients were followed without intervention. Five patients were vaccinated with recombinant HBV vaccine by the standard three-dose protocol after cessation of immunosuppressant administration. RS was defined as disappearance of anti-HBs and appearance of HBsAg and HBV-DNA with or without clinical hepatitis. Progressive decreases in anti-HBs titer were observed in all pre-HSCT anti-HBs-positive recipients. In 18 of the 20 patients with pre-HSCT anti-HBs, anti-HBs titer decreased to less than the protective value (

Description: Development of anti-hepatitis B surface antigen antibody (anti-HBs) and clearance of hepatitis B virus (HBV) from serum usually indicate resolution of hepatitis in patients infected with HBV. However, most patients in whom HBV has been eliminated from the serum still have HBV DNA in the liver that is detectable by using polymerase chain reaction. Reactivation of this dormant HBV in the liver is known as reverse seroconversion (RS), which was reported to be a rare complication of hematopoietic stem cell transplantation (HSCT). However, the precise frequency of RS and results of long-term follow-up after RS have not yet been reported. We retrospectively studied HBV serological markers in fourteen patients with anti-HBs before allogeneic HSCT who were followed up for more than 1 year. Patients’ characteristics are as follows: median age at time of HSCT, 35 years (range, 22–52 years); M:F ratio, 9:5; hematological disorders: CML 5, ALL 4, MDS 3, SAA 2. No patients had prior history of vaccination or HBV-specific immunoglobulin usage. All donors were negative for hepatitis B surface antigen (HBsAg), and four donors were confirmed to be negative for anti-HBs. Only one case (case 1) had relapse of hematological malignancy during the follow-up period. RS is defined as disappearance of anti-HBs and appearance of HBsAg, HBV-DNA, and clinical hepatitis. The follow-up period varied from 15 to 92 months (median, 48 months). The actual risk of disappearance of anti-HBs and RS were calculated using the Kaplan-Meier method. Progressive decreases in anti-HBs titer were observed in all 14 cases. In 12 of the 14 cases, anti-HBs titer had decreased to under the protective value (

Description: Secondary clonal hematological disease in donor cells has rarely been reported as a complication of allogeneic stem cell transplantation in hematological disease. We report a case of myelodysplastic syndrome that showed cytogenetic abnormalities of t(2;3) and monosomy 7, which developed two years after peripheral blood stem cell transplantation for aplastic anemia and one year after liver transplantation for drug-induced hepatic failure. A 23-year-old female was diagnosed as having a severe-type aplastic anemia in April, 2000. Treatment with immunosuppressive drugs was not successful. Nineteen months later, she received allogeneic PBSCT from an HLA-matched elder on November 12, 2001. Her clinical course after PBSCT was marked by serious drug-induced hepatitis. Ten months after allogeneic PBSCT, she suddenly developed hepatic failure. On September 29, 2002, she was emergently transplanted with living donor-derived liver from the sibling who was the donor for allogeneic PBSCT. One month after liver transplantation (LT), pancytopenia had gradually progressed. At that time, chromosomal analysis showed 46, XX (20/20), and chimerism analysis of PB showed 100% donor-type. Late graft rejection of bone marrow was not suspected due to there being no relative lymphocytosis and the persistence of 100% complete donor-type chimerism. Thereafter, pancytopenia worsened, even with the stable complete donor-type chimerism, and G-CSF and EPO were administered. Bone marrow aspirate at seven months after the start of cytokine therapy showed trilineage dysplasia, suggesting secondary myelodysplasia. Cytogenetic analysis at that time showed t(2;3) in 17/20 cells. Eight months later, at 31 months post allogeneic PBSCT and 21 months post-LT, her bone marrow showed chromosomal abnormality with t(2;3) and additional monosomy 7 in 14/20 cells. There was no evidence of graft rejection because of sustained 100% donor-type chimerism. There was no possibility of second SCT because of hepatic dysfunction and hyperbilirubinemia even after LT as well as repeated intra-abdominal bacterial infection through a gastrostomy tube for nutrition. Bone marrow aspirations performed two and six months later showed an increased proportion of t(2;3) and monosomy 7 to 100%. She suddenly died of intra-abdominal bleeding due to profound thrombocytopenia 42 months after allogeneic PBSCT and 32 months after LT. The donor is currently alive and well with completely normal hematological data. This secondary malignancy of donor origin is most frequently seen in patients with leukemia. We suspect that the chromosomal abnormalities are related to hepatitis-associated aplastic anemia, administration of granulocyte colony-stimulating factor and erythropoietin for post-transplant pancytopenia, and repeated infections after liver transplantation.

