bluuebunny/crossref_metadata_2025 huggingface dataset:
ADAM17 as a novel therapeutic target for HER2-positive breast cancer.
Authors: Sukor Sumainizah , McGowan Patricia M. , Mullooly Maeve , Pierce Aisling , Crown John , O'Donovan Norma , Duffy Michael J.
Published: March 2020

622

Background: Although the HER2 gene is amplifiend/overexpressed in 15-20% of breast cancers, only a proportion of these patients benefit from anti-HER2 therapy. Clearly additional biomarkers and/or therapeutic targets are necessary to enhance efficacy and improve outcome in these patients. Here, we tested the hypothesis that inhibition of ADAM17-mediated release of HER ligands may enhance response to trastuzumab and lapatinib. Methods: The ADAM17-selective inhibitor, PF-5480090 (Pfizer) both alone and in combination with lapatinib, trastuzumab or 5FU was tested for potential growth inhibitory effects on a panel of 4 HER2-positive breast cancer cell lines (BT474, MDA-MB-453, SKBR3 and JIMT-1). Results: Using the MTT viability assay, treatment with 1 µM TMI-2 resulted in a significant reduction in cell proliferation compared to vehicle control in BT474 (p=0.01), MDA-MB-453 (p < 0.005), JIMT-1 (p=0.002) and SKBR3 cells (p < 0.005). Addition of PF-5480090 to lapatinib resulted in a significant reduction in cell growth compared to lapatinib alone (JIMT-1: p < 0.005; SKBR3: p < 0.005; MDA-MB-453: p < 0.005), while addition of PF-5480090 to trastuzumab resulted in significant reduction in cell growth compared to trastuzumab alone (JIMT-1: p < 0.005; SKBR3: p < 0.005; MDA-MB-453: p=0.001). Addition of PF-5480090 to 5FU resulted in significant reduction in growth compared to 5FU alone (JIMT-1: p < 0.005; SKBR3: p < 0.005; MDA-MB-453: p=0.001). Consistent with its ability to block proliferation, addition of PF-5480090 significantly reduced release of TGFalpha (BT474: p=0.003; JIMT1: p=0.023; SKBR3: p=0.036 and MDA-MB-453: p=0.014). Conclusions: Inhibitionof ADAM17 resulted in growth inhibitory responses in HER2-positive breast cancer cell lines. Furthermore, addition of PF-5480090 to lapatinib, trastuzumab or 5FU resulted in significant growth inhibition compared to these agents alone. We propose that inhibition of ADAM17 may be used in combination with existing treatments for HER2-positive breast cancer. Acknowledgement. The authors thank SFI (SRC award, 08/SRC/B1410 to MTCI) for funding this work.
HER2 assessment and Ki-67 labeling index in a cohort of male breast cases: The Ich Network on Cancer Research (INCaRe) experience.
Authors: Masci Giovanna , Caruso Michele , Losurdo Agnese , Salvini Piermario , Carnaghi Carlo , Di Tommaso Luca , Zuradelli Monica , Manuguerra Giovanna , Rota Selene , Aiello Rosa Anna , Gullo Giuseppe , Torrisi Rosalba , Beretta Giordano D. , Santoro Armando
Published: March 2020

623

Background: The overall incidence of male breast cancers (MBC) is around 1% of all breast cancers and is on the rise.Most of our current knowledge regarding its biology and treatment strategies has been extrapolated from its female counterpart. However, from literature data, it is more and more evident that MBC has biological differences compared with female breast cancer (FBC). While hormone receptors are more frequently positive in MBC than in FBC, HER-2 seems to be less expressed in MBC than in FBC, with data ranging from 0 to 18%; no data on Ki-67 have been so far reported. Methods: We retrospectively analyzed the immunohistochemical expression of hormone receptors status, HER-2 protein expression, and Ki-67 in 76 consecutive MBCs, treated within the Humanitas Institutes Network on Cancer Research (INCaRe). HER-2 determinations were carried out according to ASCO/ACP and NEQAS guidelines: cases with score 2+ at IHC were further examined by fluorescent in situ hybridation (FISH). Results: From 2000 to 2011, we treated 76 male breast cases (age 25-87, median 64): 72 patients (94%) had ductal carcinoma and 4 had rare histotypes (2 papillary, 1 mucinous and 1 cribryform). Thirthy-two of 76 patients (42%) had positive axillary lymph-nodes, while 6 (8%) were metastatic at diagnosis. Of these, estrogen receptor and progesterone receptor were positive in 96% and 93% patients respectively; HER-2, evaluable in 67 patients, was positive in 11 (16%). Ki-67 was evaluable in 75 patients and was > 20% in 24 cases (32%), with 20/24 (26%) with Ki-67 > 30%. Grading was evaluable in 65 patients: G1 in 2 (3%), G2 in 41(63%) and G3 in 22 (34%), respectively. Conclusions: In these series, MBC show different patterns from FBC, with some favorable aspects such as higher hormone receptor status and much lower HER-2 expression and some unfavorable features, such as higher Ki-67 values. Although further studies are needed to confirm these data, different treatment strategies would be suggested in MBC than its female counterpart.
Efficacy of INK128, an mTORC1/mTORC2 kinase inhibitor, in breast cancer models driven by HER2-PI3K-AKT-mTOR pathway.
Authors: De Pradip , Sun Yuliang , Wu Hui , Rommel Christian , Liu Yi , Dey Nandini , Leyland-Jones Brian
Published: March 2020

