High-dose Cytarabine Therapy Research Articles

Residual diffusion-weighted imaging hyperintense signal in primary central nervous system lymphoma can predict early recurrence.

The treatment response of primary central nervous system lymphomas (PCNSLs) is mainly evaluated using postcontrast T1-weighted imaging (T1WI). Because poorly enhanced lesions may contain residual tumors, the combination of evaluation methods will potentially improve the accuracy of determining treatment effectiveness. In this study, we evaluated the usefulness of diffusion-weighted imaging (DWI) in predicting recurrence among patients with PCNSL who achieved complete response (CR)/unconfirmed CR (CRu). Fifty-four patients newly diagnosed with PCNSL who were treated at our institution and achieved CR/CRu at the end of treatment were included in this study. The patients were divided into two groups according to the presence or absence of residual DWI hyperintense signal at the tumor site at the end of treatment. Kaplan-Meier analysis was performed to analyze the median overall survival (OS) and progression-free survival (PFS). The mean age of the 54 patients was 66.4 ± 13.3 years. The induction therapies were HD-MTX in 20 patients, R-MPV in 29 patients, and other chemotherapies in five patients. Radiotherapy was performed in 35 patients, high-dose cytarabine therapy in 14 patients, and autologous hematopoietic stem cell transplantation in one patient, and of the 54 patients, 10 had no consolidation therapy. The residual DWI hyperintense signal sign was observed in 18 patients. The R-MPV regimen was statistically associated with a lower rate of residual DWI hyperintense signal (p = 0.0453). The median PFS was statistically shorter in the residual DWI hyperintense signal group than in the non-residual DWI hyperintense signal group (14.0 months vs. 85.1 months) (p < 0.0001, log-rank test). A residual DWI hyperintense signal at the end of treatment was statistically associated with shorter PFS. Among patients who achieved CR/CRu evaluated based on postcontrast T1WI, DWI could be a valuable additional sequence to predict the early recurrence of PCNSL.

Early-stage corneal toxicity secondary to high-dose systemic cytarabine: a case report

BackgroundHigh-dose systemic cytarabine chemotherapy may cause fine corneal opacities and refractile microcysts, which are densely distributed in the center of the cornea. Most previous case reports on microcysts have been those following complaints of subjective symptoms, and the findings at the initial stage of development and time-course changes are still unknown. This report aims to clarify the time-course changes of microcysts using slit-lamp photomicrographs.Case presentationA 35-year-old woman who was treated with high-dose systemic cytarabine therapy (3 courses of 2 g/m2 every 12 h for 5 days) for acute myeloid leukemia and presented with subjective symptoms, such as bilateral conjunctival injection, photophobia, and blurred vision, on the 7th day of treatment in both the first two courses. Anterior segment findings by slit-lamp microscopy revealed microcysts densely distributed in the central region of the corneal epithelium. In both courses, microcysts disappeared within 2–3 weeks upon prophylactic steroid instillation. In the 3rd course, daily ophthalmic examinations were conducted from the start of the treatment, and on the 5th day without subjective symptoms, the microcysts in the corneal epithelium appeared evenly and sparsely distributed throughout the cornea except for the corneal limbus. Thereafter, the microcysts accumulated towards the center of the cornea and disappeared gradually. The change from low-dose to full-strength steroid instillation immediately following the occurrence of microcysts in the 3rd course resulted in the peak finding being the mildest compared to that in the past two courses.ConclusionsOur case report revealed that microcysts appeared scattered throughout the cornea before the appearance of subjective symptoms and then accumulated in the center and disappeared. A detailed examination is necessary to detect early changes in microcyst development resulting in prompt and appropriate treatment.

Usefulness of leadless pacemaker implantation to continue chemotherapy for Burkitt's lymphoma without device infection despite repeated systemic infections.

Usefulness of leadless pacemaker implantation to continue chemotherapy for Burkitt's lymphoma without device infection despite repeated systemic infections.

Effect of 0.1% Fluorometholone on the Prevention of Eye Disorders Caused by High-Dose Cytarabine Therapy: a Propensity Score Analysis

Effect of 0.1% Fluorometholone on the Prevention of Eye Disorders Caused by High-Dose Cytarabine Therapy: a Propensity Score Analysis

ML-4 A case of primary CNS lymphoma diagnosed 5 years after stereotactic radiosurgery

