Clinical Features of Patients with Multiple Myeloma and C-MYC Rearrangements

Abstract Abstract 5090 Background: The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth, and apoptosis. c-MYC is located on the long arm of chromosome 8 (8q24.1) and its rearrangement has been reported in 15% of myeloma patients independent of the disease stage (Avet-Loiseau et al. Blood 2001). However, the clinical significance of c-MYC rearrangement is not well described. Here we report the characteristics and outcome of 7 myeloma patients with c-MYC rearrangements that were treated at our institution. Methods: Between July 2007 and May 2011, we identified 7 patients (4 males, 3 females) who had c-MYC rearrangements on fluorescence in situ hybridization (FISH) analyses at the time of diagnosis. The primary objective of this study was to describe the patient characteristics, response to therapy, time to progression (TTP), and overall survival (OS). Results: Median age at diagnosis was 58 years (49–72). There were 4 Caucasians, 2 African-Americans and 1 Asian. International Staging System stage was I, II, and III in 3, 2, and 2 patients, respectively. Two patients had serum creatinine of ≥2 mg/dL as well as Hgb ≤10 g/dL, two other patients had hypercalcemia at diagnosis. Six (85%) patients had myelomatous bone lesions at diagnosis. Plasma cell counts in bone marrows ranged from 20%-78%, with a mean of 51%. Abnormalities involving chromosome 8q24.1, the c-MYC locus, were detected on conventional cytogenetics in all 7 patients, including t(8;14)(q24.1) in 3 cases, a t(2;8)(p12;q24.1), a variant of the t(8;14), in 2 cases, and an abnormal chromosome 8 with unknown material attached to the 8q24.1 region confirmed by FISH in two cases. This is in contrast to an earlier report where only 25% of patients with c-MYC rearrangement on FISH had corresponding cytogenetic abnormalities. Three patients also had a del(13)(q14.1)/RB1, one of whom also had a del(17)(p13)/TP53, while two other patients had t(11;14)(q13;q32) involving CCND1-XT/IGH rearrangements. Six patients (85%) received induction with a bortezomib+ dexamethasone regimen, and one patient received thalidomide+ dexamethasone. Five patients achieved a partial (PR) or very good partial remission (VGPR) to induction, while 2 patients had <PR, with an overall response rate of 71%. Four patients went on to receive high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). Three of these patients were in first remission, while one patient progressed prior to auto-HCT. Median follow up in all patients was 17.7 months (range 2.6–22.4). Two patients progressed at 4.4 and 4.5 months after the start of induction therapy, and 2 more patients progressed after auto-HCT, 14.4 and 16.1 months after the start of induction. Median TTP was 14.4 months, and median OS was 20.2 months. The TTP and OS appear to be shorter than what has been reported for standard-risk myeloma patients (24 and 72 months, respectively). Conclusion: This is the first report describing clinical characteristics of myeloma patients with c-MYC rearrangements. All 7 patients had concurrent translocations involving chromosome 8q24 on conventional cytogenetics, and had a shorter TTP and OS than our historical data. The role of c-MYC rearrangement in myeloma needs to be explored in prospective studies. Disclosures: No relevant conflicts of interest to declare.

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C-MYC Rearrangement: A Marker for High-Risk Myeloma

Blood ◽

10.1182/blood.v120.21.4989.4989 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4989-4989

Author(s):

