The Cumulative Dose But Not The Frequency Of Infusions Is a Risk Factor For The Development Of Osteonecrosis Of The Jaw (ONJ) In Myeloma Patients Who Receive Zoledronic Acid (ZA)

Abstract The administration of ZA in patients with symptomatic myeloma is associated with reduction of SREs and possible improvement of survival; its use however, is associated with increased risk of osteonecrosis of the jaw (ONJ). Longer exposure and more infusions of ZA have been associated with higher incidence of ONJ. It has been suggested that longer intervals between ZA infusions may reduce the risk of ONJ; however, this has not been proven. Since 2008, we have adopted a strategy in which ZA is discontinued in patients who remain in remission for more than 2 years, while ZA is administered every 8-12 weeks, after the first year, in patients who have achieved vgPR or CR. The aim of our analysis was to assess the incidence of ONJ in a prospectively studied population treated with ZA and to asses potential risk factors related to dosing and schedule of ZA. Since 2003, all patients in the Department of Clinical Therapeutics (Athens, Greece) undergo dental evaluation before ZA initiation and are instructed to avoid procedures that predispose to ONJ. Only patients who received ZA and survived at least 6 months post their first ZA infusion were included in the analysis. Relative dose frequency of ZA (RDF) was calculated as the average number of weeks between infusions of ZA (weeks between first and last infusion divided by the number of infusions). Time of exposure to ZA was calculated from the date of first infusion until the date of last infusion. Death due to myeloma and development of ONJ were treated as competing events. Between January 2000 and January 2013, 266 patients with symptomatic myeloma fulfilled the above criteria and were included in the analysis. Median age was 68 years (range 36-87 years) and 47% were males. Median follow up was 36 months and 35% of the patients have died. The median number of ZA infusions was 16 (range 1-107) and the median time of exposure to ZA was 29 months, corresponding to 9073 person-months of exposure. Median RDF was one infusion per 7.9 weeks (interquartile range (IQR) 5.8-11.4 weeks). ONJ developed in 26 (10%) patients. Median time from first ZA infusion to development of ONJ was 28 months (range 6-122 months). Accounting for death as a competing event, 1-year risk of ONJ was 1.2% (95% CI 0.3-3%), 2-year risk was 5% (95% CI 2.5-8.5%), 3-year risk was 8.5% (95% CI 5-13%), 4-year risk was 11.5% (95% CI 7.3-17%) and 5-year risk was 14% (95% CI 9-19%) (Figure). The respective survival rates were 93%, 84%, 76%, 65% and 56% at 1, 2, 3, 4 & 5 years. The median time of exposure to ZA was 28 months (IQR 22-46 months) for patients who developed ONJ vs. 24 months (IQR 11-42 months) for those who did not (p=0.2). However, the median number of ZA infusions was 23 for those who developed vs. 14 for those who did not develop ONJ (p=0.004). Increasing number of ZA infusions was associated with higher risk of ONJ: 2.3% of patients who received <10 infusions developed ONJ vs. 12% of patients who received 10-19 infusions vs. 15% of patients who received 20 or more ZA infusions (p=0.012). The incidence rate of ONJ for patients who started ZA before 2008 was 0.31 per 100 person-months vs. 0.26 per 100 person-months for those who started after 2008 (p=0.4). The incidence of ONJ at 3-years was 13.6% (95% CI 8-20%) for patients with an RDF <8 weeks vs. 2.6% (95% CI 0.5-8%) for patients with RDF of ≥8 weeks (p=0.018). However, after adjusting for RDF of ZA infusions, only the number of ZA infusions remained significant (p=0.03). The multivariate analysis showed that both the number and the frequency of ZA infusions were associated with a shorter time to ONJ development. More specifically, average frequency of infusion <8 weeks was associated with a 15-fold (95% CI 4-55, p<0.001) increase in the risk of ONJ, while for every infusion of ZA the risk of ONJ increased by 9% (95% CI 4-14%, p<0.001). In conclusion, our data, in a large population of consecutive unselected patients with symptomatic myeloma who received ZA, indicate that ONJ remains a frequent complication in patients who receive ZA for prolonged periods and the risk increases with the number of ZA infusions. More frequent infusions of ZA are associated with earlier development of ONJ, but the risk of ONJ is associated mainly with the cumulative dose of ZA. Prospective clinical trials should examine if less frequent administration of ZA can reduce the risk of ONJ without compromising its antiresorptive effect. Disclosures: No relevant conflicts of interest to declare.

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Evaluation of Patients with Myelodysplastic Syndromes (MDS) Obtaining Stable Disease with the Use of Decitabine.