Central nervous system primary malignant lymphoma (PCNSL) is rarely diagnosed as multiple metastatic brain tumors. Almost tumors recure early after receiving stereotactic radiosurgery (SRS). Regardless of the fact, the following case report displays PCNSL, diagnosed five years after the initial treatment with SRS as brain metastases of unknown primary origin. This extraordinal case suggests long-term follow-up regarding PCNCL. The case was a 55-year-old woman with a history of a total hysterectomy for cervical cancer. She developed left paralysis. Brain MRI confirmed a 27 mm contrast-enhanced lesion in the right frontal lobe and three other lesions. SRS was performed as a diagnosis of multiple brain metastases for urgent symptom relief. No extra-cranial cancerous lesions were found. Unknown primary cancer was a probable diagnosis at that time. Two years after SRS, local regrowth of tumor of the right frontal primary motor area was discovered. Re-irradiation was performed. Cerebral edema, contrast enhancement, and left paralysis progressed following five months, taking an oral corticosteroid. Craniotomy and debulk. The pathological diagnosis was brain radiation necrosis due to no viable tumor cells. New lesions in the left temporal lobe and basal ganglia appeared three years after surgery. Awake craniotomy was performed for the left temporal lobe lesion. Histopathology showed diffuse growth of tumor cells with a high nucleo-cytoplasmic ratio and irregular nuclear shape. Immunohistochemistry revealed positive CD10, CD20, CD45 (LCA), MUM1, and negative CD3, CD5. The Ki- 67 labeling rate was as high as almost 100% to diagnose diffuse large B-cell lymphoma, PCNSL. Multidrug chemotherapy consisting of rituximab, high-dose methotrexate, procarbazine, and vincristine were performed. Complete remission was obtained without any serious adverse events. Considering the residual radiation necrosis, whole-brain irradiation was avoided. Moreover, consolidation therapy was performed only with high-dose cytarabine therapy.

S2562 Relapsed Acute Myeloid Leukemia With Isolated Conjugated Hyperbilirubinemia Secondary to High-Dose Cytarabine Therapy

S2562 Relapsed Acute Myeloid Leukemia With Isolated Conjugated Hyperbilirubinemia Secondary to High-Dose Cytarabine Therapy

Abstract LB-178: Identification of DNA 5hmC decision signature biomarkers for azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk AML

Abstract DNA 5hmC biomarkers to predict the outcomes to the of azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy for patients with high-risk AML. Azacitidine (AZA), a DNA methyltransferase inhibitor and epigenetic modulator, has been combined with chemotherapy to treat high-risk AML patients for better clinical outcomes. However, the complete remission (CR) rate and prognosis remains unsatisfactory. Here, we proposed that the use of AZA for high-risk AML patients helped to sensitize leukemia cells to chemotherapy. We analyzed 45 high-risk AML patients who had received AZA treatment followed by High-dose cytarabine and mitoxantrone (AZA-HiDAC-Mito) therapy. We performed RNA-Seq and DNA 5hmC-Seq on available RNA/DNA samples. By comparing differential expressed genes between patients responded to therapy (CR or CRi, responder) and those did not (non-responder), we found that patients with better response had lower expression on ephrin receptor gene and AR pathway related genes. Using XGBoost machine learning model, we developed an 11-gene-5hmC signature to predict treatment outcomes, and it achieved 87.76% sensitivity and 87.10% specificity (AUC=0.911). The signature was also capable of distinguishing which patients would have better response to HiDAC-Mito only treatment, indicating that the signature had a potential to serve as a general predictor for intensive chemotherapy. Our findings show that DNA 5hmC patterns could be used as the prognostic biomarker for AZA-HiDAC-Mito therapy, which could guide further biomarker-based clinical trials. Citation Format: Dali HAN, Wei Zhang. Identification of DNA 5hmC decision signature biomarkers for azacitidine prior to hi-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk AML [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-178.

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11

AbstractThe prognostic impact of KIT mutation on core-binding factor acute myeloid leukemia (CBF-AML) remains controversial. We registered 199 newly diagnosed de novo CBF-AML patients, aged 16 to 64 years, who achieved complete remission. They received 3 courses of high-dose cytarabine therapy and no further treatment until hematological relapse. Mutations in exons 8, 10-11, and 17 of the KIT gene were analyzed. Furthermore, we analyzed mutations in 56 genes that are frequently identified in myeloid malignancies and evaluated minimal residual disease (MRD). The primary end point was relapse-free survival (RFS) according to KIT mutations. The RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio, 1.92; 95% confidence interval, 1.23-3.00; P = .003). Based on subgroup analysis, KIT mutations had a prognostic impact in patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11, and only exon 17 mutation had a significant prognostic impact. Multivariate Cox regression analysis with stepwise selection revealed that the KIT exon 17 mutation and the presence of extramedullary tumors in patients with RUNX1-RUNX1T1, and loss of chromosome X or Y and NRAS mutation in patients with CBFB-MYH11 were poor prognostic factors for RFS. MRD was evaluated in 112 patients, and it was associated with a poorer RFS in the patients with CBFB-MYH11, but not in those with RUNX1-RUNX1T1. These results suggested that it is necessary to separately evaluate AML with RUNX1-RUNX1T1 or CBFB-MYH11 according to appropriate prognostic factors. This study was registered at www.umin.ac.jp/ctr/ as #UMIN000003434.

