A Phase II Trial of TBL 12 Sea Cucumber Extract in Patients with Untreated Asymptomatic Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3992-3992
Author(s):  
Ajai Chari ◽  
Amitabha Mazumder ◽  
Lauren Ditrio ◽  
Zachary Galitzeck ◽  
Sundar Jagannath
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Pneumococcal Pneumonia ◽  
Sea Cucumber ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Bone Lesions ◽  
Open Label ◽  
M Spike

Abstract Abstract 3992 Background: Patients with smoldering multiple myeloma (MM) may remain asymptomatic (ASx) for variable amounts of time and are therefore typically monitored without treatment. Chemoprevention trials using thalidomide have found the toxicity to be prohibitive and longer follow up is needed for the early systemic treatment with lenalidomide and dexamethasone of high risk ASxMM. Based on encouraging preclinical data with bioactive food supplements in MM curcumin (Bharti et al., Blood 2003), resveratrol (Bhardwaj et al, Blood 2006), and a component of green tea extract (Shammas et al, Blood 2006) many patients are already using these agents without definitive proof of efficacy or safety. The sphingolipids/glycosides contained in sea cucumbers have also been shown preclinically to have a number of antitumor properties including antiangiogenesis direct tumor cytotoxicity, and also of particular relevance to MM, the inhibition of osteoclastogenesis (Kariya et al, Carb Res 2004). TBL12, an extract of sea cucumber, has been commercially available since 1981 and used by human subjects as a food supplement without any reported toxicities. We therefore designed a pilot phase II study to determine the safety and efficacy of TBL12 in patients with ASxMM and here we present updated data. Methods: Patients were required to have ASxMM with measurable disease, defined as monoclonal immunoglobulin spike (m-spike) on serum electrophoresis of ≥ 1 g/dL and/or urine m spike of ≥ 200 mg/24 hours. If non-secretory, then abnormal free light chains (FLC) were required. A total of 20 patients with ASxMM were given open label TBL12, formulated as a liquid gel (manufactured by Unicorn Pacific Corporation, IND 103,543) to be kept frozen until the time of consumption. Patients ingested 2 units of 20 ml twice per day, for a total of 80 units per day. Disease parameters were monitored monthly and treatment was continued until disease progression. Results: 23 patients were screened, with 3 failures, and the remaining 20 patients proceeded with study treatment. The median age of the patient was 58 years (range 22–75), with 11 males and 9 females. The phenotypes were 14 IgG, 5 Ig A, and one kappa light chain. Generally, this was a population at high risk for progression of disease (PD), with 14 patients having a serum m spike > 3 g/dl and bone marrow plasma cells (BM PC) > 10%. The median BM PC for all patients was 38% (range 10 to 90). (With the additional high risk criteria of a FLC ratio <0.125 or >8, 13 patients were high risk.) Of the remaining 6 patients, all had immunoparesis and 4 had markedly elevated FLC ratios (range 307-incalculable) and the remaining 2 patients had 9.2 g urine m spike and an IgA phenotype. Compliance was excellent and the treatment was well tolerated with only grade 1 nausea. There was one SAE, a pneumococcal pneumonia requiring admission, which was felt to be unrelated to study treatment. A total of 9 patients remain on treatment, having completed a median of 24 monthly cycles of TBL12 (range 20–30 cycles). The median progression free survival (PFS) has not been reached by Kaplan-Meyer survival analysis, including for high risk patients. The best response to date has been a minimal response (MR) for 5 cycles. 3 patients are on intermittent bisphosphonates therapy q 3–12 months for osteoporosis or equivocal bone lesions unchanged since screening. 8 patients came off study for PD after a median of 7.5 cycles (range 2–18). The reasons for PD include: 1 hypercalcemia, 1 acute renal insufficiency (after 2 cycles with 9.2g urine m spike at screening), 2 for anemia (one after 3 cycles with 90% BM PC at screening), and 1 for a new bony lesion on MRI. 2 patients withdrew consent after cycle 6 and 8, and 1 was removed after cycle 13 due to investigator discretion after the pneumococcal pneumonia SAE. Conclusions: In this pilot study of high risk ASxMM patients, TBL12 is well tolerated and 9 (45%) patients remain on treatment with one MR noted. The expected rate of PD for high risk ASxMM is 52% at 2 years (Dispenzieri et al, Blood 2008) and to date, median PFS has not been reached in this study. Also, of note, in contrast to 10 of 16 pts in the placebo arm of lenalidomide in ASxMM study developing bone PD (Mateos et al, ASH 2009), only 1 patient in this study has bone PD. This may reflect anti-osteoclastogenesis effects of TBL12 observed in vitro. Further studies are required. Disclosures: No relevant conflicts of interest to declare.