Blood ◽

10.1182/blood.v114.22.2790.2790 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2790-2790

Author(s):

Henry G. Kaplan ◽

Michael Milder

Keyword(s):

Stable Disease ◽

Dna Methyltransferase ◽

De Novo ◽

Conflicts Of Interest ◽

Clinical Importance ◽

Hematologic Malignancies ◽

Median Number ◽

Outpatient Setting ◽

Entire Cohort ◽

Increased Risk

Abstract Abstract 2790 Poster Board II-766 BACKGROUND: MDS is a group of hematologic malignancies associated with reduced quality of life related to progressive cytopenias and increased risk of infections and bleeding. Successful treatment in MDS is typically defined in terms of complete remission (CR). Treatment with decitabine, a DNA methyltransferase inhibitor, has led to CR in 9 to 39% of MDS patients. Many patients have responses that do not meet criteria for CR or partial remission, but may be of clinical importance, especially for older MDS patients. Since patients who achieve stable disease may receive benefits from treatment, it was of interest to evaluate patient characteristics and treatment response results of those who achieved stable disease with decitabine. METHODS: 99 patients with de novo (n=88) or secondary (n=11) MDS were treated with decitabine, 20 mg/m2 daily for 5 days every 4 weeks in an outpatient setting (Steensma et al. J Clin Oncol 2009). No dose reductions were allowed but dose delays were permissible. Any FAB, including CMML, were eligible if ECOG 0-2 and normal hepatic and renal function. Supportive care, including blood products, were permitted. G-CSF was permitted for serious infection or sepsis. Twenty-three patients (18 de novo and 5 secondary MDS) achieved stable disease as the best response by IWG 2006 criteria. RESULTS: At baseline, stable disease patients had a median age of 75 years (70% >70 years) and were mainly men (70%). Ten patients had RA, 7 had RAEB, 4 had RAEB-t, and one each had RARS or CMML. The IPSS scores for these patients were Low (n = 1; 4%), INT-1 (n = 8; 35%), INT-2 (n = 5; 22%), and High (n = 9; 39%). Cytogenetics were good 10 (43%), 1 (4%) intermediate, 10 (43%) poor, or unknown 2 (9%). At baseline 19 (83%) were RBC transfusion dependent, 3 (13%) platelet transfusion dependent. 22 patients were ECOG 0-1. Five patients had received prior cytotoxic chemotherapy, none with azacitidine or decitabine. The median number of cycles initiated was 5.0 (range 2 – 19). At the time of the analysis, 12 of the 23 patients had died with a median survival of 19.2 months (95% CI: 9.4, not estimable). This is consistent with the survival response (19.4 months (95% CI: 15, not estimable) for the entire cohort, which included the stable disease patients, 50% who achieved a hematologic improvement or better, and 10% with progressive disease with decitabine (15% not assessable). Median time to AML or death was 16.1 months (95% CI: 7.2, not estimable). Three of 19 RBC-dependent patients at baseline became transfusion independent for at least 8 weeks with treatment. Conversely, 3 of 4 baseline RBC-independent patients became transfusion dependent. One of 3 platelet-dependent patients became transfusion independent. Three of 20 platelet-independent patients at baseline became transfusion dependent. Of ten patients evaluable for cytogenetic responses, 2 patients had partial cytogenetic responses. Eleven out of 23 patients had at least one related SAE. Myelosuppression-related adverse events were common (≥10%) in these 23 patients with grade 3 or higher adverse experiences of anemia (26%), febrile neutropenia (17%), neutropenia (39%), and thrombocytopenia (30%). CONCLUSIONS: In an outpatient setting, approximately one-quarter of MDS patients maintained stable disease with decitabine treatment, with acceptable and manageable toxicity. Overall survival in this subset of patients appeared to be similar to that observed with the entire cohort, which included 50% of patients with an objective clinical benefit. Larger analyses are needed to fully understand the characteristics of and treatment-related benefits for patients who achieve stable disease with decitabine treatment. Disclosures: No relevant conflicts of interest to declare.

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Essential Thrombocythemia Patients with CALR Mutations Have Increased Platelet Activation Markers Compared to JAK2V617F Mutated Patients

Blood ◽

10.1182/blood.v124.21.3223.3223 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3223-3223

Author(s):

Maya Koren-Michowitz ◽

Hagit Hauschner ◽

Yulia Shuly ◽

Meital Nagar ◽

Elena Ribakovsky ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Conflicts Of Interest ◽