626

Background: Downstream of the PI3K-AKT pathway, the mTOR has been shown to be essential effector in promoting cell proliferation, survival, mRNA translation and tumor susceptibility. Aberrant activation of the PI3K-AKT-mTOR pathway occurs frequently in breast tumor (BT) and contributes to resistance to trastuzumab (T). Using a HER2 amplified BT model; we investigated the antitumor efficacy of the dual mTORC1/mTORC2 kinase inhibitor INK128 alone and in combination with T. Methods: The antiproliferative and HER2-mediated cellular signaling (pAKT, pP70S6K, pS6RP, p4EBP1 and p-ERK) effects of INK128 alone and in combination with T were evaluated in HER2 amplified T-sensitive (BT474), T-resistant (BT474HR), and HER2 amplified/PIK3CA mutated (HCC1954, UACC893) BT cell lines by MTT assay and Western blots. Athymic mice bearing BT474 and BT474HR xenograft tumors were treated with INK128 and T (alone and in combination). Results: (1)INK128 exhibited excellent in vitro cell killing activity in MTT assay with IC50’s below 50nM. INK128 was more potent when combined with T, (2) INK128 blocked mTORC1, mTORC2 and thus did not cause the mTORC2 activation of AKT observed with rapalogues, (3) inhibition of phosphorylation of AKT(S473), P70S6K, S6RP, and 4EBP1(T37/46, T70) was observed following INK128 treatment, and the combination of INK128 and T more effectively blocked the PI3K-AKT-mTOR pathway, (4) INK128 dose-dependently blocked 3D-ON-TOP clonogenic growth of HER2+ cells. This effect was potentiated in the presence of T and (5) xenograft data show that the combination of INK128 and T has strongly enhanced anti-tumor effect in both sensitive and resistant models, something that cannot be achieved by either monotherapy. Conclusions: Our data suggest that 1) therapeutic targeting of the PI3K-AKT-mTOR signaling should be effective in abrogating resistance to T therapy in HER2+ BT, 2) INK128 mitigates the feedback activation of AKT caused by selective inhibition of mTORC1 and 3) targeting both the HER2 and the mTORC1/2 signaling pathways is an attractive strategy to enhance the clinical activity of T therapy, as well as to prevent or delay the development of resistance.
Detection of trastuzumab (T) level in human serum using quartz crystal microbalance (QCM) piezo-immunosensors by immobilization of a HER2 mimotope-derived synthetic peptide and its potential application in breast cancer.
Authors: Chisti Mohammad Muhsin , Shang Yuqin , Muslimani Alaa , Singh Pankaj R , Mernaugh Ray , Jaiyesimi Ishmael A. , Zeng Xiangqun
Published: March 2020

628

Background: Varied clinico-pathological response to monoclonal antibodies like T has been reported either due to presence of antibodies, rapid clearance or low density of target receptor/antigens. This demands need for an assay to monitor serum T therapeutic levels to ensure appropriate dosage. Enzyme-linked immunosorbent assay (ELISA) is still the most widely used technique to detect T level in human serum which is expensive and time consuming. For the first time, we established a platform to detect T level by using a small (<2.2 kDa), inexpensive, highly stable HER2 mimotope-derived synthetic peptide immobilized on the surface of a gold quartz electrode. Methods: HER2 mimotope was used as a substitute for the HER2 receptor protein in QCM assays to detect T level. The validation samples were prepared from the standard T solution in 10% human serum at three concentrations (10, 20 and 40 ug/ml). The changes in frequencies (ΔF) of sera from 3 female patients , 61, 32 and 44 years old , with ER/PR positive, HER2/neu positive metastatic breast cancer were obtained by calculating the differences between frequency shifts in pre and post T infusion.T level was calculated by equation, (ΔF +1.0022) ÷ 0.9997 μg / ml. Results: We showed that assay sensitivity was dependent upon the amino acids used to tether and link the peptide to the sensor surface and the buffers used. QCM assay was capable of detecting T serum level as low as 0.038 nM (linear operating range of 0.038–0.859 nM). T levels of 3 patients were 43.34, 121.96 and 193.18 μg /ml corresponding to pre and post infusion ΔF of 3.33, 11.19 and 18.31 respectively. The time frame of assay was 20-30 minutes. These results were in concordance with previously published results using ELISA. Conclusions: For the first time, we have established a low cost, highly sensitive, fast, synthetic peptide based QCM assay which could be used as a basis for developing a new generation of affinity-based Immunosensor assays to monitor serum levels of T and other monoclonal antibodies, helping physicians to determine the clinical efficacy of these drugs and ensuring appropriate dosages.
Effect of heterogeneity of HER2 expression on brain metastases of breast cancer.
Authors: Hosonaga Mari , Arima Yoshimi , Sugihara Eiji , Kohno Norio , Saya Hideyuki
Published: March 2020

635

Background: HER2-overexpressing or triple-negative [ER(-)/PR(-)/HER2(-)] breast cancers are associated with increased risk of brain metastases. The mechanisms leading to metastasis in each subtype are not well known. Methods: We introduced the wild-type HER2 gene into MDA-MB-231-luc-D3H2LN (231-Luc) cells, which are triple-negative breast cancer cells, and established HER2-expressing (63.2%) cells as 231-Luc-HER2 cells. We investigated the tumor formation following orthotopic inoculation and brain metastasis following intracardiac injection into nude mice. Metastasis was detected by bioluminescence imaging and confirmed in H&E staining and immunohistochemistry of vimentin and HER2 expressions. Flow cytometry analysis was used to detect the proportion of CD44+/CD24- cells, a maker for stem-like breast cancer cells. Results: 231-Luc-HER2 cells formed larger tumors in orthotopic xenograft models compared to 231-Luc cells, however, no significant difference was observed in proliferation in vitro. Neither 231-Luc-HER2 nor 231-Luc metastasized in the brain from the breast after orthotopic inoculation. After intracardiac injections of the 231-Luc-HER2 cells, brain metastasis developed (7/13 mice, 53.8%). Immunohistochemical analysis revealed that most metastasized cells expressed HER2, although we had injected a mixture of HER2-positive and HER2-negative cancer cells. Interestingly, administering Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, effectively prevented HER2-positive cells to colonize the brain. However, the HER2-negative 231-Luc-HER2 cells developed into brain metastases. In fact, the 231-Luc cells, which are HER2-negative, also metastasized in the brain (10/16 mice, 62.5%). Flow cytometry analysis of the 231-Luc-HER2 cells showed that HER2-positive cells decreased the population of CD44+/CD24- (HER2+/CD44+/CD24-: 86.8% and HER2-/CD44+/CD24-: 96.3%). Conclusions: The mechanism of brain metastases of HER2-positive breast cancer cells is different from that of HER2-negative breast cancer cells. It is therefore important to consider an additional therapeutic approach when dealing with HER2-negative cells in tumors having the heterogeneity of HER2 expression.
A phase II trial of azacitidine (NSC-102816) and gemtuzumab ozogamicin (NSC-720568) as induction and post-remission therapy in patients of age 60 and older with previously untreated non-M3 acute myeloid leukemia: SWOG S0703 protocol—Report on the good-risk patients.
Authors: Nand Sucha , Gundacker Holly , Godwin John E. , Willman Cheryl L. , Norwood Thomas , Erba Harry Paul , Howard Dianna S. , Coutre Steven E. , Othus Megan , Appelbaum Frederick R.
Published: March 2020