Isabella C. Glitza ◽

Gary Lu ◽

Su Chen ◽

Robert Z. Orlowski ◽

Muzaffar H. Qazilbash

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Response To Therapy ◽

Chromosome 8 ◽

Plasma Cell Leukemia ◽

Disease Stage ◽

High Dose ◽

Cell Leukemia ◽

Hematopoietic Stem ◽

Conventional Cytogenetics

Abstract Abstract 4989 Background: The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth, and apoptosis. c-MYC is mapped to the 8q24. 1 on the long arm of chromosome 8 and its rearrangement has been reported in 15% of myeloma patients independent of the disease stage (Avet-Loiseau et al. Blood 2001). However, the clinical significance of c-MYC rearrangement is not well described. Here we report the characteristics and outcome of myeloma patients with c-MYC rearrangements that were treated at our institution. Methods: We identified 18 patients (11 males, 7 females) with c-MYCrearrangements either on fluorescence in situ hybridization (FISH) analyses or conventional cytogenetics, who were treated at the M.D. Anderson Cancer Center. The primary objective was to describe the patient characteristics, response to therapy, time to progression (TTP), and overall survival (OS). Results: Median age at diagnosis was 56. 5 years (21–72). Overall, 8 patients (44%) presented with or progressed to either plasma cell leukemia (PCL: 6) or plasmablastic myeloma (PBM: 2). Abnormalities involving chromosome 8q24. 1, the c-MYC locus, were detected on conventional cytogenetics in all 18 patients, including t(8;14)(q24. 1;q32) in 6 cases, t(2;8)(p12;q24. 1) in 3 cases, t(8;22) (q24. 1;q11. 2) in 4 cases, t(8;20)(q24. 1;q13. 3) in one case, and an abnormal chromosome 8 with unknown material attached to the 8q24. 1 region in 4 cases. Five patients (27%) had a del(13)(q14. 1)/RB1, one of whom had a del(17)(p13)/TP53, while 3 other patients had t(11;14)(q13;q32) involving CCND1-XT/IGHrearrangements. Twelve patents (66%) received induction with a novel agent: bortezomib-based = 8 (44%) and thalidomide- based = 4 (22%). Six patients (33%) received induction with conventional chemotherapy regimens: CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) = 2, pulsed steroids only = 2, EPOCH (Etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide) = 1 and melphalan + prednisone =1. Nine patients achieved a partial response (PR, 50%) and 4 patients achieved a very good partial remission (VGPR, 22%), with an overall response rate of 72% to induction. Thirteen patients (72%) went on to receive high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). Four patients died of disease progression before auto-HCT while one patient opted for stem cell harvest and cryopreservation only. Median time to auto-HCT was 7. 1 months (3. 6–12. 7). Median follow up in all patients was 13 months (range 3. 4–105). Fifteen patients had progressed, with a median TTP of 7. 1 months and a median OS of 20. 2 months. Patients with PCL or PBM had significantly shorter OS (p=0. 04). Conclusion: This is the first report describing clinical characteristics of myeloma patients with c-MYC rearrangements. c-MYC rearrangement is associated with a higher incidence of plasma cell leukemia or plasmablastic myeloma, short TTP and OS. Disclosures: No relevant conflicts of interest to declare.

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Comparative Analysis of the Value of Consolidation with Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT) Versus High-Dose Cytarabine (HDAC) Based Chemotherapy in Patients (pts) with Acute Myeloid Leukemia (AML) with Chromosome Seven Abnormalities

Blood ◽

10.1182/blood.v120.21.2029.2029 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2029-2029

Author(s):

Elias J. Jabbour ◽

Hagop M. Kantarjian ◽

Betul Oran ◽

Farhad Ravandi ◽

Hady Ghanem ◽

...

Keyword(s):

Complete Remission ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Response To Therapy ◽

Chromosome 7 ◽

High Dose ◽

Consolidation Chemotherapy ◽

Hematopoietic Stem ◽

Platelet Recovery

Abstract Abstract 2029 Background: The karyotype of leukemic cells in pts with AML is one of the most pronounced prognostic factors determining response to therapy and overall outcome. Pts with AML and chromosome 7 abnormalities have poor prognosis and AHSCT is highly indicated for such pts. Aims: To determine to what extent AHSCT reduces relapses and improve survival in pts with AML with chromosome 7 abnormalities compared with alternative post remission therapy. Methods: We reviewed 2167 consecutive pts with AML referred to our department between 2000 and 2011. Among them, 325 were diagnosed with chromosome 7 abnormalities as a single abnormality (n=53, 16%) or complex (n=272, 84%). Of these, 126 pts (39%) were induced with IA based regimen and 49 (39%) of them achieved a complete remission (CR) or complete remission without platelet recovery (CRp) and pursued consolidation therapy. These pts were matched with 33 pts with available donors who were referred to receive an ASHCT in first CR. Results: Median age for pts receiving consolidation chemotherapy versus AHSCT was 56 (range, 19–78) and 49 (range, 22–71) years, respectively (<0.001). Of the 33 pts who received an AHSCT, 17 received their stem cells from related siblings, 15 from unrelated matched donors, and 1 from a haplo-identical donor. Conditioning regimen were fludarabine and busulfan in 26 pts and fludarabine and melphalan in 7 pts. Graft versus host disease (GVHD) prohylaxis consisted mainly of tacrolimus and short methotrexate. Median time to engraftment was 12 days for neutrophils (range, 9–20) and 19 days for platelets (range, 10–53). Acute Grade 3/4 and chronic GVHD were observed at the rate of 3% and 45%, respectively. With a median follow-up of 29 weeks (range, 14–239) for pts receiving consolidation chemotherapy and of 168 weeks (range, 5–454) for pts receiving AHSCT, the 4-year event-free survival (EFS) rates were 4% and 51%, respectively (p<0.001). The median EFS for pts receiving consolidation chemotherapy and AHSCT were 17 (range, 1–330) and 51 (range, 1–456) weeks (Figure 1), respectively. The 4-year OS rates were 7% and 62%, respectively (p<0.001), with the median survival being 35 (range, 1–568) and 389 (range, 1–456) weeks, respectively (Figure 2). Conclusion: AHSCT applied as a consolidation in first CR in pts with chromosome 7 abnormalities is associated with a significant reduction of the relapse rate and improvement of OS compared to alternative post remission therapy. Disclosures: No relevant conflicts of interest to declare.