A Phase II Trial of TBL 12 Sea Cucumber Extract In Patients Withuntreated Asymptomatic Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5042-5042
Author(s):  
Amitabha Mazumder ◽  
Ajai Chari ◽  
Lauren Ditrio ◽  
Zachary Galitzeck ◽  
Sundar Jagannath
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase Ii ◽  
Sea Cucumber ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
High Risk Patient ◽  
Risk Patient ◽  
M Spike

Abstract Abstract 5042 Patients with smoldering multiple myeloma (MM) may remain asymptomatic (ASx) for variable amounts of time and are therefore typically monitored without treatment. Chemoprevention trials using thalidomide found prohibitive toxicity and longer follow up is needed for early systemic treatment with lenalidomide/dexamethasone of high risk ASxMM. Based on encouraging preclinical data with bioactive food supplements in MM curcumin (Blood 2003), resveratrol (Blood 2006), and a component of green tea extract (Blood 2006) many patients are already using these agents without definitive proof of efficacy or safety. Preclinically, sphingolipids/glycosides contained in sea cucumbers have also demonstrated antitumor properties including antiangiogenesis direct tumor cytotoxicity, and also of particular relevance to MM, the inhibition of osteoclastogenesis. TBL12, an extract of sea cucumber, has been commercially available since 1981 and used by human subjects as a food supplement without any reported toxicities. We therefore designed a pilot phase II study to determine the safety and efficacy of TBL12 in patients with ASxMM. Methods Patients were required to have ASxMM with measurable disease, defined as serum m spike ≥ 1 g/dL and/or urine m spike ≥ 200 mg/24 hours. If non-secretory, patients were required to have abnormal free light chains (FLC). A total of 20 patients with ASxMM were given TBL12, formulated as a liquid gel (manufactured by Unicorn Pacific Corporation, IND 103,543) to be kept frozen until the time of consumption. Patients ingested 2 units of 20 ml twice per day, for a total of 80 units per day. Disease parameters were monitored monthly and treatment was continued until progression of disease (PD). Results 23 patients were screened, with 3 failures, and the remaining 20 patients proceeded with study treatment. The median age of the patient was 58 years (range 22–75), with 11 males and 9 females. The phenotypes were 14 IgG, 5 Ig A, and one kappa light chain. Generally, this was a high risk ASxMM population, with 14 patients having a serum m spike ≥ 3 g/dl and bone marrow plasma cells (PC) ≥ 10%. The median bone marrow PC involvement for all patients was 38% (range 10 to 90). (With the additional high risk criteria of a FLC ratio <0.125 or >8, 13 patients were high risk.) Of the remaining 6 patients, all had immunoparesis and 4 had markedly elevated FLC ratios (range 307-incalculable) and the remaining 2 patients had 9.2 g of bence jones proteinuria (BJP) and an IgA phenotype. Compliance was excellent and the treatment was well tolerated with only grade 1 nausea. There was one SAE, a pneumococcal pneumonia requiring admission, which was felt to be unrelated to study treatment. A total of 11 patients remain on treatment, having completed a median of 11 monthly cycles of TBL12 (range 6–17 cycles). The best response to date has been stable disease. Notably, one high risk patient demonstrated a flattening in the rate of rise of the m spike concordant with the initiation of study treatment (see Figure 1). 6 patients came off study for PD after a median of 6.5 cycles (range 2–10). The reasons for PD include: 1 hypercalcemia, 1 acute renal insufficiency (after 2 cycles with 9.2g BJP at screening), 1 for anemia (after 3 cycles with 90% marrow PC at screening), and 1 for a new bony lesion on MRI. 2 patients withdrew consent after cycle 6 and 8, and 1 was removed after cycle 13 due to investigator discretion after the pneumonia SAE. -1 year I + 1 year TBL 12 initiated Conclusions In this pilot study of high risk ASxMM patients, TBL12 was well tolerated and 11 patients (65%)remain on treatment. The expected rate of progression for this population from diagnosis is 52% at 2 years, however, the median time to progression has not been yet reached in this study. Additional follow up is required and data will be updated at the annual meeting. The decrease in the rate of rise in the m-spike in a high risk patient concomitant with the initiation of study treatment is suggestive of a biologic effect of TBL12 in MM and warrants further study of TBL 12 in a larger cohort of patients. Disclosures: No relevant conflicts of interest to declare.