6502

Background: In pts with AML, response rates to standard chemotherapy decrease and early death rates increase with age. Whereas pts < 56 yrs of age have a complete remission (CR) rate of 65% and 30 day mortality risk of <3%, the respective figures are 33% and 31% in pts > 75 yrs. This trial was designed to improve safety and efficacy by using agents with low toxicity, different mechanisms of action and possible synergy. The treatment could be given in the outpatient setting. Methods: Newly diagnosed pts with non-M3 AML, 60 yrs or older, were treated as follows: Induction: Hydroxyurea 1500 mg b.i.d till WBC <10,000/mcL, followed by azacitidine 75 mg/m2/day s/cu or iv days 1-7, gemtuzumab ozogamicin (GO) 3mg/m2 on D8. Induction treatment was repeated for residual disease on D14. Pts achieving CR received a consolidation treatment identical to the induction treatment. This was followed by 4 cycles of azacitidine 75/m2/day, D1-7, given q 4 weeks. Subsequent therapy was optional. Promoter and global methylation studies were performed at defined time points. Results: Pts were stratified into good risk (age 60-69 or Zubrod 0-1) and poor risk (age ≥70 and Zubrod 2 or 3) groups. The results presented here are from the good risk cohort. Eighty-three pts were entered of whom 79 are evaluable. Median age was 71 yrs (60-88) and 49 were males. Thirty-five achieved CR/CRi (44%: 95% CI 33%-56%). Median overall survival was 11 months and median relapse-free survival with patients achieving a CR/CRi was 8 months. Six patients (8%), 3 with disease progression, died within 30 days of registration. The main non-hematologic toxicity was neutropenic fever (Grade 3 or higher), seen in 27 patients. Conclusions: The combination of hydroxyurea, azacitidine and GO is associated with a low induction mortality, can be given in the outpatient setting and produces results which compare favorably with standard chemotherapy regimens in elderly patients with AML. Our results are sufficiently encouraging to warrant further studies of this approach. Clinical Trials.govIdentifier: NCT00658814.
Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up.
Authors: Hochhaus Andreas , Shah Neil P. , Cortes Jorge E. , Baccarani Michele , Bradley-Garelik M. Brigid , Dejardin David , Kantarjian Hagop
Published: March 2020

6504

Background: In the phase 3 DASISION trial of dasatinib v IM in patients (pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates of complete cytogenetic response (CCyR) and major molecular response (MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P=0.001, meeting the primary endpoint. Methods: Pts were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Results: Minimum 24-month follow-up (median 26.6 months) is reported here. 24-month molecular response rates were higher for dasatinib v IM: MMR (BCR-ABL ≤0.1%) 64% v 46%, P<0.0001; MR4 (BCR-ABL ≤0.01%) 29% v 19%, P=0.0053; MR4.5 (BCR-ABL ≤0.0032%) 17% v 8%, P=0.0032. MMR rates were higher for dasatinib in all Hasford risk groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had maintained their MMR at 24 months, respectively. Pts receiving dasatinib v IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts receiving dasatinib (n=9; 3.5%) transformed to accelerated/blast phase v IM (n=15; 5.8%) on study or during follow-up after discontinuation. 24-month overall and progression-free survival were similar for dasatinib v IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few additional adverse events (AEs) were reported between 12 and 24 months in both arms, with grade 3/4 nonhematologic AE rates ≤1%. In each arm, 10 pts had a BCR-ABL mutation detected at time of discontinuation. For dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs (7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v <1%), death (2% v <1%), and other (4% v 8%). Few pts discontinued between 12 and 24 months for dasatinib (n=19; 7%) and IM (n=16; 6%). Conclusions: Updated data with minimum 36-month follow-up will be presented, including mutation analyses in pts who discontinued, progressed, or had suboptimal response. Pts receiving dasatinib had a lower transformation rate and higher molecular responses v pts receiving IM, supporting the use of dasatinib in newly diagnosed CML-CP.
Efficacy and tolerability of lenalidomide (LEN) in patients (pts) 75 and older versus those younger than 75 with RBC transfusion-dependent low/int-1-risk MDS and del 5q.
Authors: Fenaux Pierre , Guerci-Bresler Agnes , Muus Petra , Sekeres Mikkael A. , Giagounidis Aristoteles , Deeg H Joachim , Greenberg Peter , Skikne Barry , Yu Xujie , List Alan F.
Published: March 2020

6522

Background: LEN is the approved treatment for pts with RBC transfusion-dependent Low/Int-1-risk MDS and del 5q. In 2 multicenter trials (MDS-003/-004) LEN lead to RBC transfusion independence (TI) for ≥ 26 wks in 35–58% of pts and cytogenetic response (CyR) in 25–73%. Most common grade (G) 3–4 adverse events (AE) were neutropenia and thrombocytopenia, a safety concern in elderly pts. We evaluated efficacy and tolerability of LEN in pts ≥ 75 y vs < 75 y in MDS-003/-004 trials. Methods: Pts received LEN 5 mg × 28 d, 10 mg × 21 d, or 10 mg × 28 d (all 28 d cycles). Dose reductions were required for G4 neutropenia (both trials) and platelet counts < 30 x 109/L (MDS-003) or < 25 x 109/L (MDS-004). Results: 32% of the 286 pts were ≥ 75 y. Baseline (BL) characteristics, LEN treatment, and optional G-CSF use are shown in Table. In pts ≥ 75 y vs < 75 y: RBC-TI ≥ 26 wks was 39 vs 47% (P = NS); CyR was 64 vs 54% (P = NS); 2-y AML progression rates were 10 vs 19% (P = NS); 2-y overall survival rates were 62 vs 73% (P = .001); G3–4 AE: neutropenia (63 vs 76%; P = .024), thrombocytopenia (56 vs 49%; P = NS), infection (36 vs 20%; P = .003); median time to recovery to ANC > 1 x 109/L was 0.7 vs 0.7 mo (P = NS) and to platelet counts > 100 x 109/L was 3.3 vs 1.7 mo (P = NS). 59% pts ≥ 75 y and 49% pts < 75 y discontinued LEN due to AE (33 vs 26%; P = NS), lack of effect (32 vs 49%; P = NS), or death (15 vs 6%; P = NS). Dose reduction and discontinuation rates are shown in Table. Conclusions: Pts ≥ 75 y and < 75 y had comparable response and AML progression rates. In pts ≥ 75 y, LEN appears to be well tolerated but the higher infection rate justifies close follow-up. [Table: see text]
Stage I findings of a two-stage phase II study to assess the efficacy, safety, and tolerability of barasertib (AZD1152) compared with low-dose cytosine arabinoside (LDAC) in elderly patients (pts) with acute myeloid leukemia (AML).
Authors: Martinelli Giovanni , Kantarjian Hagop , Jabbour Elias , Quintas-Cardama Alfonso , Ando Kiyoshi , Bay Jacques-Olivier , Wei Andrew , Gröpper Stefanie , Owen Kate , Pike Laura , Schmitt Nicola , Stockman Paul , Giagounidis Aristoteles
Published: March 2020