Prospective Evaluation of Prognostic Relevance of Gene Mutations and Minimal Residual Disease in Acute Myeloid Leukaemia with RUNX1-RUNX1T1 or CBFB-MYH11

Background: Although acute myeloid leukaemia (AML) with RUNX1-RUNX1T1 and CBFB-MYH11 is categorized into a favorable cytogenetic risk group, several prognostic factors are suggested. However, those clinical significance remains controversial. We aimed to evaluate the prognostic relevance of gene mutations and minimal residual disease (MRD) in AML with RUNX1-RUNX1T1 and CBFB-MYH11. Methods: In this phase 4 trial, we enrolled AML with RUNX1-RUNX1T1 or CBFB-MYH11 patients aged 16 to 64 years old who achieved complete remission. Patients received three courses of high-dose cytarabine therapy, but no further treatment until haematological relapse. We analyzed mutations in exons 8, 10-11, and 17 of the KIT gene, and 55 genes that are frequently identified in myeloid malignancies, and also evaluated MRD. The primary endpoint was relapse-free survival (RFS) according to KIT mutation. This study is registered with UMIN Clinical Trials Registry, number UMI03434. Findings: Between May 25, 2010, and September 10, 2014, 203 patients were enrolled, and 199 patients were eligible. Median follow-up was 52·2 months (IQR 39·2-62·2). The primary endpoint RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio [HR] 1·92; 95% CI 1·23-3·00; p=0·003). Subgroup analysis showed a prognostic impact of KIT mutation in patients with RUNX1-RUNX1T1 (HR 3·27; 95% CI 1·90-5·64; p<0·001), but not in those with CBFB-MYH11, and only exon 17 mutation had such a notable impact. MRD was evaluated in 112 patients, and its presence was associated with a lower RFS in patients with CBFB-MYH11 (HR 4·55; 95% CI 1·20-17·2; p=0·03), but not in those with RUNX1-RUNX1T1. Interpretation: KIT exon 17 mutation was an unfavorable prognostic factor for RFS in AML patients with RUNX1-RUNX1T1. In contrast, the positivity of MRD was an unfavorable prognostic factor for RFS in AML patients with CBFB-MYH11. Trial Registration Number: This study is registered with UMIN Clinical Trials Registry, number UMI03434. Funding: Japan Agency for Medical Research and Development (AMED). Conflict of Interest: HKi received research funding from Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Zenyaku Kogyo Co., Ltd., FUJIFILM Corporation, Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K., and Celgene Corporation, consulting fees from Astellas Pharma Inc., Amgen Astellas BioPharma K.K., and Daiichi Sankyo Co., Ltd., and honoraria from Bristol-Myers Squibb. NDob received research funding from Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Kyowa Hakko Kirin Co., Ltd., Zenyaku Kogyo Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Celgene Co., and Sysmex Co. NA received research funding from Chugai Pharmaceutical Co., Ltd., and Toyama Chemical Co., Ltd., and consulting fee from SRL Inc. No other potential conflict of interest relevant to this article was reported. Ethical Approval: The protocol was approved by the Ethics Committees of all participating institutions.

Prospective Evaluation of Prognostic Relevance of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia: Results from the JALSG CBF-AML209-KIT Study

Prospective Evaluation of Prognostic Relevance of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia: Results from the JALSG CBF-AML209-KIT Study

A multi-institution comparison of mitoxantrone, etoposide, and cytarabine (MEC) vs. high-dose cytarabine and mitoxantrone (Ara-C Couplets) therapy for patients with relapsed or refractory (R/R) acute myeloid leukemia.

e19005Background: R/R AML has a poor prognosis, thus salvage chemotherapy is used as a bridge to HSCT, however the optimal regimen remains unknown. MEC is commonly used as salvage; ~ 66% of patient...

High-dose cytarabine-associated cerebellar toxicity: A case report

High-dose arabinoside cytarabine is used as an effective regimen for post-remission acute leukemia and refractory leukemia treatment. Most commonly used regimen is 3 g/m2 IV over 1-3 h q12 h for a total of 8-12 doses. Major toxic effects associated with cytarabine are related to bone marrow, gastrointestinal tract, and nervous system. Acute cerebellar toxicity with ataxia and dysarthria is well-known adverse effect during high-dose cytarabine therapy. This case report describes about a patient with acute myeloid leukemia on high-dose cytarabine who developed ataxia and left-sided nystagmus as cerebellar toxicity. These symptoms persisted till 2 days after the termination of high-dose cytarabine the gradually improved with steroids. PatientÂ’s good response to methyl prednisolone illustrates immune-mediated mechanism of neurotoxicity.

