Rituximab in Refractory Idiopathic Thrombocytopenic Purpura (ITP).

Abstract Background. Rituximab, a chimeric anti-CD20 monoclonal antibody effective in B-cell depletion, may be useful in autoimmune disorders by interfering with the production of auto-antibodies. Aims. To investigate the efficacy of Rituximab in patients with resistant ITP. Patients and Methods. Fourteen adult ITP patients (3 males, 11 females; median age 44.5 years [21.1–67.6]) were treated with Rituximab (375 mg/m2/weekly for four doses). The median time between diagnosis and start of Rituximab was 2 years (0.2–33.1 months). All patients had already received at least two lines of therapy (median 3; 2–6): prednisone, pulsed high-dose dexamethasone, azathioprine, immunoglobulins, interferon or splenectomy. At the start of Rituximab, the median platelet count was 10 x 109/L (3–20 x 109/L). Response definitions: complete response (CR), platelet count ≥150 x 109/L; partial response (PR), >50 <150 x 109/L; minimal response (MR), >20 ≤50 x 109/L; no response (NR) ≤20 x 109/L. After completing therapy, patients were evaluated for platelet count after 1 and 3 months, and thereafter every 3 months until relapse or start of a different treatment. Peripheral blood B lymphocytes were evaluated by flow-cytometry as CD19+ cells before treatment, 1 and 3 months after stopping therapy, and then every 3 months up to recovery. Results. One month after Rituximab therapy, 7 responses (2 CR, 4 PR, 1 MR; 50%) and 7 NR (50%) were observed. Two relapses occurred 5 and 18 months after response. The median follow-up of all treated patients is 6 months (1.8–34.6), while the median follow-up of all responsive patients is 6.1 months (2–18.7). Before starting therapy, 11/14 cases were evaluable for flow-cytometry studies. The median baseline value of peripheral blood CD19+ B cells was 137 x 106/L (58–476). One month after completing therapy, 7/9 evaluable cases showed absence of CD19+ cells and 2/9 showed a count of 9 and 4.4 x 106/L CD19+ cells, respectively. At the last available control (median follow-up of 6.8 months; 1.9–32.5), 11/14 evaluable patients had still not recovered the baseline CD19+ cell count (median value: 5.5 x 106/L; 0–287). The following side effects were observed: 1 case of papulosquamous dermatitis, 2 cases of fever. Conclusions. Seven out of 14 (50%) ITP patients had an early response to Rituximab (2 CR, 4 PR, 1 MR), that persisted in 5 cases. No late responses were observed. The response was independent of the post-therapy CD19+ cell numbers. No serious infections were observed during the clinical follow-up. No patient had to stop therapy because of severe side effects.

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Eltrombopag and High-Dose Dexamethasone As First Line Treatment For ITP

Blood ◽

10.1182/blood.v122.21.3544.3544 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3544-3544

Author(s):