6527

Background: Barasertib is the pro-drug to barasertib-hQPA, a selective Aurora B kinase inhibitor with preliminary anti-AML activity in a Phase I/II study (Löwenberg et al. Blood 2011;118:6030). Methods: AML pts aged ≥60 y considered unsuitable for intensive chemotherapy were randomized 2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg (sc twice daily for 10 days) in 28-day cycles (NCT00952588). The primary endpoint was improved objective complete response rate (OCRR: CR + CRi [Cheson criteria, but requiring CRi confirmation ≥21 days after first appearance, with partial recovery of platelets and neutrophils]). Secondary endpoints included duration of response (DoR), overall survival (OS) and safety. Results: 74 pts (barasertib, 48; LDAC, 26) received treatment and all completed ≥1 cycle. A significant improvement in OCRR was observed with barasertib (35.4% [17/48] vs 11.5% [3/26]; difference, 23.9% [95% CI, 2.7-39.9]; P<0.05); barasertib responses were seen in all cytogenetic risk groups and appeared to be durable (median DoR [range], 82 [28-321] days; vs LDAC 30-85 days). Although not formally sized to compare OS data, a trend favoring barasertib was observed (HR=0.88, 95% CI, 0.49-1.58; P=0.663; median OS, 8.2 vs 4.5 mo). Stomatitis and febrile neutropenia were the most common adverse events (AEs) in the barasertib arm with higher incidences vs LDAC (71% vs 15%; 67% vs 19%, respectively). Grade ≥3 AEs with a greater incidence in the barasertib arm were febrile neutropenia (50% vs 19%), stomatitis (29% vs 0%) and pneumonia (25% vs 8%); grade ≥3 infection rates were also higher with barasertib (40% vs 23%). For both arms, there were similar discontinuation rates due to AEs (barasertib 8.3% vs LDAC 7.7%), deaths due to AEs (12.5% vs 11.5%) and 30-day mortality (12.5% vs 15.4%). Cumulative toxicities were not observed with barasertib treatment. Conclusions: In this population with poor prognosis using standard chemotherapy, barasertib showed a significant improvement in OCRR vs LDAC, and a safety profile that was manageable and consistent with previous studies.
Impact of donor source on allogeneic stem cell transplantation for Philadelphia chromosome-negative acute lymphoblastic leukemia.
Authors: Nishiwaki Satoshi , Miyamura Koichi , Ohashi Kazuteru , Kurokawa Mineo , Taniguchi Shuichi , Fukuda Takahiro , Ikegame Kazuhiro , Sakamaki Hisashi , Morishima Yasuo , Kato Koji , Suzuki Ritsuro , Tanaka Junji ,   Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation
Published: March 2020

6533

Background: Although allogeneic stem cell transplantation (allo-SCT) could improve the outcome of adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-) ALL], the impact of the donor source, particularly the position of cord blood (CB) transplantation, is still uncertain. Methods: We retrospectively analyzed 1726 adult Ph(-) ALL patients transplanted at the first time between 1998 and 2009 with myeloablative preparative regimens who were registered in the Japan Society for Hematopoietic Cell Transplantation database. Two hundred and thirty-three received CB transplantation [first complete remission (CR1): 95, subsequent CR: 53, non-CR: 85], 809 received allo-SCT from unrelated donor (URD) (CR1: 434, subsequent CR: 158, non-CR: 217), and 684 received allo-SCT from related donor (RD) (CR1: 388, subsequent CR: 89, non-CR: 207). Results: Overall survival (OS) in patients after CB transplantation in CR1 was comparable with that after allo-SCT from URD or RD [57% in CB, 64% in URD, and 65% in RD at 4 years, respectively, P=0.11]. Donor source was not a significant risk factor for OS in multivariate analysis. Although URD was a favorable factor for relapse and an unfavorable factor for non-relapse mortality (NRM), CB was not a significant factor for them [Relapse: 22% in CB, 17% in URD, and 24% in RD at 3 years, respectively (P=0.02); NRM: 27% in CB, 23% in URD, and 13% in RD at 3 years, respectively (P=0.0001)]. Among CB recipients in CR1, age at allo-SCT (45 years or older) was solely a significant adverse prognostic factor in multivariate analysis. Among patients younger than 45 years who received allo-SCT in CR1, OS after CB transplantation was significantly better than that after allo-SCT from mismatched URD (4-year OS: 68% vs. 49%, P=0.04). Similarly, OS was not different by donor source in subsequent CR or non-CR [Subsequent CR: 48% in CB, 39% in URD and 48% in RD, P=0.33; non-CR: 18% in CB, 21% in URD, and 15% in RD, P=0.20 at 4 years, respectively]. Conclusions: Allo-SCT using CB led to similar outcomes as either RD or URD in any disease status. CB transplantation is a good alternative for adult Ph(-) ALL patients without a suitable RD or URD.
Impact of treatment prior to allogeneic stem cell transplantation for myelodysplastic syndromes: A study on behalf of the SFGM-TC and the GFM groups.
Authors: Damaj Gandhi Laurent , Duhamel Alain , Robin Marie , Michallet Mauricette , Mohty Mohamad , Vigouroux Stephane , Beguin Yves , Garnier Alice , Lioure Bruno , El Cheikh Jean , Fegueux Nathalie , Cornillon Jerome , Francois Sylvie , Rubio Marie Therese , Huynh Anne , Park Sophie , Marolleau Jean pierre , Garnier Frederico , Fenaux Pierre , Yakoub-Agha Ibrahim
Published: March 2020