Thrombus Formation ◽

Absolute Number ◽

Median Number ◽

Healthy Controls ◽

Activation Markers ◽

Increased Risk ◽

Platelet Aggregates ◽

Calr Mutations

Abstract Essential thrombocythemia (ET) is associated with an increased risk for thrombo-hemorrhagic complications. The presence of the JAK2V617F mutation, found in approximately 50% of ET patients, has been associated with increased indices of platelet (PLT) activation suggesting its casual role in thrombus formation. Mutations in CALR were recently described in the majority of JAK2V617F negative ET patients, and are associated with a decreased rate of thrombotic events. This has led us to hypothesize that CALR mutations have a different influence on PLT activation compared to JAK2V617F. To evaluate the PLT activation state, surface expression of two PLT activation markers - p-selectin (CD62P) and PAC1 was studied using specific antibodies. MFI was analyzed by flow cytometry at baseline, as well as following ADP addition to PLT rich plasma. Monocyte-platelet aggregates were studied in whole blood samples by gating CD45+/CD14+ cells and calculating the percentage of CD41+ cells in the monocytes population. The immature PLT fraction (IPF) was analyzed with the XE-5000 hematology analyzer (Sysmex UK Ltd., Milton Keynes, UK), and the absolute number of immature PLT (nIP) was calculated from the total PLT count. Low risk ET patients (N-13, M/F-5/8) and healthy controls (N-10, M/F-4/6) are included in this analysis. JAK2V617F and CALR mutations were present in 8 and 5 patients, respectively; low dose aspirin (range 75-100mg) was taken by 85% of patients and 90% of controls. Median PLT count in CALR mutated, JAK2V617F mutated and healthy subjects was 913, 579 and 247 K/uL, respectively (p=0.0002), and it was higher in CALR compared to JAK2V617F positive patients (p=0.09). Both patient subgroups had a lower baseline MFI of p-selectin and PAC1 compared to healthy controls (p-selectin: 2.8, 3 and 4.5 for JAK2V617F [p=0.01], CALR [p=0.05] and controls; PAC1: 3, 3.3 and 5.2 for JAK2V617F [p=0.01], CALR [p=0.02] and controls, respectively) with no difference between CALR and JAK2V617F mutated patients. CALR compared to JAK2V617F mutated patients had higher median number of immature PLT (30 and 10.6 K/uL, p=0.04), and a higher fraction of monocyte- platelet aggregates (90 and 58%, p=0.05). nIP and monocyte- platelet aggregates were also significantly higher in CALR mutated but not in JAK2V617F mutated patients compared to healthy controls. Interestingly, there was no difference in post ADP PLT activation (post/baseline ratio) between ET patients and healthy controls. Finally, there were correlations between the PLT counts and nIP (R=0.8, p<0.0001), monocyte- platelet aggregates (R=0.5, p=0.02), baseline p-selectin MFI (R=-0.5, p=0.02) and PAC1 MFI (R=-0.5, p=0.01). Our preliminary results suggest a correlation between PLT activation markers and the PLT numbers, which can explain why CALR mutated patients in our cohort had higher nIP and monocyte- platelet aggregates fractions. The absence of an increased ADP induced PLT activation between patients and controls in this cohort compared with previous reports could be explained by the use of aspirin in the majority of patients and the high ADP concentration used for PLT activation. These results will be further studied in a lager cohort of patients. Disclosures No relevant conflicts of interest to declare.

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Genetic Factors Related with Early Onset of Osteonecrosis of the Jaw in Patients with Multiple Myeloma Under Zoledronic Acid Therapy

Blood ◽

10.1182/blood.v124.21.2115.2115 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2115-2115

Author(s):

Pelagia Melea ◽

Tina Bagratuni ◽

Evangelos Terpos ◽

Evangelos Eleutherakis-Papaiakovou ◽

Maria Gavriatopoulou ◽

...

Keyword(s):

Zoledronic Acid ◽

High Risk ◽

Conflicts Of Interest ◽

Dose Intensity ◽

Osteonecrosis Of The Jaw ◽

Acid Therapy ◽

Ppar Γ ◽

Pathologic Fractures ◽

Increased Risk ◽

Significant Difference

Abstract Bisphosphonates are extensively used in the treatment of myeloma-related bone disease as they reduce pain and skeletal related events (SREs), such as pathologic fractures, need for radiation and surgery to the bone. One of the complications of prolonged therapy with bisphosphonates, especially of amino-bisphosphonates, such as zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). Recent studies have attempted to correlate specific genetic polymorphisms (SNPs) and ONJ. Such SNPs include cytochrome P4502C8 (CYP2C8; Sarasquete et al, Blood 2008) and peroxisome proliferator-activated receptor gamma (PPAR-γ; Di Martin et al, Br J Haematol 2011) that have been linked to increased risk of ONJ in two different series. The aim of this study was to investigate a possible association between SNPs in CYP2C8 and PPAR-γ and the risk of developing ONJ in a large number of MM patients who received ZA. We screened 36 patients who developed ONJ and 104 patients who did not develop ONJ for the SNPs of interest in PPAR-γ (rs1152003) and CYP2C8 (rs193495) genes by direct sequencing of peripheral blood derived DNA. All patients were treated with similar systemic anti-myeloma therapies during the same period of time, had received only ZA as antiresorptive therapy and were followed prospectively for the development of ONJ in a single center (Department of Clinical Therapeutics, University of Athens, Greece). The median follow up of the cohort was 72 months. The median number of ZA infusions was 27 (range: 4-107). Patients who developed ONJ had a median of 31 infusions versus 25 infusions for patients who did not develop ONJ. However, 31% of patients who developed ONJ had received less than 24 infusions of ZA. Median time to development of ONJ was 47 months (range: 7-182 months). The median relative dose intensity for ZA was 2.85 mg/month; it was 3.3 mg/month for those who developed ONJ and 2.7 mg/month for those who did not. An extraction preceded the development of ONJ in 60% of patients who developed ONJ, it was unprovoked in 20%, it was associated with trauma from dentures in another 15% and in 5% ONJ was preceded by a periodontal and/or periappical inflammation (abscess formation etc). There was no significant difference in frequency of the presence of SNPs in the two studied genes between patients with and without ONJ. However, there is a subset of patients who develop ONJ rather early, after the infusion of relatively few doses of ZA while others develop ONJ after protracted exposure to ZA. Since the most important factor associated with the development of ONJ after ZA therapy in patients with myeloma is the total dose of ZA, we analyzed separately patients who had less than 24 versus those who had at least 24 infusions of ZA. In patients with <24 infusions of ZA, the presence of SNPs in both PPAR-γ and CYP2C8 was associated with a significantly higher probability and a shorter time to development of ONJ. More specifically, the presence of SNPs in the PPAR-γ was associated with a significantly higher risk of development of ONJ with less than 24 ZA infusions (55% versus 16%, p=0.011) and at a significantly shorter time to development of ONJ (19 versus 69 months, p<0.001). The presence of SNPs in the CYP2C8 was associated with a higher risk of developing ONJ with less than 24 ZA infusions (29% versus 7%, p=0.07) and at a shorter time (44% versus 13% at 3 years, p=0.037). Combining the genotype risk, those with high risk of SNPs in both genes had a 70% cumulative incidence of ONJ within 24 months from initiation of ZA versus 17% for those carrying one of the two SNPs and 0% for those without any high risk of SNPs (p<0.001). In conclusion, our data indicate that SNPs in the CYP2C8 and PPAR-γ genes are associated with a risk of early development of ONJ. However, increasing cumulative dose of ZA increases substantially the risk of ONJ in all patients, independently of genotype-defined risk. Disclosures No relevant conflicts of interest to declare.