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Facilitation of Hematopoietic Reconstitution Via Inhibition of Bone Marrow Endothelial Cell-Mediated SDF-1 Signaling.

Blood ◽

10.1182/blood.v116.21.3859.3859 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3859-3859

Author(s):

Phuong L. Doan ◽

J. Lauren Russell ◽

Heather A. Himburg ◽

Sarah K. Meadows ◽

Pamela Daher ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Conflicts Of Interest ◽

Fold Increase ◽

High Dose ◽

Cell Recovery ◽

Hematopoietic Stem ◽

Cell Counts ◽

Hematopoietic Reconstitution

Abstract Abstract 3859 Hematopoietic stem cell (HSC) regeneration is influenced by specialized bone marrow (BM) microenvironments, but the mechanisms that drive HSC regeneration remain incompletely defined. We have recently reported that deletion of the pro-apoptotic proteins, Bak and Bax, in Tie2+ bone marrow endothelial cells (BM ECs)(Tie2Cre;Bak-/-;BaxFl/- mice) caused a significant protection of the BM HSC pool and the BM sinusoidal vasculature in mice following high dose total body irradiation (TBI). We also confirmed that this protection of the BM HSC pool was caused by protection of BM Tie2+ ECs via generation of chimeric mice (Tie2Cre;Bak-/-;BaxFl/- BM; wild type BM ECs) which contained 4.8-fold less BM long-term repopulating HSCs compared to mice bearing deletion of Bak and Bax in both BM HSCs and BM ECs. In order to determine the mechanism through which Tie2+ BM ECs regulate HSC regeneration, we generated primary BM EC lines from Tie2Cre;Bak-/-;BaxFl/- mice and Tie2Cre;Bak-/-;BaxFl/+ control mice. We then compared the capacity for Bak/Bax -/- BM ECs to support BM HSC regeneration in vitro compared to Bak/Bax +/− BM ECs. BM c-kit+sca-1+lin- (KSL) stem/progenitor cells were irradiated with 300 cGy and then placed in 7 day culture with Bak/Bax -/- BM ECs or Bak/Bax +/− BM ECs. Culture with Bak/Bax -/- BM ECs did not yield a significant increase in total viable cells, but yielded 2000-fold increased number of BM KSL cells (p < 0.05, n=3) compared to cultures with Bak/Bax +/− ECs. This significant expansion of phenotypic BM stem/progenitor cells corresponded to a 4-fold increase in CFU-S12 cells in the Bak/Bax -/- EC cultures vs. Bak/Bax +/− EC cultures (p=0.01, n=5). We subsequently compared the level of expression of several microenvironmental ligands which are putatively involved in regulating hematopoiesis. We found that BM ECs from Tie2Cre;Bak-/-;BaxFl/- mice had 37-fold lower expression of stromal-derived factor-1 (SDF-1, CXCL12) compared to BM ECs from Tie2Cre;Bak-/-;BaxFl/+ mice. Moreover, 7 days after TBI, Tie2Cre;Bak-/-;BaxFl/- mice had a 41-fold increase in total viable BM cell counts and had a persistently lower SDF-1 expression on BM ECs (2.7-fold) compared to Tie2Cre;Bak-/-;BaxFl/+ mice (p=0.003). Therefore, we hypothesized that inhibition of SDF-1 signaling might facilitate hematopoietic regeneration following injury. Interestingly, the addition of a blocking anti-SDF1 antibody to cultures of irradiated BM KSL cells with Bak/Bax -/- ECs caused a 50% increase in total cell recovery (p<0.05), a 2.5 fold increase in BM KSL cell recovery (p<0.05) and a 2.2-fold increase in BM CFC recovery (p<0.05) compared to culture with Bak/Bax -/- ECs alone. However, the addition of anti-SDF1 antibody caused a 3-fold decrease in CFU-S12 recovery compared to Bak/Bax -/- EC cultures without anti- SDF1 antibody (p<0.05). Taken together, these data suggest that inhibition of SDF-1 signaling via BM ECs accelerates BM progenitor cell regeneration following injury but is deleterious to the recovery of the BM HSC pool. Targeted therapies aimed at inhibition of SDF-1 signaling may facilitate short-term hematopoietic reconstitution following injury via modulation of BM vascular niche signaling, but this may be at the expense of the BM HSC pool. Disclosures: No relevant conflicts of interest to declare.