6534

Background: Until the early 2000s, treatment prior to SCT varied according to cytogenetics and % BM blasts and was mainly induction-type chemotherapy (ICT). The role of Azacitidine (AZA) prior to transplant remains uncertain. Methods: 163 consecutive pts (M/F=104/67; age > 18) underwent alloSCT between 2005 and 2009 from sibling (n=96) or HLA- allele-MUD (10/10) (n=67). The SC source was blood (n=142) or marrow (n=21) and conditionings were myeloablative (n=33); nonmyeloablative (n=130). Pts who did not received neither prior ICT nor AZA were excluded since the main objective of this study was to investigate the impact of prior therapy on pts’ outcome. Results: At diagnosis, FAB/WHO was: 24 RA/RARS/RCMD, 52 RAEB-1, 74 RAEB-2, 13 RAEB-t/AML; Cytogenetic: fav (n=93), int (n=32), unfav (n=37). 98 pts received prior ICT (ICT-group) and 65 had received AZA, either alone (AZA-group; n=48) or AZA preceded or followed by intensive CT (AZA-chemo-group; n=17). In AZA groups, the drug was started 38 to 941 days from transplant and discontinued 6 to 438 days before transplant with a median number of 4 cycles (range 1-26). Overall, 119 pts were considered responders at SCT (CR, PR, mCR), including 33 (69%) treated with AZA-alone, 9 (53%) with AZA-chemo and 77(78%) with ICT.While there were no differences between AZA-group and ICT-group in terms of OS, EFS, relapse and NRM, having a poor risk cytogenetic and receiving AZA-chemo prior to SCT were, in multivariate analyses, the most important factors that adversely influenced OS with [HR=3.03; 95% CI 1.84-4.96] (p<.0001) and [HR=2.72; 95% CI, 1.38-5.35] (p=.004), respectively. Pts of AZA-chemo group had the same rate of relapse but significantly higher NRM rate (p=.059) than those who received either AZA or ICT alone. Conclusions: With the goal of down-staging underlying disease before allo-SCT, AZA treatment appears to be a valid therapeutic approach, but mainly in pts receiving AZA alone with an outcome at least equivalent to pts receiving ICT prior to SCT. Allo-SCT in pts who required both AZA and chemotherapy had less satisfactory outcomes, possibly reflecting additional toxicity and/or more resistant disease.
Impact of antithymocyte globulin (ATG)-containing conditioning regimens on patients undergoing allogeneic stem cell transplantation (allo-CST) for poor risk cytogenetic IPSS myelodysplastic syndrome (PRC-MDS): A report from the French Society of Stem Cell Transplantation and Cell Therapy (SFGM-TC).
Authors: Yakoub-Agha Ibrahim , Damaj Gandhi Laurent , Robin Marie , Vigouroux Stephane , Garnier Alice , Michallet Mauricette , El Cheikh Jean , Lioure Bruno , Bay Jacques-Olivier , Contentin Nathalie , Maillard Natacha , Deconinck Eric , Duhamel Alain , Mohty Mohamad
Published: March 2020

6542

Background: Due to a risk of relapse of underlying disease in patients with PRC-MDS, the use of ATG, incorporated within the conditioning regimen prior to allo-SCT, is still controversial. Methods: Inclusion criteria included patients aged over 18 (n=101) who received allo-SCT transplanted between 1999 and 2009 from either a sibling (n=68) or HLA-allele-MUD (10/10) (n=33) for PRC-MDS. HLA matching was double-checked by the national Bone Marrow Donor Registry. Results: According to the FAB/WHO classification at diagnosis, 22 pts had RA/RARS/RCMD, 40 RAEB1, 30 REAB2 and 9 RAEB-t/AML. 34 pts had progressed to a more advanced disease before allo-SCT. At diagnosis, 89 patients had an IPSS int-2 or higher. At transplant, 36 pts were responders (CR, PR, CRm) and 62 with progressive disease (relapsed/refractory, untreated or stable disease without hematological improvement). Median age at transplantation was 54 years (range, 22-69). Pts received myeloablative conditioning (n=46) and nonmyeloablative (n=55). In this series, 48 patients received ATG as part of conditioning ('ATG' group), whereas 53 did not ('no-ATG’ group). As of April 1st 2011, 44 patients died of relapse and 22 of TRM. 3-year relapse, overall and event-free survival rates were not significantly different between the two groups. In contrast, the cumulative incidence of grade 2-4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.005). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups, a trend for a lower TRM was observed in the ATG group (p=.06). In multivariate analysis, the absence of use of ATG was associated with an increased risk of acute grade 2-4 [HR = 1.92, p=.044]. Conclusions: The addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising survival of patients undergoing allo-SCT for poor risk cytogenetic MDS.
Minimum tolerable interval of 90yttrium ibritumomab-tiuxetan to autologous stem cell transplantation after high-dose chemotherapy with carmustin, etoposide, cytarabine, and melphalan for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.
Authors: Hasenkamp Justin , Hess Georg , Hertenstein Bernd , Dreger Peter , Uharek Lutz , Gramatzki Martin , Schubert Jörg , Wulf Gerald , Truemper Lorenz , Schmitz Norbert , Glass Bertram ,   DSHNHL
Published: March 2020