Final Report of a Phase II Trial of Vorinostat, Idarubicin and Cytarabine In Previously Untreated Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2189-2189
Author(s):  
Guillermo Garcia-Manero ◽  
Francesco Paolo Tambaro ◽  
Nebiyou Bekele ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Conflicts Of Interest ◽  
Maintenance Phase ◽  
Myelogenous Leukemia ◽  
Stopping Rules ◽  
Final Report ◽  
Platelet Recovery

Abstract Abstract 2189 Introduction: Vorinostat (Vor) is an oral HDAC inhibitor with activity in AML. In vitro, the combination of Vor with idarubicin (Ida) and ara-C (A) is synergistic. We have performed a phase I trial of Vor and Ida and demonstrated that doses of vorinostat up to 500 mg po TID daily × 3 are safe in combination with Ida. Based on this, we developed a phase II trial to study the safety and activity of the triple combination in patients (pts) with AML or higher-risk MDS. Methods: Pts ages 15 to 65 years with ECOG performance of ≤ 2 with a AML by WHO criteria or INT-2 or high risk MDS by IPSS were eligible. The study had 2 phases: an initial run-in phase followed by an actual phase II. For the run-in phase pts with relapsed or refractory disease were eligible. For the phase II, pts should not have received any prior therapy for AML or higher risk MDS. Other inclusion criteria were adequate renal, hepatic, cardiac functions. Pts with APL or CBF were excluded. In the run in phase, Vor was used at the highest possible dose (500 mg po TID × 3 days on days 1 to 3) in combination with Ida-A. Once the dose of Vor was defined in the run-in phase, the phase II was to start with a primary endpoint of event free survival (EFS). The trial was monitored every 6 months and was to be stopped early if it was unlikely that the median EFS rate will be at least (more than 2%) 7 months. The study was also monitored for Vor-related excess toxicity. Pts could receive up to 2 induction cycles, 5 cycles of consolidation and 12 of maintenance. Induction therapy: Vor 500 mg po TID × 3 days, Ida 12 mg/m2 IV over 1 hour qd × 3 (days 4 to 6) and A 1.5 g/m2 IV as a continous infusion (CI) over 24 h qd (days 4 to 7). Pts who achieve a CR or CRp (CR with incomplete platelet recovery) could receive consolidation therapy as follows: Vor 500 mg po TID × 3 days on days 1 to 3, Ida 8 mg/m2 IV over 1 hour daily × 2 days (days 4 and 5) and A 0.75 g/m2 IV CI over 24 h qd × 3 days (days 4 to 6). During maintenance phase, Vor was 200 mg po TID QD x14 every 28 days for 12 cycles. PD analysis included histone acetylation, analysis of autophagy and ROS activation. Results: 3 pts were treated in the run in phase with no toxicity. All 3 responded to therapy and the study continued to the