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Multiple Solitary Plasmacytoma: Characteristics, Response To Therapy, Survival In Nine Patients From a Single Institute

Blood ◽

10.1182/blood.v122.21.5383.5383 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5383-5383 ◽

Cited By ~ 1

Author(s):

Yanru Zhang ◽

Junyuan Qi ◽

Lugui Qiu

Keyword(s):

Treatment Response ◽

Light Chain ◽

Conflicts Of Interest ◽

Early Stage ◽

Extramedullary Plasmacytoma ◽

Response To Therapy ◽

Bone Lesions ◽

High Dose ◽

Solitary Plasmacytoma ◽

Conventional Chemotherapy

Abstract Objective The International Myeloma Working Group in 2003 recognized a separate classification of plasmacytomas that occur as multiple sites of disease in soft tissue, bone, or both as multiple solitaryplasmacytoma (MSP). There are only few cases of MSP described in literatures. As a rare mylema, relatively little is known about its features, treatment response, and survival. Method we have retrospectively analyzed nine patients with MSP in our hospital from 2009 to 2013. Result The median age was 49 (26-49) years old. There were six males and three females. All but one had M-protein in serum and/ or urine. There was a predominance of lambda light chain (6/8). Most cases had multiple bone lesions (8/9).Only one had multiple solitary extramedullary plasmacytoma localized on CNS tissue and right lumber. Most (6/9) were stage III of DS for and seven cases were stage I of ISS. Six patients were treated with regimen containing bortezomib as induction therapy. And one of them underwent high-dose of chemotherapy with autologous stem cell transplantation (HDT/ASCT) at CR as part of their front-line therapy. Another three patients were treated with conventional alkylating agent combined with glucocorticoid based chemotherapy. After initial chemotherapy, seven patients reached CR, one PR. In first line combinational chemotherapy that containing bortezomib (Btz) (n=6), 100% patients achieved CR ,compared with that of 33.3% in patients treated with conventional chemotherapy (P =0.083). Date cut-off was July 20, 2013, a median follow-up of 28.5 (range2-38) months. The median OS time was 29, median progression -free survival (PFS) was 8 months. However, none of them progressed to MM. In addition, compared with the patients whose regimes included Btz (n=6), the patients who got conventional chemotherapy (n=3) had a trend towards poorer median OS (not reach versus 28 months, P = 0.116) and shorter median PFS (6 months versus 38 months, P = 0.356). Conclusion MSP was at early stage at diagnosed. Most cases were male and λ light chain type. Although there was a good treatment response, these patients easily progressed. ISS may not suitable for evaluation of prognosis with MSP.Bortezomib based therapy could further deepen degree of remission , prolong the survival. Disclosures: No relevant conflicts of interest to declare.

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Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽

10.1182/blood-2019-131332 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3714-3714

Author(s):

Lei Zhang ◽

Huacheng Luo ◽

Jing Li ◽

Hong-Min Ni ◽

Mark Sellin ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Low Dose ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Low Doses ◽

Hematopoietic Stem ◽

Increased Risk ◽

Leukemia Development ◽

Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

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Mutations in the Telomerase Complex and Expression Levels of the TERT Gene Determine Severity and Outcome of Disease in Aplastic Anemia Patients

Blood ◽

10.1182/blood.v128.22.1502.1502 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1502-1502 ◽

Cited By ~ 1

Author(s):

Arati Khanna-Gupta ◽

Durga Sarvepalli ◽

Snigdha Majumder ◽

Coral Karunakaran ◽

Malini Manoharan ◽

...