Vascular E-Selectin Protects Leukemia Cells from Chemotherapy By Directly Activating Pro-Survival NF-Kb Signalling - Therapeutic Blockade of E-Selectin Dampens NF-Kb Activation

The vascular adhesion molecule E-selectin is a key component of the Bone Marrow (BM) Haematopoietic Stem Cell (HSC) niche prompting HSC to proliferate at the expense of self-renewal (Winkler, Nat Med 2012).Only 3 - 5% of BM endothelial cells express E-selectin in steady state however E-selectin is greatly upregulated (5 - 10 fold) in BM of mice with acute myeloid leukemia (AML) raising the question; how do AML stem cells (LSC) respond to E-selectin at the vascular niche & does E-selectin signalling in AML & HSC differ?Using models of murine AML generated by retroviral transduction of MLL-AF9 or AML1-ETO oncogenes, we found leukemic blasts rapidly upregulate E-selectin-binding upon oncogenic transformation. Furthermore E-selectin adhesion promoted LSC survival to cytarabine in vitro as well as in vivo. LSC survival to chemotherapy in wildtype compared to E-selectin knockout (E-/-) mice quantified by rigorous limiting-dilution transplantation assay of 1%, 0.1%, 0.01% femur BM demonstrated that E-selectin deletion increased sensitivity of LSC to high-dose cytarabine therapy ~11-fold (900mg/kg cytarabine n=6 donors &15 recipients/gp p=0.0037). Thus E-selectin is a critical vascular niche component mediating LSC chemo resistance. Importantly these findings could be replicated by administration of a potent small molecule glycomimetic E-selectin antagonist (GMI-1271) to wt mice. Furthermore treatment with GMI-1271 (40mg/kg bidaily) for 10 days in combination with standard mouse version of 7+3 induction chemotherapy (5 days cytarabine 100mg/kg; 3 days doxorubicin 1mg/kg) was able to significantly double mouse survival over chemotherapy alone (p=0.0054; no chemotherapy median survival 25 d, AraC/Dox alone 32 d, AraC/Dox plus GMI-1271 survival 41 d; n=8 mice/gp).To understand mechanisms of this chemo-sensitisation, mice with MLL-AF9 monomyelocytic (11q23 translocation) or AML1-ETO granulocytic t(8;21) -induced AML were administered GMI-1271 or vehicle control for 5 days before sorting BM AML blasts for RNA sequencing. Analysis of differentially expressed transcripts by CuffDiff / DSeq2 revealed 170 RNAs differed following in vivo E-selectin blockade. KEGG pathway analysis indicated a pathway potentially dampened in AML blasts following GMI-1271 administration was PI3K - NF-kB signalling - raising the hypothesis that adhesion to E-selectin activates pro-survival NF-kB signalling in AML cells leading to enhanced chemoresistance.Using two in vitro assays, we confirmed E-selectin to be unique among vascular adhesion molecules tested in being able to directly activate NF-kB. Activation of NF-kB was only observed upon E-selectin mediated adhesion & was not observed following adhesion to P-selectin, PECAM-1 or VCAM-1 using either myeloid NF-kB GFP reporter cell lines or by induction of p65 NF-kB (Ser 536). Importantly E-selectin mediated NF-kB activation was completely inhibited when E-selectin antagonist GMI-1271 added.Assays repeated in presence of a specific NF-kB activation antagonist (BMS-345541 10uM 24hrs) demonstrated that NF-kB blockade alone reversed E-selectin-mediated chemoresistance in vitro. Upstream blockade of E-selectin by GMI-1271 not only inhibits NF-kB activation but also mobilizes LSC out of the protective BM niche & prevents re-entry thereby breaking the chemo resistance observed with these cells. A Phase I/II Clinical trial to study efficacy of GMI-1271 in combination with chemotherapy in AML patients (NCT02306291) is currently in progress DisclosuresWinkler:GlycoMimetics: Research Funding. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Levesque:GlycoMimetics: Equity Ownership.

A case with ZNF198-FGFR1 gene rearrangement presenting as acute eosinophil myeloid leukemia.