David Gomez-Almaguer ◽

Miguel Angel Herrera-Rojas ◽

Andres Gomez-de Leon ◽

Olga Graciela Cantú-Rodríguez ◽

Cesar H Gutiérrez-Aguirre ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

High Dose ◽

Line Treatment ◽

Front Line ◽

First Line ◽

High Dose Dexamethasone ◽

Line Therapy ◽

First Line Treatment

Abstract Introduction Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder that involves antibody and cell mediated destruction of platelets as well as suppression of their production. Prednisone is the initial standard therapy in adults1. High-dose dexamethasone as front-line therapy given as pulses of 40 mg per day for 4 consecutive days, was effective in 85% of patients, nevertheless, 50% relapsed within six months2. The prices of ITP drugs for 1 month of treatment in an adult range from prednisone; $16, eltrombopag; $5,934, intravenous immune globulin (IVIG) (80 g); $9,648, to rituximab (2 g); $15,5963. Only prednisone/dexamethasone and eltrombopag are available in oral presentation, for this reason, ambulatory treatment is an alternative for these patients. The trombopoietin receptor agonists are effective for the treatment of patients with chronic ITP, although response is dependent on continued administration. Eltrombopag is a small molecule agonist of the c-mpl (TpoR) receptor, which is the physiological target of thrombopoietin. This drug effectively raises the platelet count in adult patients (aged 18 years and over) as second/third line therapy, that is for patients refractory to corticosteroids and IVIG who have had their spleen removed or when splenectomy is not an option4. Our group, as well as others, has previously sought to improve response rates in these patients, particularly with the use of rituximab5, 6. To our knowledge neither eltrombopag nor romiplostim have been used as front line therapy in ITP, therefore the purpose of this study was to assess the efficacy of eltrombopag and dexamethasone in this setting. Patients and Methods This was a prospective, phase 2 study, using the combination of eltrombopag (50 mg PO once a day for 4 weeks) and high-dose dexamethasone (40 mg PO days 1,2,3,4) in untreated adult patients with immune thrombocytopenia or in patients with less than 7 days of treatment with corticosteroids. Complete response (CR) was defined as an increase in platelet count >100×109/L. Partial response (PR) was defined as an increase in the platelet count greater to 30 ×109/L according to standard criteria. Duration of response was considered from the day of initial administration to the first time of relapse (platelet count <30×109/L). Results Twelve consecutive patients were enrolled from June 2012 to June 2013, 6 women and 6 men. The median age at diagnosis was 50 years (range, 20 - 80 years). The median platelet count at diagnosis was 7 x 109/L (range, 2 - 29 x 109/L). Patients were followed for a median of 2.5 months (range 1.1 - 13). After steroid treatment at day +5, ten patients had responded (83.3%), five had achieved CR (41.7%), and five PR. After completing treatment with eltrombopag at day +34, all patients responded (100%), nine patients achieved CR (75%) and three PR (25%). Two patients relapsed in a median time of 39.5 days (range, 30.1 - 49), both regaining CR after treatment with another high-dose dexamethasone course and low-dose rituximab (4 doses of 100 mg every week). At 3 months follow-up 66.7% remained in CR and 33.3% in PR (n=6). At 6 months follow-up two patients remained in CR and two in PR (n=4). Time to best response achieved was 34 days from diagnosis (range, 19 – 64.1). At the end of follow-up 9 patients (75%) remained in CR and 3 patients in PR (25%). Total treatment cost per patient was $1,640 approximately. Conclusion Currently the initial treatment of ITP patients is based on prednisone or high dose dexamethasone with or without IVIG. This approach is associated with high cost and high relapse rate. The results from our pilot study suggest that high dose dexamethasone and eltrombopag are very effective as first line treatment for acute ITP in adults. This treatment is ambulatory, affordable and well tolerated; however, we still don't know if this approach will have a favorable impact on the relapse rate of this disease. Disclosures: Off Label Use: Eltrombopag as first line treatment for ITP.

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Prevalence of Large Granular Lymphocyte Proliferation in Chronic Myeloid Leukemia (CML) Patients Treated with Dasatinib.

Blood ◽

10.1182/blood.v114.22.1111.1111 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1111-1111

Author(s):

Jason Valent ◽

Charles A. Schiffer

Keyword(s):