Keyword(s):

Aplastic Anemia ◽

Disease Severity ◽

Poor Prognosis ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Response To Therapy ◽

Hematopoietic Stem ◽

Expression Levels ◽

Shelterin Complex ◽

Tert Expression

Abstract Acquired Aplastic anemia (AA) is a bone marrow failure syndrome characterized by pancytopenia and marrow hypoplasia, and is mediated by immune destruction of hematopoietic stem cells. Mutations in several genes including telomerase, a ribonucleoprotein enzyme complex, consisting of a reverse transcriptase enzyme (TERT), an RNA template (TERC), and several stabilizing proteins, and the associated shelterin complexes have been found in both congenital and idiopathic AA. In particular, several TERT and TERC mutations reduce telomerase activity in vitro and accelerate telomere attrition in vivo. Shortened telomeres have been observed in a third of idiopathic AA patients, but only 10% of these patients have mutations in genes of the telomerase complex. We have recently demonstrated that in addition to keeping telomeres from shortening, telomerase directly regulates transcriptional programs of developmentally relevant genes (Ghosh et al, Nat Cell Biol, 2012, 14, 1270). We postulate that changes in expression of telomerase associated genes, specifically TERT, contribute to the etiology of aplastic anemia. In an effort to better understand the molecular and clinical correlates of this disease, 24 idiopathic AA patient samples were collected at a tertiary medical center in Bangalore, India. Following informed consent, we performed RT-PCR analysis on harvested RNA from each patient and measured levels of TERT expression compared to that of normal controls (n=6). An 8 fold reduction in TERT expression was observed in 17/24 patients, while 7/24 patients maintained normal TERT expression. In general, TERT-low patients were younger in age (mean age 29y) compared with the TERT-normal patients (mean age 40y). TERT-low patients were more likely to have severe aplastic anemia (SAA) leading to higher mortality and poorer response to therapy, with 6/17 patients dying and 4/17 not responding to ATG therapy. Targeted panel sequencing of the 24 samples on an Illumina platform revealed that while TERT-normal patients had no mutations in genes associated with the telomerase/shelterin complex, TERT-low patients carried predicted pathogenic variants in TERT, TEP1, TINF2, NBN, TPP1, HSP90A and POT1 genes, all associated with the telomerase complex. Somatic gene variants were also identified in other AA associated genes, PRF1 and CDAN1, in the TERT-low cohort. In addition, novel predicted pathogenic mutations associated with the shelterin complex were found in two TERT-low patients in the TNKS gene. We also detected mutations in TET2, BCORL1, FLT-3, MLP and BRAF genes in TERT-low patients. Mutations in these genes are associated with clonal evolution, disease progression and poor prognosis. Our observations were further illustrated in a single patient where normal TERT expression was noted at initial clinical presentation. ATG therapy led to CR, but the patient returned within a year and succumbed to E.coli related sepsis. At that stage he had low TERT expression, suggesting that TERT expression can change as the disease progresses. Taken together, our data support the hypothesis that loss of TERT expression correlates with disease severity and poor prognosis. Our observations further suggest that preliminary and periodic evaluation of TERT expression levels in AA patients is likely to serve as a predictor of disease severity and influence the choice of therapy. Disclosures No relevant conflicts of interest to declare.

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23 Years of Management: A Retrospective Review of Treatment for Aplastic Anemia.

Blood ◽

10.1182/blood.v114.22.1091.1091 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1091-1091

Author(s):

Connie M Piccone ◽

Marie Boorman Martin ◽

Zung Vu Tran ◽

Kim Smith-Whitley

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Retrospective Review ◽

Pediatric Patients ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Complete Response ◽

Primary Objective ◽

Hematopoietic Stem ◽

Transfusion Independence

Abstract Abstract 1091 Poster Board I-113 Introduction Aplastic anemia (AA) is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia. In the past, AA was considered to be a fatal disease; however, current therapies, including bone marrow transplantation or immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CSA), are curative in the majority of patients. IST is effective at restoring hematopoietic stem cell production, but relapse and evolution to myelodysplastic syndromes remain clinical challenges. Additionally, there is no real consensus regarding optimal CSA levels, duration of CSA treatment, or the optimal use of growth factors and their relationship to the development of clonal disease. Objectives The primary objective was to review treatment management for severe AA in pediatric patients in order to elucidate treatment differences and review morbidity and mortality as they relate to treatment variation. Study Design/Methods A retrospective review of pediatric patients treated at the Children's Hospital of Philadelphia for AA (both severe and moderate) over a 23 year period was performed. Results A total of 70 patients with AA were treated at our institution from 1985 to July 2008. Exclusions included: 6 patients who received some type of initial treatment at outside institutions, 4 patients who had missing records, and 2 patients who had a diagnosis of moderate AA. Thus, a total of 58 patient records were included in the analysis. Of the total patients reviewed, 60% were male and 40% were female. 34.5% of patients were African-American, and 57% were diagnosed in 2000 or later. The mean age at diagnosis was 9.5±5.8 years. 52% fell into the category of very severe AA based on published diagnostic criteria, 45% had severe AA, and 2 patients (3%) had moderate AA. 15.5% of patients developed AA in the setting of acute hepatitis. More than half of the patients treated with IST had a complete response (CR). The average time to CR was 15±15 months. Average duration of CSA treatment was 15±13 months and 8.6±10.7 months for growth factor. Two patients (3.5%) died, one from complications unrelated to AA and one from infectious complications post-BMT after initial IST failure. Average time to transfusion independence for all patients was 8±11 months (with a range of 0-54 months). Not surprisingly, the time to transfusion independence was significantly associated with IST failure (p=0.010). Patients who failed treatment had an average time to transfusion independence of 17±16 months as compared to those who were complete responders who had an average time to transfusion independence of 3±3 months. Additionally, there was a significant association between IST failure and CSA levels (p=0.014). Patients who had nontherapeutic CSA levels overall had an increased rate of treatment failure. Of those patients who were nontherapeutic, 56% were noncompliant with CSA administration. There was no significant association between IST failure and bone marrow cellularity (p=0.251). PNH was diagnosed in 5% of patients; there were no patients with evidence of myelodysplastic syndrome (MDS). Two of the 3 patients with PNH failed initial IST. Another 2 patients had evidence of a cytogenetic abnormality (16q deletion), but never progressed to MDS. (Note: averages presented as mean±SD) Conclusions/Methods With current IST regimens, AA is curative in the majority of pediatric patients. IST failure was associated with nonadherence to CSA treatment. For patients with confirmed clonal disease, it is possible that IST failure and the ultimate development of clonal disease are related. Disclosures No relevant conflicts of interest to declare.