Description: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive hematological malignancy associated with the retrovirus human T-cell lymphotropic virus type I. Clinical outcomes of currently available chemotherapies are generally inferior with extremely poor prognosis. Previous studies have recently utilized next generation sequencing technology for the identification of mutated genes that may be pivotal in the pathogenesis of ATLL. However, the identification of indispensable genes for the proliferation and/or survival of ATLL cells remains a formidable challenge due to the complexity of genomic/epigenetic alterations in the ATLL genome. To investigate previously undescribed therapeutic targets in ATLL, we performed a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening to identify genetic vulnerabilities in ATLL cells. Three ATLL cell lines were transduced with lentiviral construct for Cas9 nuclease, followed by lentiviral delivery of the human CRISPR Brunello pooled library (Addgene 73178) of 76,456 single-guide RNAs targeting 19,144 protein-coding genes to cause DNA double-stranded cleavage by the Cas9 nuclease and loss-of-function of the respective genes. Compared with the control cell lines, 23 essential genes, including BATF3 (which we previously discovered by shRNA library screening; Nakagawa et al., Cancer Cell. 34:286-297. 2018) and novel genes (CDK6, JUNB, STAT3, and CCND2) were identified to be involved in ATLL cell proliferation and/or survival. Among these, CDK6 (cyclin-dependent kinase 6), a critical regulatory serine/threonine kinase that forms heterodimers with D-type cyclins, had the best score. The CDK6/D-type cyclin complex regulates E2F transcription factors through the phosphorylation of Rb (retinoblastoma protein), resulting in G1-S transition of the cell cycle. Utilizing publicly available microarray data from peripheral T-cell lymphoma patients, we demonstrated the higher expression of CDK6 in ATLL than that of the other subtypes of T-cell lymphomas, which prompted us to focus on CDK6 as a therapeutic molecular target in ATLL. In confirmatory experiments, two sgRNAs targeting the coding sequences of CDK6 exhibited strong toxicity in five ATLL cell lines in a temporal fashion, which was mediated by G1 cell arrest and partially through apoptosis. We confirmed on-target effect of the sgCDK6 by successfully rescuing cells from toxicity using retroviruses expressing sgRNA-resistant CDK6 cDNA in two ATLL cell lines. The knockout of CDK6 and decrease in the level of phosphorylated Rb were confirmed by immunoblot of sgCDK6-transduced ATLL cell lines. Collectively, the data showed an essential role for CDK6 in cellular proliferation and survival in ATLL. Of the 19,144 genes examined, CDK6 was considered the best vulnerable target for ATLL; therefore, we extended our analysis to evaluate the pharmacological inhibition of CDK6 in ATLL cells. Palbociclib, FDA-approved CDK4/6 inhibitor for breast cancer, was toxic in 11 ATLL cell lines and in four primary ATLL cells but the range of IC50 values were relatively broad (9-6500 nM) among ATLL lines. Because aproximately 20% of ATLL patients carry genetic alteration in a cell cycle/apoptosis regulator TP53 gene, we hypothesized that TP53 alteration may affect the sensitivity of ATLL cells to palbociclib. First, we assessed TP53 status of ATLL cell lines by Sanger sequencing and immunoblotting and showed that six TP53-altered ATLL cell lines exhibited significantly higher IC50 for palbociclib compared with five TP53-intact ATLL cell lines (p

Description: Abstract 4544 Background: Current prognostic models, including the International Prognostic Index (IPI), incorporate both patient and tumor characteristics. In contrast, recent studies show that variables related to the host adaptive immunity and the tumor microenvironment are significant prognostic variables in cases of diffuse large B-cell lymphoma (DLBCL). Recently, Wilcox and co-workers reported that lymphopenia, defined as an absolute lymphocyte count (ALC) 630/μL, at diagnosis was associated with inferior survival in patients with DLBCL treated with CHOP/R-CHOP (Leukemia, 2011). The same group also reported that the ALC/AMC ratio at diagnosis can be a biomarker to predict the clinical outcome in DLBCL patients treated with R-CHOP (Porrate et al. ASH 2011). However, it remains to be determined if these parameters can predict the outcome of autologous peripheral blood stem cell transplantation (APBSCT) in patients with DLBCL in the first remission. Methods: We retrospectively examined the predictive value of the AMC and ALC in a cohort of 55 consecutive DLBCL patients who uniformly underwent APBSCT in their first remission at Hokkaido University Hospital and Sapporo City General Hospital. At presentation, all patients were at high risk (Coiffier et al. J Clin Oncol, 1991) (1997 to 2000), or high (H)/high-intermediate (HI) risk, in the age-adjusted IPI (aaIPI) (2001 to 2012). After six cycles of CHOP (before 2000, N=16) or R-CHOP (after 2001, N=39), all patients were treated with APBSCT, followed by the MCVC regimen, consisting of ranimustine, carboplatin, etoposide and cyclophosphamide. We performed a receiver operating characteristics (ROC) analysis to determine the optimal cut-off point for both the AMC and ALC in our patients, and values of 551/uL and 1,000/uL were set for the subsequent analyses. The disease free survival (DFS) and overall survival (OS) were estimated using the Kaplan–Meier method and two-tailed log-rank test. Results: Twenty-five patients were male and thirty were female. According to the aaIPI, 15, 31, and nine patients were classified as H, HI, and low (L)/low intermediate (LI), respectively. The median duration of follow-up after APBSCT was 85 months (range 1 to 179 months). At diagnosis, the median ALC was 1,095/μL (range 286–3,396/μL) and the median AMC was 551/μL (range 63–1,870/μL). The estimated 5-year OS and DFS for the entire cohort were 78% (95% confidence interval (CI) 64–88%) and 73% (95% CI 59–83%), respectively. In contrast to the previous study, the ALC did not predict an inferior OS or DFS in a univariate analysis of dichotomized variables. The estimated 5-year OS and DFS for those who had lymphopenia (ALC551/μL) had no significant impact on the 5-year OS, with rates of 88% for those who had an elevated AMC and 73% for those who did not. However, an elevated AMC was associated with a superior 5-year DFS of 88% compared to that of 59% in the cohort which did not have an elevated AMC (hazard ratio 3.18, 95% CI 1.10–11.41, p=0.03). Conclusions: Lymphopenia or an elevated monocyte number at diagnosis did not predict a poor outcome for high-risk patients with DLBCL when APBSCT was given in the first remission. Our results suggest that the dismal outcome obtained with CHOP/R-CHOP in high risk DLBCL patients who concomitantly had lymphopenia and elevated AMC could be overcome by an APBSCT in the first remission, although these results should be confirmed in a prospective study. Disclosures: No relevant conflicts of interest to declare.