Flow Cytometry ◽

Side Effects ◽

Peripheral Blood ◽

Chronic Phase ◽

Cell Transplant ◽

Pleural Effusions ◽

Blast Phase ◽

Number Of Patients ◽

Dasatinib Treatment

Abstract Abstract 1111 Poster Board I-133 Dasatinib is a potent inhibitor of the BCR-ABL tyrosine kinase which is effective in the treatment of imatinib refractory CML. While hematologic toxicities of neutropenia and thrombocytopenia are well known, large granular lymphocytosis has been reported in only a small number of patients without prior allogeneic stem cell transplant treated with dasatinib for CML. During routine follow up of leukocyte counts in 15 consecutive patients (age range 27-77 years) treated with dasatinib, 4 patients (2 chronic-phase, 1 accelerated phase with clonal cytogenetic progression, 1 blast-phase) developed a lymphocytosis (> 3800/mm3). Peripheral blood smear and peripheral blood flow cytometry revealed a population of large granular lymphocytes (LGLs) expressing CD3, CD8, CD57, and variable expression of CD56. Lymphocytosis was first noted between 1 and 9 months after initiation of dasatinib and has persisted in 3 of the patients with a median follow up of 33 months from the onset of lymphocytosis. Peak absolute lymphocyte count ranged from 5000/mm3 to 6900/mm3 and approximately 40 to 60% of the lymphocytes were LGLs by flow cytometry with the remainder being predominantly T lymphocytes. These 4 patients with LGL lymphocytosis have all have major molecular responses and the patient with blast-phase has remained in a complete cytogenetic remission with a major molecular response 44 months after initiation of dasatinib. The 11 other patients (6 chronic-phase, 2 accelerated-phase, 3 blast-phase) treated with dasatinib for CML have not developed lymphocytosis. These patients have been followed for a median of 25 months (range 3-50 months) although some were treated with dasatinib for a relatively short period of time because of poor response of their advanced CML. Review of the peripheral blood smears from 3 of the 6 chronic phase patients without lymphocytosis who remain on dasatinib treatment did not reveal any LGLs. All of these 6 patients have had complete, sustained cytogenetic responses. A persistent pleural effusion developed in the blast phase patient with lymphocytosis approximately 12 months after lymphocytosis developed; no significant side effects were noted in the other 3 patients although one remains thrombocytopenic. Pleural effusions developed in 2 of the 6 patients without lymphocytosis who remain on dasatinib treatment. Previous reports have suggested an increased incidence of “inflammatory” type side effects such as pleural effusions and pneumonitis in patients with dasatinib related LGL proliferation, although the small number of patients in this series precludes analysis of this association. In summary, LGL proliferation was detected in a minimum of 27% of dasatinib recipients and may be associated with a beneficial response. While the mechanism of LGL proliferation has not been fully explained, it has been suggested that dasatinib mediated inhibition of immunoregulatory kinases such as Src is permissive of LGL proliferation. Further evaluation of the frequency and clinical impact of this phenomenon in the large clinical trials of patients treated with dasatinib is warranted. Disclosures Schiffer: Bristol Myers: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Eltrombopag, Low-Dose Rituximab, and High-Dose Dexamethasone Combination for Patients with Newly Diagnosed Immune Thrombocytopenia: A Pilot "Total Therapy" Study

Blood ◽

10.1182/blood.v128.22.1369.1369 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1369-1369

Author(s):

David Gomez-Almaguer ◽

Olga Cantu-Rodriguez ◽

Cesar Homero Gutierrez-Aguirre ◽

Jose Carlos Jaime-Perez ◽

Luz C. Tarin-Arzaga ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Low Dose ◽