A previously healthy 47-year-old Chinese man presented in January 2009 with extreme fatigue, fever, and night sweats. Hepatomegaly (palpable, 2 cm in the right hypochondrium) and splenomegaly (palpable, 2 cm in the left hypochondrium) were identified, and axillary lymph nodes were swollen. A laboratory investigation showed a white blood cell (WBC) count of 39.8 × 109/L with eosinophils 52% (absolute eosinophil count of 20.7 × 109/L), hemoglobin level of 14.9 g/dl and platelet count of 50.0 × 109/L. Bone marrow (BM) aspirate revealed hypercellular and occupied by approximately 22.0% blasts; eosinophils comprised 23.5% of total cellularity [Figure 1a]. Flow cytometry of these blast cells demonstrated expression of CD13, CD33, CD34, CD117, CD14, CD15, and human leukocyte antigen-DR indicating that myeloblasts were presented. Cytogenetic studies on BM showed a 46, XY, t (8;13)(p11.2;q12.1)[15]/46, idem,-7, der (14), +Mar[5] karyotype [Figure 1c]. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect gene rearrangements of BCR/ABL, FIPIL1/PDGFRA, TEL/PDGFRB were all negative as well as c-KIT and JAK2V617F mutations. Fluorescence in situ hybridization using a dual-fusion probe confirmed FGFR1 gene rearrangement [Figure 1b], the ZNF198-FGFR1 fusion test was done by RT-PCR using ZNF198-and FGFR1-specific primers (5′-TCCCTGTGCCTGTG TATATCCC-3′ and 5′-CGGGAAGCTCATACTCAGAGAC-3′, respectively) and showed a specific amplification product of 195 bp [Figure 1d]. Sequencing identified an in-frame fusion of exon 17 of ZNF198 to exon 9 of FGFR1 [Figure 1e], which was indicative of 8p11 myeloproliferative syndrome (EMS, World Health Organization [WHO] 2008, myeloid and lymphoid neoplasms with FGFR1 abnormalities[1]). Treatment was started with imatinib (400 mg once daily) plus urbason (40 mg once daily) at day 5, about 2 weeks after initiating treatment, WBC count (30.43 × 109/L) did not achieve a significant decrease and the level of hemoglobin and platelet count gradually reduced to 8.6 g/dl and 10.0 × 109/L, respectively. Therefore, imatinib and urbason therapy was stopped. Subsequently, the patient received AA (aclacinomycin plus cytarabine) regimen and had a marked initial response to the first cycle of chemotherapy: The WBC and platelet count returned to normal. However, 25 days later, the patient again developed worse, his WBC rose to 52.7 × 109/L. BM study revealed inadequate aspirate due to dry tap. At the time, a bone biopsy was performed and revealed a hypercellular with marked hypereosinophilia. High-dose cytarabine therapy was recommended and completed. Nonetheless, the patient failed to respond to aggressive chemotherapy and supportive treatment. He died in May 2009, 5 months after the initial diagnosis. Figure 1 (a) Morphologic changes of bone marrow (BM) smear (Wrighte Giemsa, 1 000) showed markedly increased abnormal myeloblasts with eosinophils. (b) Fluorescence in situ hybridization analysis of BM cells with an FGFR1 break-apart DNA probe revealing FGFR1 ...

Importance of albumin level on outcomes of high-dose cytarabine and mitoxantrone induction therapy for AML.

e18009 Background: Thousands of Americans are affected by acute myeloid leukemia (AML) with various factors affecting outcome. This study examines a patient's outcome as compared to nutritional sta...

Chemo-Immunotherapy With Hyper-CVAD/MA and Rituximab For B-Cell Lymphomas Leads To Prolonged Immune Suppression Compared To Conventional Treatment With R-CHOP

BackgroundFractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine (MA) therapy is a widely used combination chemotherapy for lymphoid malignancies. Its use in combination with Ribuximab (R) has been shown to be safe and effective for Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL). Acute toxicities of the treatment are mostly hematologic, leading to cases with neutropenic fever and infection. However, long-term toxicities in terms of patients' immune function have not been fully elucidated. PurposeTo evaluate the long-term immune function after R-hyper-CVAD/MA therapy, and to compared it with those after R-CHOP therapy. MethodPatients who have received R-hyper-CVAD/MA therapy or R-CHOP therapy for more than 6 cycles for B-cell lymphomas (diffuse large B cell lymphoma (DLBCL), BL and MCL) between January 2007 and December 2012 were identified. The patients' immune functions were assessed in regards to white blood cell (WBC) count, lymphocyte count, lymphocyte surface marker analysis and immunoglobulin (Ig) measurement. ResultAltogether, 21 patients underwent evaluation. 11 patients received R-CHOP therapy, and 10 patients received R-hyper-CVAD/MA therapy. The mean age of the patients was 57 and 53.3 years-old, respectively. All patients in the R-CHOP group had DLBCL, whereas patients who received R-hyper-CVAD/MA were either treated for BL in 4, MCL in 1 and DLBCL in 5 patients. The median time from the initiation of treatment to the assessment of immune function was 1060 (range 434 – 2475) and 947.5 (range 448 – 1966) days, respectively. In terms of immune function, IgG level, the proportion of CD4, CD8 positive (+) cells, CD4/8 ratio were significantly different between those who received R-CHOP therapy and R-hyper-CVAD/MA therapy. The median IgG level was 910 mg/dL in those who received R-CHOP therapy as opposed to 484 mg/dL in those who received R-hyper-CVAD/MA therapy. 4 patients in the R-CHOP group presented with IgG level below normal range, whereas 9 patients in the R-hyper-CVAD/MA group had an IgG level below normal range (p = 0.011). The median proportion of CD4 and CD8 (+) cells were 32.7%, 24.8% in the R-CHOP group and 23.35%, 41.35% in the R-hyper-CVAD/MA group, leading to the median CD4/8 ratio of 1.22 and 0.5, respectively. The total WBC count, lymphocyte count, proportion of CD19 (+) cells, IgM or IgA levels were within normal limit, and did not significantly differ between groups. Of the patients in the R-hyper-CVAD/MA group, 3 patients required regular immunoglobulin replacement, and 1 patient had 2 episodes of hospitalization within 2 years of last treatment, one due to viral meningitis and another due to pneumonia. None of the patients in the R-CHOP group presented with infection episodes that required hospitalization. ConclusionOur results suggest that patients with aggressive B-cell lymphoma treated with R-hyper-CVAD/MA therapy remain at higher risk of developing hypo-gammaglobulinemia, even after 5 years out of treatment. Despite the recovery of B-lymphocytes, the proportion of CD4 (+) cells remained low in those who received R-hyper-CVAD/MA therapy, leading to an increased proportion of CD8 (+) cells and decreased CD4/8 ratio. Patients who have received R-hyper-CVAD/MA therapy should be closely monitored for their immune function for a longer period due to prolonged hypogammaglobulinemia.Table 1R-CHOP (mean +/- SD)R-hyper-CVAD/MA (mean +/- SD)p-valueWBC (/mm3)4590 +/- 12864660 +/- 12470.902Lymphocyte (/mm3)1537 +/- 5911463 +/- 5580.772CD4 (%)34.1 +/- 13.024.7 +/- 7.50.049CD8 (%)23.9 +/- 10.042.5 +/- 17.80.011CD4/81.69 +/- 1.070.74 +/- 0.500.009CD19 (%)22.3 +/- 10.317.7 +/- 13.80.406IgG (mg/dL)1013 +/- 282551 +/- 3460.003IgA (mg/dL)205 +/- 77125 +/- 1130.11IgM (mg/dL)71 +/- 2496 +/- 910.396 Disclosures:Okamoto:Novartis, BMS, GSK, Kirin, Chugai, Alexion: Honoraria, Research Funding.

P3–010 - Testicular and Leptomeningeal Relapse as Myeloid Sarcoma in a Patient Initially Diagnosed with T Lymphoblastic Lymphoma