phase II. The phase II has completed accrual at 75 pts. This was the max. number anticipated if the study was to be successful. No stopping rules for EFS or toxicity were met. Pt characteristics are as follows: median age 52 years (range 19–65), WBC 5 ku/L (range 0.7 to 111), peripheral blood blasts 14% (0-92), BM blasts 40% (11-95), cytogenetics (diploid 29 (38%), -5/-7 (22%), the rest complex), Flt3 mutation in 11 (14%). Response rate is as follows: CR 57 (76%), CRp 7 (10%) for an overall response (ORR) of 86%. Diploid pts had a CR of 86% and CRp of 7% for an ORR of 93%. Pts with other CG alterations had a CR of 76%, CRp 9%, ORR 85% (p=0.03). Pts with Flt-3 ITD had a CR of 91% and CRp of 9% for an ORR of 100%. This was in contrast to an ORR of 85% for the wt Flt-3 group (p=0.2). Four pts (6%) required 2 cycles of induction for response. Induction mortality was in 3 pts (4%). No excess toxicity was observed compared to standard Ida and Ara-C therapy. With a median follow of 6.7 (0.9 to 19.4) months: OS was 15.7 months (range 0.7 to 19.4) (64% at 1 year), remission duration (RD) 9.5 months (0-18.2) and EFS 10.2 (0.7-19.4). For diploid pts, OS was 17.7 (0.9 to 19.4), RD NR (0.7 to 14.1) and EFS NR (0.9-19.4). In pts with other CG alterations was OS was 11.7 (0.7-18.9) (p=0.3); RD 8.3 (0.7-14.1), p=0.05, and EFS 8.5 (0.7 to 15), p=0.05. Probability of survival at 1 year was 73% for diploid and 58% for others. For Flt-3+ OS was 18.2 (1.4 to 18.2) vs. 15.7 (0.9-19) in wt Flt-3 (p=0.4), RD NR (0.2 to 16.6) vs 9(0-14.5) months in wt and EFS NR vs 10.2 (0.9-15-7) in wt (p=NS). OS at 1 year was 91% for Flt-3+ vs. 60% for wt Flt-3. Induction of histone H3 acetylation on day 3 was documented in only 2 of 15 (13%) pts. Beclin, a marker of autophagy, was expressed at baseline in all 15 cases analyzed. Sequential gene expression of Nrf2, CYBB, FoxO3, SOD1,2 and GST-pi was measured sequentially by Q-PCR. No activation of any of these genes was observed with therapy. Biomarkers of DNA repair (H2AX) are ongoing. Conclusion: The combination of Ida-A Vor is safe in pts with AML/MDS. ORRs are very high with this combination, particularly in diploid and Flt-3 ITD pts. Longer follow up is needed to assess effect on survival. Studies specific for Flt3 mutated pts and in combination with standard “7+3” therapy are ongoing. Disclosures: No relevant conflicts of interest to declare.

A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7116-7116 ◽  
Author(s):  
Selina M. Luger ◽  
Casey Lee O'Connell ◽  
Virginia Klimek ◽  
Maureen A. Cooper ◽  
Emmanuel C. Besa ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Single Agent ◽  
Risk Category ◽  
Open Label ◽  
Prior Therapy ◽  
Hodgkin's Lymphomas