Complete Response ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

High Dose Dexamethasone ◽

Frontline Therapy

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune disorder that results from platelet destruction and production suppression. Frontline-therapy includes corticosteroids, intravenous immune globulin or anti-D immunoglobulin. Single-agent treatments have not been successful in inducing prolonged remission, as relapse will occur in approximately 50% of patients. Low-dose rituximab (100 mg) has been used for the treatment of ITP, showing an activity almost similar to the 375 mg/m2 standard dose. We and others have reported sustained response rates ranging from 58% to 76% using rituximab plus dexamethasone as a frontline therapy. Eltrombopag is a thrombopoietin nonpeptide mimetic that has been shown to raise platelet count in chronic ITP, and we have previously reported eltrombopag/dexamethasone as a feasible frontline therapy for ITP reaching 100% response rates.The lack of sustained response in many adult patients with newly diagnosed acute ITP has stimulated the search for a treatment that modifies the natural course of the disease. Objetive: We aim to evaluate efficacy, safety, and response duration of low-dose weekly rituximab (100 mg weekly, four doses) plus high-dose dexamethasone (40 mg PO, days 1-4) in combination with eltrombopag (50 mg, days 1-28) as frontline therapy in newly diagnosed primary ITP in an ambulatory setting. Methods: This is an ongoing open-label, single-arm study performed in patients with newly diagnosed ITP from the Hospital Universitario Dr. Jose Eleuterio Gonzalez in Monterrey, Mexico (Clinical trials.gov NCT02834286). Eligible patients are 16 years or older, with bleeding manifestations and/or a platelet count ²30×109/L, without previous treatment. Patients are excluded if they had active infection, pregnancy, or a malignant disease. A complete blood count is performed at baseline, on days 3, 5, 7 and then weekly for 28 days, monthly until month 6, and every 3 months thereafter. Partial and complete responses are defined as an increase in platelet counts ³30×109/L and ³100×109/L, respectively. Results: Ten consecutive patients have been enrolled from March 2015 until July 2016. Median age was 37 years (16-61). Six patients were women (60%) and four were men (40%). Median platelet account at diagnosis was 7 « 109/L (range 1.2-28). Median follow-up has been 7 months (range 1-13). All patients achieved at least a partial response (PR) at a median of 4 days (range 3-14). Complete response (CR) was achieved in 9 patients in a median of 7 days (7-22); all of them were still in CR at the end of treatment (Day 28). One patient lost response at 28 days and received a second high-dexamethasone course maintaining CR. No significant adverse effects have occurred during treatment, only 1 patient reported mild myalgia. No relapses have been documented until now.Currently, 8 patients remain in CR and 2 in PR. Conclusion:This is the first trial evaluating the response of low-dose rituximab in combination with eltrombopag and high-dose dexamethasone in newly diagnosed patients with ITP.Low-dose rituximab in combination with eltrombopag and high dose dexamethasone is a feasible frontline therapy for ITP. This drug combination showed high response rates achieved very rapidly, with a low incidence of side effectsand might represent an attractive option in patients with ITP and substantial bleeding. Table Characteristics and follow-up of patients M: Male, F: Female, CR: Complete Response, PR: Partial Response Table. Characteristics and follow-up of patients. / M: Male, F: Female, CR: Complete Response, PR: Partial Response Disclosures Gomez-Almaguer: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Tacrolimus Plus High-Dose Dexamethasone Versus High-Dose Dexamethasone Alone As First-Line Treatment for Adult Immune Thrombocytopenia: The Phase 2, Open Label, Randomized Trial (TARGET 020)

Blood ◽

10.1182/blood-2021-152111 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 13-13

Author(s):

Zhuo-Yu An ◽

Ye-Jun Wu ◽

Yun He ◽

Xiao-Lu Zhu ◽

Hong-Xia Shi ◽

...

Keyword(s):