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Survival and prognostic factor analyses in malignant giant cell tumour of bone

10.21203/rs.2.12960/v4 ◽

2020 ◽

Author(s):

Jin Zhang ◽

Xin Wang ◽

Feng Lin ◽

Guijun Xu ◽

Haixiao Wu ◽

...

Keyword(s):

Giant Cell ◽

Cox Regression ◽

Giant Cell Tumour ◽

Large Population ◽

Survival Rates ◽

Population Based ◽

Cell Tumour ◽

Rank Test ◽

Seer Database ◽

Increased Risk

Abstract Background: The characteristics and survival of patients with malignant giant cell tumour of bone (GCTB) have not been investigated thoroughly due to the rarity of the disease. We evaluated these factors in a large cohort in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database.Methods: Data from patients who were diagnosed with malignant GCTB from 1975 to 2016 were extracted from the SEER database. The overall survival (OS) was calculated by Kaplan–Meier analysis, and intergroup differences were tested by the log-rank test. Univariate and multivariate Cox proportional hazard regression analyses were conducted to identify the independent survival factors.Results: A total of 325 patients with malignant GCTB were included. The overall 1-, 5-, and 10-year survival rates were 94.3% (95% CI: 91.7-96.8), 82.3% (95% CI: 77.9-86.6), and 80.1% (95% CI: 75.4-84.7), respectively. A potential non-linear J-shaped dose–response relationship between the age or diagnosis year and survival were found. Multivariate Cox regression showed poor survival in patients with age from 35 to 60 years (hazard ratio (HR) =9.99, 95% CI: 1.34-74.80, P=0.025), age older than 60 years (HR=62.03, 95% CI: 7.94-484.38, P<0.001), with stage T2 disease (HR=4.85, 95% CI: 1.52-15.47, P=0.008), with stage T3 disease (HR=6.09, 95% CI: 1.03-36.23, P=0.047), and with distant tumours (HR=2.76, 95% CI: 1.14-6.65, P=0.024), and extraskeletal sites (HR=3.33, 95% CI: 1.02-10.85, P=0.046).Conclusions: This large population-based series described the clinical characteristics of malignant GCTB. Patients with stage T2/3disease, distant disease and extra-skeletal sites had more odds to be with worse survival. The elder age than 34 years had a gradually increased risk for survival.

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Osteonecrosis of the jaw associated with intravenous bisphosphonate therapy—A single institution experience

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.18553 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 18553-18553 ◽

Cited By ~ 2

Author(s):

E. M. Wallace ◽

K. I. Quintyne ◽

B. M. Cantwell ◽

P. M. Calvert ◽

G. D. Leonard

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Zoledronic Acid ◽

Metastatic Breast ◽

Median Number ◽

Osteonecrosis Of The Jaw ◽

Bisphosphonate Therapy ◽

Unknown Primary ◽

Dental Procedures ◽

Increased Risk

18553 Background: Osteonecrosis of the jaw (ONJ) is a debilitating disease that has been associated with cancer therapy. Recently a link between ONJ and chronic intravenous (IV) bisphosphonates has been suggested. We assessed the incidence of ONJ and its risk factors in patients treated with IV bishosphonates at our institution. Methods: All patients with a cancer diagnosis treated at our institution with at least four cycles of either IV Zoledronic Acid, Pamidronate, or a combination of both, from 2000–2005 were evaluated using outpatient records. Patients with ONJ were identified and their characteristics were compared to all patients receiving bisphosphonate therapy. Results: One hundred and twenty-one patients were evaluated, 36 Male and 85 Female. Median age- 62 (Range 34–85). Seventy-six had metastatic Breast cancer, 25 Prostate, 7 Lung, 3 Colorectal, 3 Renal, 2 unknown primary, 1 each of Penile, Bladder, Seminoma, Lymphoma and Melanoma. Forty patients received Pamidronate infusions alone, 51 Zoledronic Acid alone and 30 a combination of the two. The median number of Pamidronate infusions was 8 (Range 4–10), Zoledronic infusions 10.7 (Range 4–32), and a combination of pamidronate and zoledronic acid was 12 (Range 5–66). Three patients developed ONJ. All 3 patients were female, had a median age of 62 (range 52–74) and had metastatic breast cancer. The median number of bisphosphonate infusions prior to the development of ONJ was 35 (Range 18–47). All patients had chest wall radiotherapy and 1 had chemotherapy and steroids. No patients had dental procedures or prolonged antibacterial therapy. Conclusions: ONJ is a complication associated with IV Bisphosphonate therapy. Our study suggests that female sex, zoledronic acid, and prolonged administration of bisphosphonates, may confer an increased risk for the development of ONJ. Further prospective studies with adequate power are needed to clarify what patients are most at risk for developing ONJ and what measures are needed to prevent its occurrence. No significant financial relationships to disclose.