Background: T lymphoblastic lymphoma (T-LBL) is a neoplasm of lymphoblasts committed to the T-cell lineage. Although the tumor cells are usually TdT-positive, occasional cases of TdT-negative and CD99-positive T-LBL have been reported. Myeloid sarcoma (MS) is a rare subtype of acute myeloid leukemia involving extramedullary anatomic sites. It may be difficult to distinguish such a rare case of T-LBL from MS. Here we report a patient who was initially diagnosed as having T-LBL and later developed testicular and leptomeningeal recurrence as MS during intensive chemoradiotherapy including central nervous system (CNS) prophylaxis.Case reportA 48-year-old man was referred to our hospital because of a supraclavicular mass. FDG-PET/CT showed increased FDG uptake in the supraclavicular and axillary lymph nodes, and a bulky mediastinal tumor. Fine needle biopsy from the mediastinal tumor was performed. Histopathologically, diffuse infiltration of medium-sized tumor cells with scant cytoplasm and dense chromatin, which was accompanied by nuclear fragmentation, was observed. Immunohistochemistry demonstrated that the tumor cells were negative for CD1a, CD3, CD8, CD20 and TdT, and positive for CD4, CD43, CD56 and CD99. Bone marrow examination revealed no evidence of the infiltration of tumor cells. He was diagnosed as having T-LBL at clinical stage II and underwent an ALL-type chemotherapy regimen. After the induction chemotherapy, he achieved partial response, and received subsequent post-remission and CNS prophylaxis therapies according to the treatment schedule. Because he noticed painless right testicular swelling, right orchiectomy was performed for diagnosis. The flow cytometric analysis of cell suspensions of the biopsied specimen revealed positivities for CD13, CD33, CD34 and MPO, and the tumor was diagnosed as MS. Cerebrospinal fluid examination showed infiltration of myeloid blasts. We started high-dose cytarabine therapy.Conclusions: We report a rare case of testicular and leptomeningeal recurrence as MS during intensive chemoradiotherapy in a patient initially diagnosed as having T-LBL. We should take the possibility of MS into consideration in cases of T-LBL having atypical features, and we strongly recommend re-biopsy to obtain an accurate diagnosis upon relapse. Background: T lymphoblastic lymphoma (T-LBL) is a neoplasm of lymphoblasts committed to the T-cell lineage. Although the tumor cells are usually TdT-positive, occasional cases of TdT-negative and CD99-positive T-LBL have been reported. Myeloid sarcoma (MS) is a rare subtype of acute myeloid leukemia involving extramedullary anatomic sites. It may be difficult to distinguish such a rare case of T-LBL from MS. Here we report a patient who was initially diagnosed as having T-LBL and later developed testicular and leptomeningeal recurrence as MS during intensive chemoradiotherapy including central nervous system (CNS) prophylaxis. Case reportA 48-year-old man was referred to our hospital because of a supraclavicular mass. FDG-PET/CT showed increased FDG uptake in the supraclavicular and axillary lymph nodes, and a bulky mediastinal tumor. Fine needle biopsy from the mediastinal tumor was performed. Histopathologically, diffuse infiltration of medium-sized tumor cells with scant cytoplasm and dense chromatin, which was accompanied by nuclear fragmentation, was observed. Immunohistochemistry demonstrated that the tumor cells were negative for CD1a, CD3, CD8, CD20 and TdT, and positive for CD4, CD43, CD56 and CD99. Bone marrow examination revealed no evidence of the infiltration of tumor cells. He was diagnosed as having T-LBL at clinical stage II and underwent an ALL-type chemotherapy regimen. After the induction chemotherapy, he achieved partial response, and received subsequent post-remission and CNS prophylaxis therapies according to the treatment schedule. Because he noticed painless right testicular swelling, right orchiectomy was performed for diagnosis. The flow cytometric analysis of cell suspensions of the biopsied specimen revealed positivities for CD13, CD33, CD34 and MPO, and the tumor was diagnosed as MS. Cerebrospinal fluid examination showed infiltration of myeloid blasts. We started high-dose cytarabine therapy. Conclusions: We report a rare case of testicular and leptomeningeal recurrence as MS during intensive chemoradiotherapy in a patient initially diagnosed as having T-LBL. We should take the possibility of MS into consideration in cases of T-LBL having atypical features, and we strongly recommend re-biopsy to obtain an accurate diagnosis upon relapse.

Influence of BMI on outcomes of high-dose cytarabine and mitoxantrone induction therapy for AML.

7106 Background: Acute Myeloid Leukemia (AML) affects thousands of Americans every year. With approximately 35.7% of the U.S. adult population being obese, it is important to understand how a patient’s BMI can affect their outcome with AML treatment. This study evaluates a high-dose cytarabine and mitoxantrone induction regimen, and the results are examined to determine the effect of BMI on outcome, in terms of induction response and survival. Methods: Eighty nine patients were treated with a High Dose Cytarabine and Mitoxantrone regimen from 2008-2012. Two doses of cytarabine 3 gm/m2 were given 12 hours apart followed by one dose of mitoxantrone 30 mg/m2on days 1 and 5. All patients were dosed based on their actual body weight. Before treatment began, the BMI for each of the patients was recorded. The outcome data was collected and analyzed. Results: Of the 89 patients, 22 patients were normal, 33 overweight, and 34 obese. The BMI readings are based on the definitions established by the WHO. The overall CR rate for all 89 patients was 65%. The CRR for normal patients was 77%, 55% for overweight patients, and 68% for obese patients. 62 (70%) patients remain alive: 73% of normal patients, 58% of overweight, and 79% of obese. 17 of patients never achieved remission, even after multiple induction courses: 2 (9%) in the normal group, 10 (30%) in the overweight group, and 5 (15%) in the obese group. Of the responders, 35% of normal patients had a relapse, 30% in the overweight group, and 21% in the obese group with median relapse free survival of 8 months, 10 months and 6 months, respectively. Conclusions: Patients with a healthier BMI were more likely to respond to induction therapy with high-dose cytarabine and mitoxantrone. However, there was no difference in relapses amongst the groups. Patients who did not respond initially were unlikely to respond to other treatments. Therefore, using actual weight to determine dosing in AML induction therapy is the appropriate strategy.