Platelet Count ◽

Combination Group ◽

High Dose ◽

Line Treatment ◽

Monotherapy Group ◽

First Line ◽

Open Label ◽

High Dose Dexamethasone ◽

First Line Treatment

Abstract Introduction Immune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders seriously endangering human health. Glucocorticoids and intravenous immunoglobulin are first-line treatments recommended by guidelines for patients with ITP. However, approximately 50%-85% of patients relapse during the first year of treatment. In addition, long-term use of glucocorticoids increases the risk for dose- and time-dependent glucocorticoid-related complications and serious side effects. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP are urgently needed. Tacrolimus is a calcineurin inhibitor, which forms a complex by binding to FK506-binding protein. It is currently widely used in the prevention of graft-versus-host disease for organ transplantation as well as for the treatment of autoimmune diseases. In addition to recent retrospective studies and case reports demonstrating its effectiveness in ITP, tacrolimus has been shown to improve anti-platelet antibody-mediated thrombocytopenia in mice, suggesting it may be a potential treatment for ITP. The aim of this study was to compare two first-line treatment options for ITP-a standard glucocorticoid-only regimen versus tacrolimus in combination with a standard glucocorticoid regimen-to determine which could help patients achieve stable platelet counts faster and experience a longer duration of remission. Methods This open-label, randomized, phase 2 trial, enrolled adult ITP patients from seven different tertiary medical centers in China. Elderly patients had confirmed, newly diagnosed, treatment-naive ITP, platelet counts <30×10 9/L, or < 50×10 9/L and significant bleeding symptoms (World Health Organization bleeding scale ≥ 2). Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral tacrolimus (initial 0.03 mg/kg/day and maintain blood concentration at 3-5 ng/mL for 12 weeks) plus high-dose dexamethasone (HD-DXM) or HD-DXM monotherapy for 12 weeks. DXM (40 mg) was administered orally daily for 4 consecutive days to both study arms. The 4-day course of DXM was repeated on days 11-14 in patients who lacked response by day 10. The primary endpoint was 6-month sustained response (SR), defined as platelet count maintained >50×10 9/L without any additional ITP-modifying therapy at the 6-month follow-up. Key secondary endpoints included initial response by day 14 (OR, platelet count ≥30×10 9/L and at least 2-fold increase in baseline platelet count and absence of bleeding; and CR, platelet count ≥ 100×10 9/L), duration of response, bleeding scores, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04747080). Results Total 140 patients newly diagnosed with ITP were randomly assigned to either the tacrolimus plus HD-DXM (n=72) or HD-DXM monotherapy (n=68) groups. At the 6-month follow-up, the proportion of patients exhibiting SR was significantly higher in the tacrolimus plus HD-DXM group than in the HD-DXM monotherapy group (65.3% vs 42.6%, p= 0.007). Of the 140 patients with ITP (males accounted for 48.6%), the mean age was 32.8 years, the mean platelet count was 16.7×10 9/L. The combination group exhibited a higher 14-day early remission rate than the monotherapy group (76.4% vs 55.9%, P=0.001). Significantly fewer treatment failures occurred in patients randomly assigned to the combination group(19.4% vs 38.2%, P=0.0014). During the follow-up period, fewer patients in the combination group experienced relapse than in the monotherapy group; the median time to relapse was 77 days (Tacrolimus+HD-DXM) vs 36 days (HD-DXM). The combination group exhibited a lower proportion of bleeding events and a lower bleeding score. The incidence of serious AEs, rescue therapy, and treatment side effects were similar between the two groups, and treatment was well tolerated by all patients, with no grade 4 AEs or treatment-related deaths reported. There was no statistically significant difference in the incidence of treatment-related AEs between the two groups. Conclusions Low-dose tacrolimus plus HD-DXM was an effective and safe treatment for ITP as first-line therapy and elicited a sustained prolonged response in adults. This therapy may be a new treatment option for adult patients with ITP. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: It includes information or discussion of off-label drug use of tacrilimus.

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Phase I/II Study of Myeloablative Anti-CD20+ Radioimmunotherapy with I-131-Rituximab in High-Risk CD20-Positive Non Hodgkin Lymphoma

Blood ◽

10.1182/blood.v120.21.3700.3700 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3700-3700

Author(s):

Kathleen Schwarz ◽

Wagner Julia ◽

Susanne Schreiber ◽

Burkhard Schmidt ◽

Alexander Hoellein ◽

...

Keyword(s):