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Autologous Hematopoietic Stem Cell Transplantation (AHCT) in Patients with Chemotherapy-Sensitive, Relapsed/Refractory (CSRR) Human Immunodeficiency Virus (HIV)-Associated Lymphoma (HAL): Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0803)/AIDS Malignancy Consortium (AMC-071) Trial

Blood ◽

10.1182/blood.v124.21.674.674 ◽

2014 ◽

Vol 124 (21) ◽

pp. 674-674 ◽

Cited By ~ 2

Author(s):

J Alvarnas ◽

J Le Rademacher ◽

Y Wang ◽

Richard F. Little ◽

G Akpek ◽

...

Keyword(s):

Median Time ◽

Highly Active Antiretroviral Therapy ◽

Cumulative Incidence ◽

Conflicts Of Interest ◽

B Cell Lymphoma ◽

Hiv Viral Load ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Increased Risk ◽

One Year

Abstract Background: HIV infection is associated with increased risk of non-Hodgkin (NHL) and Hodgkin lymphoma (HL). Historically HIV-infected patients had inferior outcomes and increased treatment-related morbidity and mortality over uninfected patients. Highly active antiretroviral therapy (HAART) improved the prognosis for patients with HAL and permitted treatment identical to that in uninfected patients. The role of AHCT in HIV-infected patients, however, remains under investigation. This BMT CTN 0803/ AMC-071 trial, sponsored by the National Heart, Lung and Blood Institute and National Cancer Institute, was designed to prospectively assess overall survival (OS) after AHCT in patients with CSRR HAL. Methods : Patients with treatable HIV-1 infection, age > 15 years, adequate organ function and CSRR aggressive NHL or HL were included. Mobilization and collection followed institutional guidelines. Patients underwent AHCT using the BEAM regimen [carmustine 300 mg/m2 (day -6), etoposide 100 mg/m2 twice daily (days -5 to -2), cytarabine 100 mg/m2 (days -5 to -2), melphalan 140 mg/m2 (day -1)]. Patients received AHCT on day 0 and standard supportive care through discharge. HAART was withheld during the preparative regimen and until therapy-related GI toxicity resolved. The primary trial objective was estimation of one-year OS. Secondary objectives included lymphoma response post-transplant, progression-free survival (PFS), transplant-related mortality (TRM), infection-related complications and recovery of hematological function (RHF) post-AHCT. RHF was defined as ANC > 1500/µl, untransfused hemoglobin > 10 gm/dL and platelet > 200,000/µl. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Results : Between July 2010 and May 2013, 43 patients were enrolled; 3 progressed prior to AHCT and were excluded from analysis. Forty patients underwent AHCT (5 female, 35 male). Median age was 46.9 years (range, 22.5-62.2). Lymphoma subtypes included diffuse large B-cell lymphoma (40%), plasmablastic lymphoma (5%), Burkitt/Burkitt-like lymphoma (17.5%) and HL (37.5%). All patients received < 2 salvage regimens. Prior to transplant, 30 patients (75%) were in complete remission (CR), 8 (20%) were in partial remission (PR) and 2 (5%) had relapsed/progressive disease (RPD). Pre-HCT HIV viral load (VL) was undetectable in 31 patients (77.5%) and detectable in 9 (22.5%) with a median VL of 84 copies/mL (interquartile range [IQR], 58-234). Median CD4 count was 250.5/µL (range 39-797, IQR 175-307). All 40 patients completed BEAM and underwent HCT. At day 100 post-HCT, 39 patients were assessed for disease response (1 inevaluable due to early death): 36 (92.3%) were in CR, one (2.6%) in PR and two (5.1%) had RPD. By one-year post-HCT, 5 patients died (3 from recurrent/persistent disease, 1 from organ failure [cardiac arrest] and 1 from invasive fungal infection). Cumulative incidence of TRM was 5.2% (95% confidence interval [CI]: 0.9%-15.7%). With a median follow-up of 24 months post-AHCT, estimated probability of one-year OS was 86.6% (95% CI: 70.8%-94.2%) (Figure 1). By one-year, 5 patients relapsed post-HCT, 3 of whom subsequently died. The cumulative incidence of relapse/progression at one-year post-HCT was 12.5% (95% CI: 4.5%-24.8%). Estimated probability of one-year PFS was 82.3% (95% CI: 66.3%-91.1%) (Figure 2). Within one-year of HCT, 13 patients experienced grade 3 and 2 patients grade 4 toxicities (1 patient with mucositis and 1 patient with dyspnea/hypoxia/ cardiac arrhythmia/hypotension). Seventeen patients (42.5%) developed a total of 42 episodes of infection within one-year post-HCT, including 9 with an infection severity grade of severe. Median time to neutrophil engraftment (> 500/µl) was 11 days (range, 9-32).Median time to platelet transfusion-independent engraftment >20,000/µl was 18 days (range, 9-176); 1 patient died prior to platelet recovery. Eleven (28.9%) of 38 evaluable patients and 24 (75%) of 32 evaluable patients achieved RHF by 100 days and 1-year post-HCT, respectively. Discussion : Patients with HAL may successfully undergo AHCT with favorable outcomes. AHCT should be considered the standard of care for patients with relapsed/refractory HAL who meet standard eligibility criteria. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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A Predominant Mutation in Regulatory Region of SERPINC1 Gene and Venous Thrombosis