6543

Background: High-dose therapy and autologous stem cell transplantation (ASCT) in patients (pts) with aggressive B-NHL failing from immunochemotherapy including rituximab show poor outcome with 3y PFS of 39% (Gisselbrecht et al. JCO 2010). Combining BEAM with 90yttrium ibritumomab tiuxetan is a promising option to enhance the efficacy of the high-dose regimen. Methods: Pts without disease progression during salvage therapy of relapsed or refractory CD20+ aggressive B-NHL were included in this prospective, multicenter, phase I/II trial. Primary endpoint was the maximum tolerated dose of 90Yttrium ibritumomab tiuxetan given as close as possible to ASCT defined as <2 pts with dose limiting toxicity in a 6+6 pts cohort. First, we reduced the time interval of 90yttrium ibritumomab tiuxetan (0.4 mCi/kg body weight) to ASCT from 14 to 12 and then 10 days. Subsequently it was planned to increase the 90yttrium ibritumomab tiuxetan dose. Results: From 2006 to 2009 26 pts, median age 58y (34-66) were enrolled. Histology included 14 DLBCL, 6 FL III°, 5 transformed FL and 1 aggressive B-NHL without further subtyping. 11/26 pts had relapse/progression within 1y after diagnosis. Secondary IPI was >1 in 14 pts. Response to salvage therapy was CR in 6/26 pts and PR in 12/26 pts. 20/26 pts achieved CR after ASCT. Engraftment showed no significant differences in pts of different cohorts with median recovery of leukocytes (>1/nl) and platelets (>25/nl) at d +10 and +13. Two early deaths (d +7, +18) occurred due to infections. 90Yttrium ibritumomab tiuxetan (0.4 mCi/kg body weight) at d -10 of ASCT was determined as minimum tolerated interval of radioimmunotherapy to ASCT after BEAM. Median follow-up of the survivors is 3.3 y. 3y PFS and OS is 67% (95% CI, 49%-85%) and 75% (95% CI, 58%-92%), respectively. Main cause of death was relapse/progression with 27% (95% CI, 6%-38%) at 3y. Conclusions: Z-BEAM followed by ASCT was safe and feasible and results in a high response rate with durable remissions in rituximab pretreated patients with aggressive B-NHL. Extended studies at the maximum tolerated dose and confirmation of superiority compared to conventional ASCT are warranted.
Prevalence of autoimmune manifestations in patients with large granular lymphocytic leukemia: Exploratory analysis of a series of consecutive patients.
Authors: Bockorny Bruno , Grabska Joanna , Codreanu Ion , Mewawalla Prerna , Silver Joel , Dasanu Constantin
Published: March 2020

6555

Background: Review of literature suggests certain autoimmune abnormalities to accompany LGL leukemia. The present study was set to identify the prevalence of autoimmune phenomena in LGL leukemia patients and compare it with same in general population. Methods: We conducted both retrospective and prospective analyses in a series of consecutive patients (n=11) with LGL leukemia that had been followed in outpatient setting. Median age was 71 years ( ± 14 years). The presence of associated autoimmune disorders in our cohort was compared to the published prevalence of these conditions in general population. Statistical analysis: The obtained values were tested for statistical significance using Fisher’s exact test for small number of observations (95% confidence); a p value < 0.05 was considered significant. Results: A total of 45% patients in our study were diagnosed with autoimmune conditions. Identified autoimmune disorders included rheumatoid arthritis [RA] (n=3), Hashimoto thyroiditis (n=3), Felty syndrome (n=1), aplastic anemia (n=1), pernicious anemia (n=1), and leukocytoclastic vasculitis (n=1). Statistical analysis showed the following significance: Hashimoto thyroiditis (p=0.044), RA (p=0.003), Felty syndrome (p<0.001), aplastic anemia (p<0.001), pernicious anemia (p<0.001), and leukocytoclastic vasculitis (p<0.001). Statistical difference was also noted for autoimmune serologic abnormalities, with ANA positivity present in 63.6% of the cases (p< 0.001) and RF present in 50% of the patients (p=0.005). Conclusions: Nearly half of LGL leukemia patients in our cohort had autoimmune conditions, thus significantly exceeding the overall prevalence in general population. Statistically significant differences were recorded for RA, Hashimoto thyroiditis, Felty syndrome, aplastic anemia, pernicious anemia, leukocytoclastic vasculitis, ANA and RF positive serologies. The prevalence of Hashimoto thyroiditis and ANA positivity in our patient cohort was significantly higher than the one in existing literature. Given the relatively small size of the analyzed cohort, larger studies are expected to confirm our findings.
Predicting outcome based on minimal residual disease (MRD) using multiparameter flow cytometry (FC) in acute myeloid leukemia (AML) patients (Pts).
Authors: Sardesai Sagar D , Tan Wei , Ford Laurie Ann , Deeb George , Block Anne Marie W. , Sait Sheila N.J. , McCarthy Philip L. , Vigil Carlos E , Griffiths Elizabeth A. , Thompson James E , Wang Eunice S. , Wallace Paul K , Wetzler Meir
Published: March 2020

6565

Background: Most AML pts will experience relapse caused by persistent leukemic cells during complete remission (CR). The aim of our study was to predict outcome in AML pts in CR by assessing their MRD using standard 4-colour FC panels available at our institute. Methods: We queried our AML database between 1/2004 to 10/2010 for newly diagnosed untreated AML pts >18 years of age who achieved CR after one induction regimen. Treatment included 7+3 or similar intensive approaches. The gating strategy used a series of Boolean regions that best defined the diagnostic abnormal population based on its expression patterns using three 4-colour FC panels (F7-CD38,CD10,CD19,CD34; F9-C11b,CD33,CD13,CD34; F38-CD15,CD56,CD7,CD34). The same regions were applied to post-induction samples, and the number of residual events was determined. Results: 140 AML patients with a median age of 64 (range 24-93) years, including 74 females (52.8%) were analyzed; 67 (47.8%) patients relapsed. Eighty-eight (62.8%) pts were CD34-positive (CD34+) at diagnosis. Normal karyotype was detected in 27 (30.7%): FLT-3 ITD was detected in 4/23 (17.4%) and NPM-1 mutation was detected in 1/15 (0.07%) samples. Median follow-up for CD34+ pts was 17.9 months. Forty-two (30%) pts underwent stem cell transplantation (SCT) in first CR: 31 (22.1 %) were allogeneic and 11 (7.9%) autologous. In multivariate analysis, a detectable MRD in any of the 3 panels at or beyond week 16 among CD34+ AML pts in CR was significantly associated with inferior relapse free survival (F7: P=0.035 , F9: P=0.027, F38: P=0.042). In addition, MRD ≥ week 16 using panel F9 was also significantly associated with inferior overall survival (P=0.0224). In pair-wise comparison, those who were MRD-negative ≥ week 16 did not benefit from SCT compared to the non-SCT group. Similar analyses among CD34– AML pts did not achieve statistical significance. Conclusions: MRD+ by FC in CD34+ AML is an independent prognostic factor and can identify pts who may benefit from SCT/more intensive therapy to maintain remission. However, the value of studying MRD in CD34– AML requires further consideration. More effort is needed to identify stem cells in CD34– AML.
Analysis of outcomes of patients (pts) with blastic plasmacytoid dendritic cell neoplasm (BPDCN).
Authors: Pemmaraju Naveen , Thomas Deborah A. , Kantarjian Hagop , O'Brien Susan Mary , Daver Naval Guastad , Nazha Aziz , Pierce Sherry , Garcia-Manero Guillermo , Cortes Jorge E. , Faderl Stefan
Published: March 2020