Overall Survival ◽

Response Rate ◽

Complete Response ◽

High Dose Chemotherapy ◽

High Dose ◽

Non Hodgkin Lymphoma ◽

Grade 3 ◽

Anti Cd20

Abstract Abstract 3700 Background: Radioimmunotherapy (RIT) has been successfully used to treat primary and relapsed/refractory CD20+ Non-Hodgkin-Lymphoma (NHL). Myeloablative anti-CD20 RIT allows delivering high radiation doses to lymphoma sites when followed by autologous stem cell infusion (autoSCT). However, RIT is infrequently used at present and long-term data is lacking. Patients, Design and Methods: 23 patients with relapsed/refractory CD20+ NHL who did not achieve a complete response to salvage chemotherapy were enrolled in this Phase I/II trial to evaluate RIT with 131I-labelled Rituximab (131I-R) in a myeloablative setting between January 2000 and October 2004. Biodistribution and dosimetry studies were performed in all patients to determine 131I activity required to induce a total body dose of 21 to 27 Gy to the critical organs lung and kidney. In 6/23 patients RIT was combined with high dose chemotherapy (HD-CTx) followed by autoSCT. 8/23 patients received a sequential HD-CTx with a second autoSCT. The median follow-up is 9.5 years. Results: 188–525 mCi 131I were delivered to achieve the limiting organ dose. No grade 3/4 non-hematologic toxicity was seen with RIT alone. Significant grade 3/4 toxicity (mucositis, neutropenic fever, pneumonia, sepsis) including one therapy related death was observed in all patients treated with RIT combined with HD-CTx/autoSCT. The overall response rate was 87% (64% complete response rate). The median progression free (PFS) and overall survival are 47.5 and 101.5 months. After long-term follow up, 9 patients are progression free and 10 patients are alive. An elevated (>1) international prognostic index (IPI) was most predictive for overall survival. Conclusion: Myeloablative 131I-Rituximab RIT followed by autoSCT is feasible, well tolerated and effective in high risk CD20+ NHL and prolongs PFS compared to last standard chemotherapy. Patients additionally treated with high dose chemotherapy experienced significantly increased toxicity. Long-term results for progression free survival and overall survival in this trial are encouraging. Disclosures: No relevant conflicts of interest to declare.

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Low-Dose Rituximab and High-Dose Dexamethasone As Front-Line Therapy in Adult Patients with Primary Immune Thrombocytopenia

Blood ◽

10.1182/blood.v120.21.3332.3332 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3332-3332

Author(s):

David Gomez-Almaguer ◽

Luz C. Tarin-Arzaga ◽

Brizio Moreno-Jaime ◽

Jose C. Jaime-Pérez ◽

Adrián A. Ceballos-López ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Low Dose ◽

Complete Response ◽

High Dose ◽

Newly Diagnosed ◽

Front Line ◽

High Dose Dexamethasone ◽

Line Therapy ◽

Primary Immune Thrombocytopenia

Abstract Abstract 3332 Introduction Corticosteroids are the initial standard therapy for primary immune thrombocytopenia (ITP). A short course of high-dose dexamethasone as initial therapy is an alternative to prednisone with high initial responses, but about half of the patients relapse. Low dose rituximab has been used in the treatment of relapsed ITP, showing a similar activity to the standard dose. The aim of this prospective study was to evaluate the efficacy, safety and response duration of low-dose rituximab plus short pulses of high-dose dexamethasone as front-line therapy in newly diagnosed ITP adults. Methods Patients ≥18 years old with newly diagnosed received dexamethasone, 40 mg/day/i.v. for 4 consecutive days (+1, +2, +3, +4), rituximab was administered at a fixed dose of 100 mg as an i.v. infusion weekly for 4 consecutive doses (days +1, +8+, +15 and +22). The use of rescue therapy was allowed, using the same schedule of dexamethasone, before day 30, but only if the platelet count was < 20×109/L. A complete blood cell count was performed at enrollment, weekly for the first 28 days, monthly until month 6 and then every 3 months. The degree of response was defined as follows: a complete response (CR) was a platelet count ≥ 100 × 109/L; a complete sustained response (CSR) was considered if it was maintained for six months. Partial response (PR) was defined as a platelet level between 50 and 100 × 109/L; an overall response (OR) was defined as partial or complete response. Patients with a platelet count <30 × 109/L were considered non-responders (NR). Time-to-response (TTR) and time-to-complete response (TCR) were also assessed, as well as the safety profile and side effects incidence according to the National Cancer Institute Common Toxicity Criteria version 3.0. Results Twenty-one consecutive patients were enrolled from December 2009 to December 2011 (17 women and 4 men); median age was 51 years (range, 18–82). The median platelet count at baseline was 5.19 × 109/L (range, 0.3–24.2 × 109/L). Patients were followed for a median of 12 months (range, 1–25). At day +28, sixteen patients (76.2%) had CR, three patients had PR (14.3%), with the OR being 90.5%. At month six, 16 of 21 patients (76.2%) had achieved CSR. Seven patients received a second course of dexamethasone (one at day +8 and six at day+15) (Table 1). The median duration of response was 12 months (range, 7–25 months). The median time to reach TTR and TCR was 8 days (range, 4–28). Partial response was achieved in two patients who were further treated with danazol and prednisone, being subsequently splenectomized. The relapse rate was 15.8%. The 6- and 12- month cumulative RFS were both 84%; the 6- and 12-month cumulative TFS probabilities were 94% and 87%, respectively (Fig. 1). Overall, combination therapy in our group was well tolerated with a lower incidence of adverse effects during infusion in this trial according to the data reported in previous studies. Conclusions The combination of low-dose rituximab and high-dose dexamethasone as front-line therapy for adults with ITP was effective and safe with a high OR rate and a low incidence of relapse. These data need to be confirmed in a prospective randomized clinical trial including a sample size with enough power to reach statistically significant conclusions. Disclosures: No relevant conflicts of interest to declare.