Blood ◽

10.1182/blood.v126.23.4669.4669 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4669-4669 ◽

Cited By ~ 1

Author(s):

Bei Hu ◽

Qingyun Wang ◽

Liang Tang ◽

Yu Hu ◽

Han Liu

Keyword(s):

Dna Sequencing ◽

Venous Thrombosis ◽

Transcription Initiation ◽

Conflicts Of Interest ◽

Large Population ◽

Regulatory Region ◽

Case Control ◽

Control Group ◽

Antithrombin Deficiency ◽

Increased Risk

Abstract Background Antithrombin (AT) is a critical physiological anticoagulant in haemostasis. SERPINC1, the gene encoding antithrombin, is 13.5kb in length and located on chromosome 1q23-25. Mutations in the SERPINC1 gene may cause antithrombin deficiency and are supposed to confer a high risk for venous thrombosis. However, most mutations reported so far are located in the coding or splicing region of this gene. Therefore, we investigate SERPINC1 gene to identify possible regulatory variants that would increase susceptibility of thrombosis in Chinese people. Methods and Results The potential promoter and 5'-untranslated region of SERPINC1 was screened by direct DNA sequencing in 100 individuals diagnosed with unprovoked venous thrombosis. Further genotyping was performed by Restriction Fragment Length Polymorphism (RFLP) analysis in case-control populations (1750 vs 1900). By DNA sequencing, we identified a c.-11.G>A transition, located 11bp upstream from the transcription initiation codon. Next case-control study showed that this mutation was present in ten individuals of thrombosis group and two of control group. All the mutation carriers we identified were heterozygotes. Therefore, individuals carrying the mutant A allele conferred a 5.42-fold increased risk for venous thrombosis (p<0.05) . Conclusion The c.-11G>A mutation of SERPINC1 gene is a risk factor for venous thrombosis in the Chinese population. It's the first time that a predominant mutation in the regulatory region of SERPINC1 gene reported to be associated with venous thrombosis in a large population. Disclosures No relevant conflicts of interest to declare.

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Fotemustine (MUFORAN) in Combination with Once Weekly Bortezomib and Dexamethasone (B-MuD): Good Clinical Activity and Favourable Toxicity Profile for Treatment of Relapsed Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v120.21.2957.2957 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2957-2957

Author(s):

Silvia Mangiacavalli ◽

Alessandra Pompa ◽

Lara Pochintesta ◽

Cristiana Pascutto ◽

Federica Cocito ◽

...

Keyword(s):

Multiple Myeloma ◽

Median Time ◽

Conflicts Of Interest ◽

Single Agent ◽

Gastrointestinal Symptoms ◽

Median Number ◽

Hematological Toxicity ◽

Clinical Activity ◽

Dose Escalation Study ◽

Advanced Phase

Abstract Abstract 2957 Fotemustine (Muphoran), a nitrosourea alkylating agent approved for metastatic melanoma, and recently used in alternative autotransplant condition regimen (FEAM) for lymphoma patients, has proven to be active as single agent in Multiple Myeloma (MM) refractory-relapsed patients. Given the importance of reaching high-quality response even beyond frontline setting, and the proven activity of the proteasome inhibitor bortezomib + dexamethasone therapy, we explored by means of a phase I-II dose escalation study the feasibility and the efficacy of the three drug combination bortezomib (B) + fotemustine (Mu) + dexamethasone (D) (B-MuD) in MM patients (pts) relapsed after at least one therapy. The study has been approved by our local ethical committee; all pts signed written informed consent. Fotemustine was administered at two dose levels (80–100 mg/m2 i.v.) on day 1. The original 21-day schedule was early amended due to extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1,3 mg/ m2 i.v. on days 1, 8, 15, 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, 22) for a total of six courses. Twenty-four pts have been enrolled: M/F 13 (54%)/11(46%), median age 69 years (44–83), median number of previous therapies 2 (1–5). Previous treatments included autologous transplant in 13 pts (54%), bortezomib in 8 pts (33%), oral melphalan in 11 pts (46%) and thalidomide in 15 (63%). The MTD of Fotemustine was tested to be 100 mg/m2. Six pts dropped-out: 4 pts for extra-hematological toxicity, 2 for progression. The overall response rate was of 62% (CR 8%, VGPR 33%, PR 21%). Median time to first response was 36 days (range 21–83) with a median DOR of 19.4 months (95% CI 11.6–23.7 months). After a median follow-up of 24.3 months (range 1.6–32.8 months), the median OS was 28.5 months (95% CI 22.1-NR). The median TTP and the median PFS were 20.5 (95% CI 11.9–22.2 months) and 19.1 (95% CI 11.9–22.2) months respectively. Median time to next therapy (TNT) was 16.2 months (4–25.2). There was a correlation between response and PFS (p=0.0002). B-MuD resulted effective in patients previous exposed to bortezomib without difference in terms of response (p=0.25) and PFS (p=0.87) when compared to bortezomib-naive patients. As far as toxicity was concern, one-hundred and thirty-three AE of any grade were observed, 65 hematological (49%) and 68 (51%) non-hematological; Thrombocytopenia was the most common AE (32%) overall. Extra-hematological toxicity included neuropathy (23%), infections (14%), gastrointestinal symptoms (7%). Half of the events occurred during the first two cycles (49%), most were manageable, with 69% resolved or improved, 15% unchanged, 15% worsened. In conclusion B-MuD is effective and well tolerated in relapsed MM even in patients in advanced phase and previously exposed to several lines of therapies, including bortezomib. Disclosures: No relevant conflicts of interest to declare.