7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + marrow-CR + PR + SD) was 80% (16/20). Ten patients (50%) had baseline marrow blast counts ≥10% (protocol-defined high risk). Responses in high-risk patients included 5 (50%) with CR + marrow-CR and 2 (20%) with SD. Six patients (30%) had an on-treatment marrow blast count of 0. These included 3 patients in the high-risk category, with baseline blast counts of 11%-15%. CR was observed in one patient, a 74-yr-old male with previously untreated RAEB. In this patient, marrow blasts fell from a baseline of 11% to 0% following 1 cycle of treatment; CR with normalization of all cell lines was achieved by late Cycle 3. He remained on study for 1 yr. Most drug-related AEs in the study were grade 1 or 2. The most common drug-related grade 3/4 events were nausea (15%), vomiting, fatigue, anemia, thrombocytopenia and febrile neutropenia (10% each). There was one death (5%), due to pneumonia that was not felt by the investigator to be drug related. Conclusions: The combination of mocetinostat and 5-azacitidine in patients with MDS demonstrated an acceptable safety profile and encouraging evidence of clinical benefit. Further clinical studies are warranted. Clinical trial information: NCT00324220.

Effects of Ofloxacin Administration on the Reliability of Urine Glucose Testing

1996 ◽  
Vol 30 (5) ◽  
pp. 469-472
Author(s):  
Tsong-Mei Tsai ◽  
Brian F Shea ◽  
Paul F Souney ◽  
Fred G Volinsky ◽  
Joseph M Scavone ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Tertiary Care ◽  
Urine Samples ◽  
Care Hospital ◽  
Open Label ◽  
Urine Glucose ◽  
Glucose Testing

OBJECTIVE: TO study the effects of ofloxacin on the reliability of urine glucose testing. DESIGN: Open-label, nonrandomized. SETTING: A university-affiliated tertiary care hospital, ambulatory clinic. PARTICIPANTS: Ten healthy volunteers (8 men and 2 women) aged 22-39 years. MAIN OUTCOME MEASURES: Phase I (in vitro) involved the addition of selected amounts of ofloxacin to a set of standard 50-mL urine samples prepared to simulate glycosuria. Phase II (in vivo) involved the oral administration of ofloxacin 400 mg to 10 subjects. Urine was collected: (1) immediately predose, (2) pooled 0–4 hours postdose, and (3) pooled 4–8 hours postdose. Known glucose concentrations were then added to these samples. Clinitest and Diastix tests were performed on all samples. The accuracy of these tests in determining glucose concentrations was compared among urine samples taken before and after ofloxacin dosing. RESULTS: None of the ofloxacin concentrations in phase I (0,25,50, 100, 200,400, and 800 μg/mL) influenced these testing methods at the urine glucose concentrations of 0.0%, 0.5%, 1%, and 2%. Likewise, the accuracy of these two tests was unaffected by ofloxacin administration in phase II. CONCLUSIONS: In single-dose administration, ofloxacin does not interfere with Clinitest or Diastix for determining urine glucose concentrations. Supported by a grant from the RW Johnson Pharmaceutical Research Institute. Presented in abstract form at the American College of Clinical Pharmacy 1994 Winter Practice and Research Forum, February 6–9, 1994, San Diego. CA.

scholarly journals Production of interleukin-1 by bone marrow myeloma cells

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 380-387 ◽  
Author(s):  
F Cozzolino ◽  
M Torcia ◽  
D Aldinucci ◽  
A Rubartelli ◽  
A Miliani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Interleukin 1 ◽  
Long Bone ◽  
Bone Lesions ◽  
Normal Donor ◽  
Biologic Activity ◽  
Culture Supernatants

Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT- specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti- IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.

scholarly journals Postoperative XELOX therapy for patients with curatively resected high-risk stage II and stage III rectal cancer without preoperative chemoradiation: a prospective, multicenter, open-label, single-arm phase II study

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Tsunekazu Mizushima ◽  
Masataka Ikeda ◽  
Takeshi Kato ◽  
Atsuyo Ikeda ◽  
Junichi Nishimura ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
High Risk ◽  
Local Recurrence ◽  
Phase Ii ◽  
Group Performance ◽  
Phase Ii Study ◽  
Preoperative Chemoradiation ◽  
Stage Ii ◽  
Stage Iii ◽  
Open Label

Abstract Background Preoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer. Methods We performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stage II and stage III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and capecitabine (2000 mg/m2/day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS). Results Between August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29–77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of ‘0’ and 14 had scores of ‘1’. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8–78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7). Conclusions Postoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides adequate 3-year DFS prospects. Trial registration This clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.