6578

Background: BPDCN, formerly known as CD4 + CD56 + hematodermic tumor or blastic NK cell lymphoma, is a rare and aggressive hematologic malignancy. Little is known about outcomes of pts with BPDCN. Methods: We conducted a retrospective review of pts meeting following criteria: pathological diagnosis of BPDCN confirmed by an experienced hematopathologist and age ≥ 18. Results: 13 pts, diagnosed October 1998-July 2011, were identified. Median (med) age: 62 years (range 20-86 years), 12 (92%) were male. Bone marrow (BM) involved in 9 (69%), skin 8 (62%), lymph nodes 5 (38%), brain 1 and uterine/ovarian 1 pt. Immunophenotype by flow cytometry: CD4+ (11/11 pts), CD56+ (10/11 pts), TCL-1+ (4/4 pts). Karyotype (8 pts): del(12) (1pt), complex (2), and diploid (5). Med CBC: WBC 5.8 x 109/L (1.7-76.5), Hb 12.3 g/dL (8.3-17.0), platelet 107 x 109/L (44-255). Med BM blasts: 22% (0-77). 10 pts received first-line therapy with Hyper-CVAD alternating with high-dose methotrexate(MTX) and cytarabine (HCVAD) (in 1 pt following one cycle of CHOP), CHOP (2), oral MTX (1). Med follow-up time: 9 months (mo) (2-14 mo). Med number chemotherapy regimens: 1 (1-5). Complete remission (CR) in 10 pts. Med CR1: 19 mo (4-39 mo). Med overall survival (OS) 29 mo (1-44 mo). 9 pts have died, unknown cause (3), multi-organ failure (6). 10 pts received HCVAD as part of first line therapy: med OS: 29 mo (1-44 mo), med CR1: 21 mo (4-39 mo), 9/10 (90%) pts achieved CR1; 1 pt did not achieve CR1 (died, pneumonia, day 15). 9 pts (69%) had BM involvement (7 with other organs involved besides BM). 4 (31%) pts had no BM involvement; all 4 of these pts had skin involvement only. Med OS, med CR1 of pts with BM involvement: 23 mo (1-44mo), 22 mo (4-39mo), respectively. Med OS, med CR1 of skin only pts: 29 mo (2-31 mo), 7 mo (6-19 mo), respectively, p=not significant. 4 pts received stem cell transplant (SCT) (2 allogeneic ,2 autologous). Med OS for pts receiving SCT (n=4) was 31 mo(8-31 mo) versus med OS for non-SCT group (n=9) of 29 mo (1-44), p=not significant. Conclusions: Despite intensive multi-agent chemotherapy and SCT, response rates are low and survival is short. Better understanding of the biologic basis of this disease and novel treatment approaches for treatment of BPCDN are crucial.
FLT3 mutations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).
Authors: Bhamidipati Pavan Kumar , Daver Naval Guastad , Kantarjian Hagop , Pierce Sherry , Daver Roshni , Cortes Jorge E. , Ravandi Farhad , Mathisen Michael , Pemmaraju Naveen , Nazha Aziz , Kadia Tapan M. , Jabbour Elias , Borthakur Gautam , Faderl Stefan , Garcia-Manero Guillermo
Published: March 2020

6597

Background: FLT3 mutations occur in one third of acute myeloid leukemia (AML) patients (pts) and predict poor outcome. The incidence and impact of FLT3 in MDS/ CMML is unknown. Methods: We conducted a retrospective review at MDACC to identify FAB MDS/ CMML pts with FLT3 mutations at diagnosis. Results: From 1996 to 2010; 2052 MDS/ CMML pts had mutation analysis. 45 (2.2%) had FLT3 mutations (internal tandem duplication-ITD or D835) at diagnosis. 29 pts had MDS and 16 had CMML. Median (Med) age was 64 years (21 to 83) and 69% were males. FAB groups: 3 pts with refractory anemia (RA), 11 pts with refractory anemia-excess blasts (RAEB), 18 pts with refractory anemia-excess blasts in transformation (RAEB-T) and 13 pts with CMML. IPSS: 3 in Low (7%), 16 in Int-1 (36%), 11 in Int-2 (24%), and 15 in High (33%). Med white count, hemoglobin, platelet count and marrow blast percent at diagnosis were 5.2 x 109/l (1.2 to 211), 10.0 g/l (6.8 to 14.9), 78 x 109/l (8 to 429), and 14% (1 to 28), respectively. FLT3 ITD and FLT3 D835 mutations were present in 32 (71%) and 13 pts (29%), respectively. Karyotype was diploid in 30 (66%); -5/-7 in 5 (11%), 11q in 1 (2%), and others in 9 pts (19%). All 5 pts with -5/ -7 had the ITD mutation. Concurrent mutations were identified in RAS, NPM1 and C-Kit in 6 (13%), 3 (7%) and 1 (2%) pt, respectively. Med overall survival (OS) for FLT3 pts was 15 months compared to 17 months for non FLT3 pts (P=0.9). 18 pts had RAEB-T: 13 (72%) received AraC-based therapy and 3 (17%) received hypomethylating therapy (HMT) with complete remission (CR) in 14 pts (78%). 14 pts had RA/ RAEB: 5 (36%) received AraC-based therapy and 7 (50%) received HMT with CR in 5 (37%) and hematological improvement (HI) in 4 (28%). 13 pts had CMML: 4 (31%) received AraC-based therapy and 6 (46%) received HMT with CR in 3 (23%) and HI in 3 (23%). Repeat FLT3 was available on 16 pts achieving any response and was absent/ decreased in 14 (88%), stable in 1 (6%) and increased in 1 (6%). Notably, the 14 pts with absent/ decreased FLT3 had med OS of 27 months versus 12 months for remaining group (P=0.004). Conclusions: FLT3 occurs in MDS/ CMML at a lower frequency than AML and does not predict poor outcome. Pts who achieve absent/ decreased FLT3 seem to have significantly improved overall survival.
A comparison of CR versus CRi response following CPX-351 treatment of newly diagnosed AML in elderly patients (pts).
Authors: Lancet Jeffrey E. , Cortes Jorge E. , Kovacsovics Tibor , Hogge Donna , Kolitz Jonathan E. , Tallman Martin S. , Chiarella Michael , Louie Arthur Chin , Feldman Eric Jay
Published: March 2020