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Treatment With Decitabine (DAC) After Azacitidine (AZA) Failure In High Risk Myelodysplastic Syndrome (MDS) and Advanced Chronic Myelomonocytic Leukemia (CMML)

Blood ◽

10.1182/blood.v122.21.2796.2796 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2796-2796 ◽

Cited By ~ 2

Author(s):

Thorsten Braun ◽

Amina Cherait ◽

Celine Berthon ◽

Christophe Willekens ◽

Sophie Park ◽

...

Keyword(s):

High Risk ◽

Median Time ◽

Stable Disease ◽

Conflicts Of Interest ◽

Allogeneic Bone Marrow Transplantation ◽

Median Number ◽

Cross Resistance ◽

Allogeneic Bone ◽

Monosomy 7 ◽

Significant Difference

Abstract Background Outcome of patients with high risk MDS and CMML who failed treatment with AZA remains poor with a median survival of 5-6 months (Prebet; JCO 2011 29:3322). No established therapy is available for the majority of those patients at this stage except allogeneic bone marrow transplantation in a few eligible patients. The rationale for DAC treatment after AZA failure is based on somewhat different pharmacological properties between those 2 hypomethylating agents (HMAs) (Hollenbach; Plos One 2010 5:e9001). Conflicting results for DAC salvage after AZA failure have been reported with 0-28% response rates (RR) in small patient series, and an overall survival up to 11 months (Borthakur; Leuk Lymphoma 2008 49:690; Prebet; JCO 2011 29:3322; Bhatnagar, ASH 2012 Abstr #3858). We retrospectively reviewed a larger cohort of 36 patients in this setting. Methods Characteristics, overall response rate (ORR) and outcome were studied in high risk MDS and CMML patients who received DAC after AZA failure from June 2007 to April 2013 in three French hematology departments. Response criteria were based on IWG 2006 for MDS and CMML with WBC <13G/L and also included for CMML with WBC >13 G/L evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD) (based on Wattel; Blood 1996 88:2480). Results Median age of the 36 patients was 70.5 years (range 53-84), and M/F: 21/15. Median time from diagnosis to AZA onset was 5.7 months and all patients at AZA onset had IPSS ≥ int-2 MDS/CMML or CMML-2 (EU label for AZA). Median number of cycles of AZA received was 8 (3-41) and 8 patients had received less than 6 cycles (2-5) including 1 who received HSCT, 1 with progressive disease (PD) and 6 in whom AZA was considered ineffective after less than 6 cycles. Overall, 20 patients had primary AZA failure, 1 PD and 15 had relapsed after achieving CR (n=9), PR (n=1), mCR (n=1), mCR+HI (n=2) or SD+HI (n=2), 3 of whom had been allografted. Apart from the 3 last patients, responders were still receiving AZA when relapse occurred. Median number of treatments received after AZA and before DAC was 0 (range 0-3), including low dose cytarabine (n=5), intensive chemotherapy (n=5), clofarabine (n=5) and rigosertib (n=3). Twenty patients received DAC immediately after AZA failure and median time from AZA to DAC treatment for all patients was 3.6 months. At onset of DAC, 22 patients had AML post MDS (including 11 RAEB-t), 8 had RAEB-2, 1 RAEB-1, 1 CMML-2 and 4 CMML-1.Median marrow blast count was 23% (range 7-82). Karyotype was normal in 15 (41.7%) patients, 9 (25%) patients had unfavorable cytogenetics including 7 complex karyotypes and 2 monosomy 7, five (13.9%) patients had +8, three (8.3%) del 20q, 3 (8.3%) other anomalies and 1 (2.8%) cytogenetic failure. IPSS-R was intermediate for 3, high for 11 and very high for 6 patients and could not be evaluated for 16 patients, mainly those with overt AML. 2 CMML patients had SMG and 1 skin involvement. Median number of DAC cycles administered was 3 (1-27) with 12 patients receiving at least 6 cycles. Seven patients (19.4%) were responders to DAC according to IWG 2006 criteria including 3 marrow CR, 2 stable disease (SD)+HI-E, 1 SD+HI-P and 1 SD+HI-N. In a CMML patient with SD, specific skin lesions resolved upon treatment with DAC and a patient with marrow CR underwent HSCT. Median OS from onset of DAC was 7.3 months without significant difference between responders and non-responders. Responses were short lived (2.5-6 months) with 2 responders currently ongoing with short follow up (2.5+ and 3+ months respectively) and 2 non-responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Of note, 6 of the responses were seen in patients who did not receive DAC immediately after AZA. Conclusion Treatment of DAC after AZA failure yielded modest ORR (19.4%) and no CR was achieved in this patient cohort. Responses were generally short lived but 2 patients had prolonged stable disease for 21 and 27 cycles respectively. OS remained poor. Those results do not support absence of cross resistance between AZA and DAC, at least in most higher risk MDS. Disclosures: No relevant conflicts of interest to declare.