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Combined Analysis of Treatments for Pediatric T-ALL in KYCCSG Protocols, ALL-96 and ALL-02.

Blood ◽

10.1182/blood.v114.22.4102.4102 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4102-4102

Author(s):

Yasuhiro Okamoto ◽

Yoshihisa Nagatoshi ◽

Akinobu Matsuzaki ◽

Aiko Suminoe ◽

Hideki Nakayama ◽

...

Keyword(s):

Maintenance Therapy ◽

Chromosomal Abnormalities ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Cranial Irradiation ◽

High Dose ◽

Costal Margin ◽

Hematopoietic Stem ◽

Combined Analysis

Abstract Abstract 4102 Background Previously we reported the result of Kyushu-Yamaguchi Children's Cancer Study Group (KYCCSG) protocol, ALL-96, for pediatric acute lymphoblastic leukemia (ALL) (ASH meeting in 2005). The 7-year event-free survival (EFS) and overall survival (OS) rates were 72% (95% CI; 68 - 76 %) and 85 % (95% CI; 80 - 90 %), respectively. Following protocol, ALL-02, was aimed to assess the usefulness of polymerase chain reaction (PCR)-based minimal residual disease (MRD) in the same context as ALL-96 protocol. Purpose In this combined analysis, we analyzed the outcome and risk factors for relapse/survival in children with T-ALL who were treated with the ALL-96/ALL-02 protocols. Study Design and Treatment A total of 42 patients (22 of 218 in ALL-96 and 20 of 165 in ALL-02, 26 males and 16 females) with median age of 8 years (range 1 - 14) were treated. Patients were classified into 2 groups, standard risk (SR) and high risk (HR). HR patients had one of the followings: high white blood cell (WBC) counts more than 50,000/μl, T-cell immunophenotype, central nervous system (CNS) disease at diagnosis, organomegaly (hepatomegaly or splenomegaly more than 5 cm below costal margin), M2/3 marrow at day 15 of induction therapy. Both protocols consisted of induction, early intensification, consolidation, late intensification and maintenance therapy. Predonisolone (PSL), weekly vincristine (VCR), 4 doses of daunorubicin (DNR), 8 doses of L-asparaginase (L-asp) and 2 or 4 doses of intrathecal (IT) methotrexate (MTX) depending on the CNS status, were given during induction. In early intensification, DNR, cytarabine (CA), etoposide and 6-mercaptopurine (6-MP) were given. Consolidation consisted of intermediate dose of MTX, combination of cyclophosphamide(CPM), CA and 6-MP, and high dose CA. Late intensification similar to induction included 2 weeks of dexamethasone (DEX), weekly VCR, 2 doses of pirarubicin, single dose of CPM, 5 doses of L-asp and IT-MTX followed by combination of CA, 6-MP, IT-MTX along with 18 Gy cranial irradiation in 12 fractions. In ALL-96 protocol, patients were randomized to receive maintenance therapy of either combination of 6-MP/MTX and DEX/ VCR pulse (A-arm) or LSA2L2-type therapy (B-arm). In ALL-02 protocol, A-arm was chosen as a maintenance therapy based on result of ALL-96. No patient underwent hematopoietic stem cell transplantation (SCT) in 1st complete remission (CR). Results Median follow-up periods were 96 and 38 months in ALL-96 and ALL-02, respectively. Two patients were off-protocol before achieving CR because of toxicity and chromosome abnormality with t(4;11). Induction rate in 40 patients was 95%. All 14 events were relapses and TRM rate was 0%. Last event occurred at 40 months. The sites of relapse were isolated BM in 9, isolated testis in 2, isolated CNS in 1 and combined sites in 2. Nine died from disease progression and 2 died from toxicity after SCT in 2nd CR. The 4-year EFS and OS rates in all patients were 55 % (95 % CI; 39 – 71 %) and 71 % (95 % CI; 56 -86 %), respectively. EFS of ALL-96 and ALL-02 were 50 %[95 % CI; 29 -71 %]) and 65 % [95 % CI; 45 - 85 %]), respectively. OS of ALL-96 and ALL-02 were 59 % [95 % CI; 39 – 80 %]) and 90 % [95 % CI; 77 - 103 %]), respectively (p = 0.063). EFS of patients treated in A and B arm were 60 % [95 % CI; 41 -71 %]) and 55 % [95 % CI; 25 - 84 %]), respectively. None of age, sex, organomagaly, WBC, chromosomal abnormalities, CNS status, protocol, and maintenance arm was identified as a risk factor for relapse or survival. Two of 10 (ALL-96) and 3 of 4 (ALL-02) relapsed patients have survived with allogeneic SCT. Conclusion Although T-ALL patients received an intensified treatment including cranial radiation, the outcome was unsatisfactory. One possible explanation for better OS in ALL-02 protocol is that the majority of relapsed patients in ALL-02 were salvaged by SCT in 2nd CR. Disclosures: No relevant conflicts of interest to declare.