IgM Multiple Myeloma: A Rare Subtype Highly Sensitive to Lenalidomide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5220-5220
Author(s):  
Alvaro Moreno-Aspitia ◽  
Antony Charles ◽  
Tejal Patel ◽  
Celine Bueno ◽  
Abba Zubair ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transient Response ◽  
Low Dose ◽  
Plasma Cells ◽  
Poor Response ◽  
Response To Therapy ◽  
Bone Lesions ◽  
Best Response ◽  
M Spike

Abstract Background: IgM multiple myeloma (MM) are very rare plasmaproliferative disorders representing 0.5–1.2% of all cases of MM and &lt; 0.2% of all IgM monoclonal gammopathies. Clinical criterion are not always helpful in differentiating IgM MM from Waldenstrom macroglobulinemia. However, the presence of lytic bone lesions, absence of lymphadenopathy and/or hepatosplenomegaly, presence of translocation of the immunoglobulin heavy chain locus at 14q32 [t(11;14), t(14;16), t(4;14)], and strong expression of CD138 by the plasma cells are useful in the diagnosis of IgM MM. It has been our experience and of others that these cases have an aggressive behavior at presentation, shorter survival than IgG and IgA MM and poor response to therapy for lymphoplasmacytoid lymphomas. We present here 2 cases of IgM MM with a dramatic response to Lenalidomide and low dose dexamethasone (Rev/Dex) Results: Baseline patient characteristics at time of diagnosis of IgM MM and therapy outcome are presented in the following 2 tables: Table 1. Case 1 2 Age and sex 72 (F) 73 (F) Serum M-spike (g/dL) 5.3 6.2 Urine M-spike (mg/dl/24 hrs) 72 412 Serum IgM (mg/dL) 8,590 11,000 BM plasma cells percentage 90 20 Plasma cell immunophenotyping CD138+++, partial CD20, CD56− CD138+++, partial CD20, CD56− Cytogenetics (Standard and/or FISH) Standard: normal FISH: not done on initial biopsy. On follow up there were insufficient number of plasma cells to perform test Standard: of 20 metaphases, 6 had a complex hypotetraploid karyotype with relative loss of 13q, 14, 15, 16, 20, and 22, and numerous unbalanced rearrangements. FISH: a plasma cell clone with monosomy 13 and IGH/c-MAF fusion, t(14;16). In addition, approximately 60% of plasma cells had a tetraploid clone with the same anomalies as well as relative loss of p53 Bone lesions Multiple non-traumatic spinal fractures and of stenum Several lytic lesions of long bones Renal insufficiency No No Anemia (Hbg g/dL) Yes (8.7) Yes (8.1) Hypercalcemia (Ca mg/dL) Yes (12.5) Yes (11.4) Beta 2 microglobulin (mg/dL) 5.79 8.51 Serum viscosity (cpoise) 5.9 4.8 Table 2. Best Response to therapy Case Therapy Best Response Comments 1 Rituxan, then Fludarabine based therapy Transient response Rapid progression after partial and transient response to each therapy 1 Lenalidomide + LD-Dex sCR after cycle #6. Currently on CR 18 months later IgM declined from 8,590 to 43 mg/dL after 4 cycles of Rev/Dex. 2 Lenalidomide + LD-Dex VGPR after cycle #2 IgM declined from 11,000 to 463 mg/dL after cycle 3. Complete disappearance of M-spike in serum; BM to be done after cycle #4 Conclusions: This is the first report that we are aware of a rapid and dramatic response to lenalidomide and low dose dexamethasone in these rare cases of IgM MM with poor response to NHL-type treatment. Lenalidomide-based therapy might abrogate poor prognosis cytogenetics in this unusual subtype of MM (case #2), however, follow up for this patient is still very short.