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Ibrutinib in Patients (Pts) with Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) with Relapsed Disease Post Allogeneic Stem Cell Transplantation (alloSCT)

Blood ◽

10.1182/blood.v126.23.4345.4345 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4345-4345 ◽

Cited By ~ 1

Author(s):

Issa F. Khouri ◽

Elias Jabbour ◽

Rima M Saliba ◽

Celina Ledesma ◽

Jan A Burger ◽

...

Keyword(s):

B Cell ◽

Median Time ◽

Progressive Disease ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Survival Rates ◽

Lymphocytic Leukemia ◽

Severe Neutropenia ◽

Ki 67 ◽

Bulky Disease

Abstract Background: Ibrutinib has demonstrated efficacy in clinical trials for relapsed and refractory MCL and CLL. There is a paucity of information regarding its safety and efficacy after failing alloSCT. Clinical data suggest that B-cell dysfunction contributes to chronic graft-versus-host-disease (GVHD). It is speculated that this may be due to hyper-responsiveness of the B-cell receptor, which can be abrogated by disrupting the signaling downstream by the use of ibrutinib. Purpose: To study the safety, toxicity, survival rates and risk of GVHD in patients with CLL and MCL who relapsed post an alloSCT at our center. Methods: Retrospective review in MCL and CLL pts who received ibrutinib post alloSCT between 12-1-2011 and 12-1-2014. The study was approved by IRB. Results: We identified 22 pts with CLL (n=16) and MCL (n=6) who failed alloSCT with either nonmyelablative (n=17, 77%) or ablative (n=5, 23%) conditioning. Twelve (55%) received their transplants from HLA-compatible siblings and 10 (45%) from unrelated donors. Median time from alloSCT to progression was 12 months (range, 5-94 months). Ten (45%) failed to respond to donor lymphocyte infusion (DLI). The median time from progression post alloSCT and starting ibrutinib was 17 months (range, 0.5-88 months).When starting ibrutinib, median age was 63 (range, 47-73) years. Ten (43%) pts had bulky disease. Median β2-microglobulin was 4 mg/L (range, 2.7-10). Five (23%) CLL had 17p deletion. Median hemoglobin in CLL pts was 12.3 g/dL (range, 9.2-17.6), median platelets was 109,000/ µL (range, 8000-301,000), median absolute lymphocyte counts were 2,300/µL (range, 310-64,400). All MCL pts had elevated Ki-67 of >30% and 5 (83%) were blastoid. Median % of donor T cell (range, 27-100) and myeloid cells (range, 84-100) was both 100%. The ibrutinib starting dose was 420 mg in 12 (55%) and 560 mg in 10 (45%) pts. With a median follow-up time of 15 (range, 4-38) months, median overall survival (OS) was not reached for CLL, whereas this was of 17 months for MCL pts. Eighteen-month OS rate for CLL and MCL pts were 87% and 33%, respectively (P=0.08) and the 18-month progression-free survival rates were 87% and 33%, respectively (P=0.03). Survival rates were similar in CLL pts with or without 17p deletion. At the time of this analysis, 12 (75%) CLL pts (3 in CR, 4 in PR, 4 in stable disease and one with progressive disease) and 3 (50%) MCL pts (1 in PR, I in stable and 1 with progressive disease) remain alive. Ten episodes of grade 2 infection (3 of which were related to pneumonia) and one septic shock occurred during the course of ibrutinib treatment. Two of these infections occurred in the setting of severe neutropenia. One (5%) pt developed atrial fibrillation that required cardioversion. One (5%) pt experienced bleeding post a tooth extraction that required hospitalization and transfusions. With their prior alloSCT course and DLI, 8 (36%) pts had grade 1-2 acute GVHD, 3 (14%) had acute grade 3-4 GVHD and 7 (32%) had chronic GVHD. At the time ibrutinib was started, all pts were off immunosuppression and 3 had signs of limited chronic GVHD. At ibrutinib initiation, the 3 pts with limited chronic GVGD progressed to extensive GVHD at 43, 105 and 153 days respectively. All 3 had involvement of the mouth, skin (one with severe scleroderma) and 1 had acute gastro-intestinal diarrhea and bleeding. All responded to initiating tacrolimus, systemic steroids and reducing the ibrutinib dose. Conclusions: Our results show that the use of ibrutinib after alloSCT is safe in pts who do not have active GVHD. The treatment can improve OS especially in CLL pts. This warrants further studies incorporating the drug in an upfront transplant strategy. Disclosures No relevant conflicts of interest to declare.

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