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Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) in CLL: First Results of An EBMT Randomized Trial Comparing Autotransplant Versus Wait and Watch.

Blood ◽

10.1182/blood.v114.22.877.877 ◽

2009 ◽

Vol 114 (22) ◽

pp. 877-877

Author(s):

Mauricette Michallet ◽

Peter Dreger ◽

Laurent Sutton ◽

Ronald Brand ◽

Sue Richards ◽

...

Keyword(s):

Conflicts Of Interest ◽

Progression Free Survival ◽

Disease Status ◽

Primary Objective ◽

Phase Iii ◽

Induction Treatment ◽

Hematopoietic Stem ◽

Binet Stage ◽

The Impact

Abstract Abstract 877 This phase-III randomized EBMT-intergroup trial studied the impact of a consolidating autoHSCT vs no consolidation for patients with CLL in Binet stage A progressive, B or C , in CR, nodular PR or VGPR after first or second line therapy. The primary objective was to show that autoHSCT increased the 5-year progression-free survival (PFS) by 30%. Although it had been calculated that 270 patients were to be randomized, the study was terminated by the steering committee in July 2007 due to poor accrual. Here we present a first analysis based on 69% of expected follow-up forms. Results: Between November 2001 and July 2007, 223 patients were enrolled (SFGM-TC/FCLLG n=98, MRC n=62, GCLLSG n=32, SAKK n=10, other EBMT centers n=17). There were 74% males and 26% females. Binet stages were progressive A 13%, B 67%, C 20%; 59% were in CR, and 41% in very good or nodular PR. Of note, SFGM-TC/FCLLG included only patients in CR. 82% of the patients were enrolled in 1st, and 18% in 2nd remission. Patients were randomized between group 1 (autoHSCT n=112) and group 2 (observation n=111) after an induction treatment which was left at the discretion of the investigators. Median PFS was 43 months in the observation group but not reached in the autoHSCT group; 5-year PFS was 48% and 65%, respectively (p=0.005). Accordingly, autoHSCT halved the relapse risk (5-year relapse incidence 25% vs. 51%; HR 0.4 [0.23-0.71], p=0.002). Cox modeling for randomization arm, Binet stage, disease status, line of treatment, contributing group (country), and the interaction between randomization arm and contributing group confirmed that autoHSCT significantly improved PFS (HR 0.41 [0.23-0.75] p=0.004). The beneficial effect of autoHSCT was stable over all contributing groups although patients accrued by SFGM-TC/FCLLG overall had a significantly better PFS than patients from other countries (HR 0.2 [0.08-0.55], p=0.001). At 5 years, the probability of OS was 92% and 91% for autoHSCT and observation, respectively. Significant differences in terms of non-relapse death were not observed. At the last follow up, among 205 evaluable patients, 186 are alive (147CR, 39 relapse), 19 died (14 from relapse and 5 from non-relapse causes) . In conclusion, in patients with CLL in first or second remission, consolidating autoHSCT reduces the risk of progression (PFS) by more than 50%, but has no effect on overall survival. Disclosures: No relevant conflicts of interest to declare.