High-Dose Cytarabine (HD araC) in the Treatment of Leukemias: a Review

Cytarabine (araC) has served as the backbone of acute myeloid leukemia (AML) treatment for nearly forty years. High-dose cytarabine (HD araC) therapy resulted from a theoretical model developed in the 1970s that attempted to maximize the anti-leukemia effect of cytarabine. Since that time, HD araC has been utilized mostly in consolidation therapy for AML and in patients with relapsed or resistant AML. The development of araC and HD araC preceded our current understanding of AML biology-that it is a heterogeneous disease, not a single clinical entity. Thus, the optimal dose, schedule, and clinical setting for the use of cytarabine in hematologic malignancies remain uncertain. Research is now better defining the optimal use of HD araC based on leukemia cell karyotype and molecular signature. Here we review the pharmacodynamics of araC, the landmark studies that established the role of HD araC in AML, and research defining the role of HD araC based on the unique biologic properties of the leukemia cell.

Gender Is A Major Determinant of Cytidine Analogue Metabolism and May Contribute to Differences in Treatment Outcomes

Abstract 1434Cytidine analogues are mainstays in hematologic malignancy therapy. One documented limitation of therapy is interindividual variability in cytidine analogue pharmacokinetics that compromises predictability, safety and efficacy. Causes of interindividual variability include single nucleotide polymorphisms (SNPs) in cytidine metabolizing enzymes, particularly cytidine deaminase (CDA): the CDA SNP A79C (rs2072671) is present in >70% of Caucasians and decreases CDA enzyme activity. Gender is another known genetic determinant of cytidine analogue clinical activity, although the pathway is unknown (Dimopoulou et al, Ann Oncol 2004). With high dose cytarabine therapy, CDA may be saturated, dampening the clinical impact of CDA SNPs. However, the recently approved cytidine analogues 5-azacytidine and decitabine are used as single agents at relatively low doses, and interindividual variability could have greater clinical significance, since drug levels may be close to minimum thresholds required for efficacy. To evaluate this possibility, the impact of A79C and gender on treatment outcomes was examined in a cohort of patients with myelodysplastic syndrome (MDS, n=127) and acute myeloid leukemia (AML, n=74) classified by WHO criteria, initiated on treatment between 1/2002 and 12/2007, with IRB approved tissue-banked bone marrow samples available for analysis for the A79C SNP by sequencing and SNP array, and with verifiable follow-up and survival annotation. Other variables analyzed were those known to have major prognostic importance in patients with MDS and AML (bone marrow myeloblast percentage, karyotype, age). Patients were analyzed in three treatment groups: (i) did not receive cytidine analogues (n=35), (ii) treated with cytarabine (n=76), (iii) treated with 5-azacytidine or decitabine (n=90). In all three treatment groups, heterozygosity or homozygosity for A79C was not associated with significant differences in overall survival (OS). Similarly, there was no significant difference in overall survival in females versus males who were treated with cytarabine or who did not receive cytidine analogues. However, in the 5-azacytidine/decitabine treatment group, females had significantly longer overall survival than males (median 1033 v 563 days, Log Rank p=0.014). In multivariate analysis incorporating age, karyotype, bone marrow blast percentage and A79C, only age, gender and karyotype were significantly (Cox Proportional Hazards p<0.01) associated with survival, with the hazard ratio for female gender 0.356 (95%CI 0.165–0.766). An important caveat is that MDS in females has a less aggressive natural history (Nosslinger et al, Ann Oncol 2010), therefore, it is possible that gender differences in cytidine analogue metabolism do not underlie the difference in overall survival. Nonetheless, in AML myeloblasts (GSE15434) and normal liver tissue (measured by microarray), CDA mRNA expression in females was significantly lower than in males (Wilcoxon test p=0.005 and p=0.025 respectively). To measure functional CDA activity, uridine conversion from cytidine by plasma was measured by uHPLC (Dionex). As expected, there was a significant 2-fold decrease in mean enzyme activity in individuals homozygous for the A79C variant (CC, n=32) compared to individuals homozygous for the ancestral allele (AA, n=32, t-test p=0.02). However, the decrease in mean enzyme activity in females (n=48) compared to males (n=48) was even greater (3-fold, t-test p<0.001). In an analysis of decitabine pharmacokinetics after administration of oral decitabine 1 mg/kg to female (n=18) and male (n=18) adult mice, plasma levels of decitabine measured by LCMSMS were consistently higher in females at all time-points (1.169-4.375 fold at the different time points, paired t-test p=0.001). In conclusion, decreased cytidine analogue conversion to uridine counterparts in females, most likely from differences in CDA expression, could be relevant to gender differences in treatment outcomes with 5-azacytidine or decitabine. Disclosures:No relevant conflicts of interest to declare.