Prolonged Administration of Azacitidine with or without Entinostat Increases Rate of Hematologic Normalization for Myelodysplastic Syndrome and Acute Myeloid Leukemia with Myelodysplasia-Related Changes: Results of the US Leukemia Intergroup Trial E1905

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 601-601 ◽  
Author(s):  
Thomas Prebet ◽  
Steven D. Gore ◽  
Zhuoxin Sun ◽  
Peter L. Greenberg ◽  
Mark Juckett ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Histone Deacetylase Inhibitors ◽  
Response Rate ◽  
Median Number ◽  
Primary Objective ◽  
Prolonged Administration ◽  
Current Standard ◽  
The Us

Abstract Abstract 601 Background: The current standard of treatment for high risk myelodysplastic syndromes (MDS) is azacitidine (AZA) administered 75mg/m2/d days 1 – 7 (525 mg/m2/cycle) each 4 weeks. This approach improves survival; however, many AZA-treated patients (pts) continue to require blood products. The US registration trial (CALGB9221 trial; Silverman JCO 2002 and JCO 2006) showed a trilineage response rate (CR plus PR plus trilineage hematologic improvement [TL], IWG 2000) of 15%. Histone deacetylase inhibitors (HDACi) synergize with azanucleosides in vitro to re-express genes silenced through promoter methylation. In a previous phase I pilot study (J0443 study, NCT00101179), we showed that the combination of AZA and the orally bioavailable HDACi entinostat (MS-275) was effective and tolerable for pts with MDS and AML with myelodysplasia-related changes. The recommended Phase II schedule was AZA 50 mg/m2/d s.c. for 10 days (500 mg/m2/cycle) and entinostat 4 mg/m2/d PO on day 3 and day 10 of AZA on a 28 days cycle basis. Methods: E1905 US Leukemia Intergroup study (NCT00313586) is a phase II 1:1 randomized trial of AZA (50 * 10)+ entinostat (arm B) vs AZA (50 * 10) alone (arm A). Following six cycles of treatment, pts with documented clinical response (IWG 2000: CR, PR or TL) continued for the lesser of a total of 24 cycles or disease progression. The primary objective was to determine whether either arm significantly increased the rate of hematologic normalization (HN: CR + PR + TL) compared to CALGB9221 results (i.e. 15% to 30%). Patients were stratified according to the type of disease (i.e. MDS low risk vs MDS high risk vs CMML vs AML). Results: 150 pts were accrued and 136 analyzed (13 ineligible; 1 death before treatment), including 88 MDS, 5 CMML and 43 AML. Median age was 72 years. Poor risk cytogenetics were found in 31% of the patients. IPSS Int-2/High risk patients represented 72% (n=63) of the MDS cohort. There was no difference in pts characteristics between the 2 arms. The median number of administered cycles was 6 (range: 1–24). Toxicities in both arms were acceptable with a trend to an increase in grade IV platelet adverse events in Arm B (63% vs 46%, p=0.07) and grade III-IV fatigue in arm B (23% vs 13%, p=0.13). Overall HN rate was 28%: 10% CR, 8% PR and 10% TL. The HN rates by arm were A: 31% (12/9/10); B 24% (7/7/10) (p=NS). Non-trilineage hematologic improvement was achieved in an additional 12% of pts in arm A and 19% of pts in arm B; thus, total hematologic response was 43% and 44%. The median time to best response was 6 months in both arms (range: 1–14); median duration of response was 11 months (range: 1–18) in arm A and 10 months in arm B (range: 2–19, p=NS). With a median follow-up of 17 months, median overall survival was 18 months in arm A and 13 months in arm B (p=0.15). Conclusions: The rate of hematologic normalization in response to AZA 50 mg/m2/day * 10 in Arm A was twice that observed in C9221. The addition of entinostat examined in E1905 did not improve the response rate. Confirmation of improved response following prolonged administration of lower daily doses of AZA will require direct comparison to the currently approved dose regimen. Disclosures: Gore: Celgene: Consultancy, Research Funding, stock options; Syndax: Consultancy.