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Outcome of Patients with Relapsed/Refractory AIDS-Related Lymphoma In the AIDS Malignancy Consortium (AMC) 1997–2008

Blood ◽

10.1182/blood.v116.21.3569.3569 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3569-3569

Author(s):

Ariela Noy ◽

Ulas Darda Bayraktar ◽

Neel Gupta ◽

Adam M. Petrich ◽

Page Moore ◽

...

Keyword(s):

Conflicts Of Interest ◽

Progression Free Survival ◽

Standard Of Care ◽

Infectious Complications ◽

High Dose ◽

Hiv Diagnosis ◽

Curative Intent ◽

Hematopoietic Stem ◽

The Impact ◽

Aids Related Lymphoma

Abstract Abstract 3569 Introduction: High dose therapy (tx) with autologous hematopoietic stem cell transplantation (AHSCT) in (rel/rfr) lymphoma is the standard of care in the general population with chemosensitive disease. The feasibility of second line therapies (Tx) and AHSCT in (rel/rfr) AIDS related lymphoma (ARL) has been shown in a number of trials. However, the true impact of 2nd line tx and AHSCT is unknown, as nearly all studies focus on those already with disease sensitive to 2nd therapy going onto transplantation. The only recent study capturing patients (n=50) before 2nd line tx showed 49% progression-free survival (Re et al. Blood 2009). Here, we retrospectively analyzed the outcome of patients (pts) presenting at 13 US AIDS Malignancy Consortium sites with (rel/rfr) ARL in the HAART era. Patients and Methods: HIV-positive pts initiating tx for (rel/rfr) ARL between 1997–2008 were included. Overall survival (OS) was calculated from the initiation of 2nd line tx. Results: A total of 126 pts received 2nd line tx. Only those 88 pts who received 2nd line with curative intent to treat (ITT) were included in the analysis. Baseline and selected clinical characteristics are summarized in the table. Median CD4 at HIV diagnosis was 110 (n=37) with a range of 12 to 1000. At ARL dx, median CD4 was 152 (5-803). 47% had an opportunistic infection (OI) prior to ARL. 2nd line tx were: ICE (n=34), EPOCH (n=16), ESHAP (n=11), High-dose MTX variants (n=10), Hodgkin's specific tx (n=5), DHAP (n=4) and others (n=8). Thirty-two (36%) had a response to 2nd line tx (CR, n=21; PR, n=11). Of 50 pts with grade ≥3 toxicities, the most common were thrombocytopenia (46%) and neutropenic fever (44%). Six pts died during 2nd line tx due to infectious complications, with 1 aspergillosis. Best response to 2nd line tx: Thus, CR/PR was 32/88 (36%) in ITT analysis. Only 10/32 CR/PR pts went onto AHSCT due to availability and changing treatment paradigms. Conditioning was BEAM (n=9) and Bu/Cy (n=7). No pt went onto allotransplant. At AHSCT day +90, 10 pts were in CR. For all pts, median follow-up was 122 weeks (range, 8–597), median OS was 38 weeks (95% CI, 27–63). Reflecting the 65% prevalence of pts refractory to 2nd line tx in the non-AHSCT group, OS was longer in pts who underwent AHSCT compared to those who did not (2-year OS: 55.3% vs. 31.0%). Surprisingly, 1-year OS in the CR/PR pts was 87.5±12.5% for AHSCT and 81.8±8.2% for non-AHSCT. One Burkitt pt survived a year without AHSCT. Discussion: Rel/rfr ARL was treated aggressively in this largest ever reported cohort, but CR/PR was only 32/88 (36%) in ITT analysis. Not all CR/PR pts went onto AHSCT due to changing treatment paradigms and regional availability. Aggressive 2nd line tx and ASHCT was feasible despite prior low CD4 and OI, but DFS may be possible without transplant. We cannot draw conclusions about the impact of AHSCT from this retrospective cohort. Similarly, it is not known whether survival in (rel/rfr) ARLs is equivalent to the HIV negative population. The current paradigm is to offer pts with rel/rfr ARLs AHSCT if disease is chemosensitive and no contraindication exist. New strategies are needed for 2nd line therapy, particularly in rel/rfr BL. Disclosures: No relevant conflicts of interest to declare.

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