6601

Background: A Phase 2b study randomized untreated elderly AML pts to CPX-351 or 7+3. CPX-351 improved leukemia clearance (88% v 71%, <5% marrow blasts), CR+CRi rate (67% v 51%), and was particularly effective in pts with adverse karyotype and antecedent hematologic disorders (sAML). Survival following CRi is usually inferior compared to CR. CPX-351 markedly prolongs plasma drug levels and maintains the 5:1 molar ratio for optimal leukemic cell killing potentially delaying hematologic recovery among CRi patients. Consequently, we compared the characteristics and outcomes of pts achieving CR v CRi. Methods: Untreated AML pts, aged 60-75, PS= 0-2, SCr < 2.0 mg/dL, total bilirubin <2.0 mg/dL, ALT/AST <3 x ULN, and LVEF ≥50% were eligible. Pts were randomized 2:1 to receive up to 2 inductions and 2 consolidations with CPX-351 (100 u/m2; D 1, 3, 5; 90 min infusion) or 7+3 (cytarabine=100 mg/m2 and daunorubicin=60 mg/m2). Consolidation with stem cell transplantation (SCT) was permitted. The 1o endpoint was CR+CRi rate. The 7+3 control arm had only a single CRi among 21 responders. The CPX-351 arm had 15 CRi (27%) and 41 CR (73%) allowing a CR v CRi comparison to be made. Results: CR and CRi pts were balanced by age, race, and PS. The CRi group had more males (87% v 51%), more baseline WBC>20K (27% v 15%), and more adverse karyotype (40% v 27%) and sAML (47% v 29%). A smaller proportion of CRi pts received post-remission chemotherapy (47% v 73%) but had similar rates of SCT (13% v 20%). Most CRi pts had delayed platelet recovery (80%). By 1-year more CRi pts had relapsed (54% v 39%) and more had died (54% v 34%). Contributing causes included: relapsed AML (7 CRi v 10 CR pts), complications post SCT (1 CRi v 1 CR pt), chemotherapy complications (0 CRi v 2 CR pts) and unknown causes (0 CRi v 1 CR pt). The survival curves were not significantly different (p=0.39). Conclusions: More CRi patients had adverse karyotype and sAML and most (53%) received no post remission chemotherapy. Survival was not significantly different compared to CR patients but was markedly better than that of non-responders. These data suggest that CRi following CPX-351 provides clinically meaningful benefit, a finding that needs to be confirmed in a larger randomized study.
Impact of immunoglobulin heavy chain variable region mutational status on the outcome of patients with chronic lymphocytic leukemia harboring isolated 13q deletion.
Authors: Domingo Gelenis C. , Dalia Samir , Chavez Julio C. , Carballido Estrella M. , Aguayo-Hiraldo Paibel I. , Sweet Kendra Lynn , Crescentini Robert M. , Sokol Lubomir , Cultrera Jennifer L. , Shah Bijal D. , Lancet Jeffrey E. , Sotomayor Eduardo M. , Komrokji Rami S. , Pinilla-Ibarz Javier
Published: March 2020

6608

Background: Several prognostic factors can predict the course of chronic lymphocytic leukemia (CLL). Among them, the IGVH mutational status and the presence of cytogenetic abnormalities are the strongest predictors of outcome. Mutated IGVH and deletion 13q independently confer a survival advantage. CLL patients with mutated IGVH in combination with deletion 13q have a better prognosis when compared to their unmutated IGVH counterparts. However, there is limited data on the outcome of patients harboring favorable deletion 13q and the unfavorable unmutated IGVH. This study aimed at identifying patients with these two indicators in order to obtain important prognostic information. Methods: We used the Moffitt Cancer Center Total Cancer Care (TCC) database to find patients with a diagnosis of CLL between January 1993 and December 2009. Individual charts were reviewed for demographic data and CLL cytogenetics, including IGVH mutation status and presence of deletion 13q. We analyzed the impact of having deletion 13q in combination with an unmutated IGVH on the overall survival (OS) for this subset of CLL patients using Kaplan Meier curves with SPSS statistical software. Results: 546 patients were identified during the aforementioned time period with a diagnosis of CLL. Median age was 62.5 years. 144 (26.4%) of these patients had IGVH and cytogenetic analysis available. 53 patients had 13q deletion as their sole genetic abnormality. Patients with unmutated IGVH and positive for deletion 13q were 19/53 (35.8%). Patients with mutated IGVH and positive for deletion 13q were 34/53 (64.2%). Patients with mutated IGVH and positive for deletion 13q had an OS of 17 years. While patients with unmutated IGVH and positive deletion 13q had a lower median OS of 12 years (91.2% vs 78.9%, p=0.05). Hazard ratio for patients with IGVH mutated and positive deletion 13q was 0.4, p=0.05. Conclusions: Mutated IGVH appears to be associated with improved OS in patients with isolated 13q deletion when compared to patients with unmutated IGVH and isolated 13q deletion. Further research is needed to assess these mutations in relation to other cytogenetic abnormalities in CLL.