Thalidomide in Advanced Mastocytosis. Results from an Open-Label, Multicentric, Phase II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1754-1754
Author(s):  
Berengere Gruson ◽  
Olivier Lortholary ◽  
Danielle Canioni ◽  
marie-Olivia Chandesris ◽  
Fanny Lanternier ◽  
...  
Keyword(s):  
Mast Cell ◽  
Missing Data ◽  
Phase Ii ◽  
Conflicts Of Interest ◽  
Phase Ii Study ◽  
Single Agent ◽  
Open Label ◽  
Effective Response ◽  
Kit Mutation ◽  
Tryptase Level

Abstract Abstract 1754 Background: Mastocytosis is characterized by the abnormal accumulation of mast cells in various tissues responsible for organ failure and/or systemic symptoms that can be disabling and alter the quality of life (QOL). Beside symptomatic treatments, cytoreductive drugs such as a-interferon, purine analogs and to a less extent imatinib mesylate (in case of c-kit mutation other than D816V) and masatinib were shown to be effective but rare complete or long-term remissions were obtained. Thalidomide is an anti-angiogenic immuno-modulatory and anti-inflammatory drug that has preliminary been shown to have an activity in aggressive systemic mastocytosis (ASM) (Damaj et al, BJH 2008). We report the result of a multicentric, open-label, phase II study using thalidomide as a single agent in advanced SM (NCT00769587). Patients and Methods: Twenty patients (pts) were enrolled (1 missing data): smoldering systemic (SSM, n=9), ASM (n=6) and with an associated clonal hematologic non mast cell lineage disease (SM-AHNMD, n=4). Infiltrated organs were bone marrow (n=16), skin (n=14), splenomegaly (n=10), hepatomegaly (n=6), intestinal tract (n=6), lymph nodes (n=1). Median serum tryptase level at inclusion was 83.4 ng/L (range 5.3–775) and all patients except one carried the c-kit D816V mutation. Patients presented with anemia (n=6), thrombocytopenia (n=6) and neutropenia (n=1). Four patients were excluded, 1 for missing data and 3 were not evaluable. Thalidomide was administered orally at a starting dose of 50 mg/day and was progressively increased up to 200 mg/day or appearance of side effects. The duration of treatment was 6 months (1 cycle= 1 month). Responder patients may continue on thalidomide for a maximum of 12 months or progression. Primary objective was to determine the effective response rate by assessing the tumor burden. Secondary objectives were to assess the tolerance of thalidomide and to evaluate the QOL, depression (Hamilton score), pruritis, and handicap (Afirmm V2 score) related to mast cell disease. Results: Sixteen pts [7 males, 9 females; median age 65 years (range 43–76)] who received at least one cycle of thalidomide were analyzed. The median number of thalidomide cycles was 6 (range 1–20) and the median dose received was 100mg/d. Partial response was obtained in 9 pts (56%), 4 pts remained stable (25%) and 3 pts progressed (19%). Pruritis score decreased significantly from 6.5 (95% CI 4.74–12.26) to 4 (95% CI 0–5.25) (p=0.03); the Afirmm score tended to improve from 116.5 (95% CI 55.0–168.3) to 92.5 (95% CI 37.4–131.2) (p=0.38) with no improvement of QoL and Hamilton scores, median tryptase level or cytopenia. Skin infiltration disappeared only in 2 of 14 patients concerned. Treatment discontinuation was due to failure in 4 pts, side effect in 2 pts and patient's decision in 2. Thalidomide was continued in five pts as a maintenance therapy for a median duration of 6 mo (4–14). The most relevant toxicities (grade 3–4) consisted in peripheral neuropathy (12.5%) and myelosuppression (18.7%). Conclusions: Thalidomide is an acceptable and effective treatment in advanced SM. Disclosures: No relevant conflicts of interest to declare.

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