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Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial

Blood ◽

10.1182/blood-2006-08-036947 ◽

2007 ◽

Vol 110 (10) ◽

pp. 3557-3560 ◽

Cited By ~ 386

Author(s):

Paul G. Richardson ◽

Pieter Sonneveld ◽

Michael Schuster ◽

David Irwin ◽

Edward Stadtmauer ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Agent ◽

Response Duration ◽

Proteasome Inhibition ◽

Initial Response ◽

Complete Response ◽

High Dose ◽

High Dose Dexamethasone ◽

Protein Reduction

AbstractInitial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

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Combination of ATRA and High-Dose Dexamethasone As First-Line Treatment in Adult Immune Thrombocytopenia:a Randomized, Phase 2, Open-Label Trial

Blood ◽

10.1182/blood-2019-125242 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 899-899 ◽

Cited By ~ 1

Author(s):

Qiu-Sha Huang ◽

Yi Liu ◽

Jing-Bo Wang ◽

Jun Peng ◽

Ming Hou ◽

...

Keyword(s):

Platelet Count ◽

Combination Group ◽

High Dose ◽

First Line ◽

Open Label ◽

Platelet Counts ◽

High Dose Dexamethasone ◽

First Line Therapy ◽

Treatment Naïve

Introductions Immune thrombocytopenia (ITP) is an acquired thrombocytopenia caused by immune-mediated platelet destruction and impaired platelet production. As the immunosuppressive therapy, high-dose dexamethasone (HD-DXM) has been recommended as the standard first-line treatment. Nevertheless, approximately half of ITP patients relapse within 6 months and require further therapies. All-trans retinoic acid (ATRA) is a derivative of vitamin A that has an immunomodulatory effect on hemopoiesis. Our previous study demonstrated that ATRA could induce a more rapid and long-lasting response in patients with corticosteroid-resistant or relapsed ITP (Lancet haematology, 2017). In addition, we found that ATRA corrected impaired platelet production by regulating the complement-IL-1β loop and TNFAIP3/NF-κB/SMAD7 signaling pathway in ITP (Br J Haematol, 2018; Haematologica, 2019). These findings suggested that the addition of ATRA to HD-DXM in treatment-naive patients could improve sustained response rate based on the synergetic function. Here, we present the results of the first prospective, multicenter, randomized, controlled trial with the largest cohort to date comparing the efficacy and safety of HD-DXM plus ATRA vs HD-DXM as first-line therapy in newly diagnosed adult primary ITP patients. Methods In this open-label, randomized, phase 2 trial, we enrolled adult ITP patients from 6 different tertiary medical centers in China. Eligible subjects had confirmed newly-diagnosed, treatment-naive ITP; platelet counts <30×109/L or platelet counts < 50×109/L and significant bleeding symptoms (WHO bleeding scale 2 or above).Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral ATRA (10 mg twice daily) plus HD-DXM or HD-DXM monotherapy for 12 weeks. DXM was administered orally at 40 mg daily for 4 consecutive days to both arms. The 4-day course of dexamethasone was repeated on days 11 to 14 in the case of lack of response by day 10(Figure 1). The primary endpoint was 6-month sustained response (SR) defined as platelet counts maintained > 50×109/L without any additional ITP-modifying therapy at the 6-month follow up. Key secondary endpoints were initial response by day 14 (OR: platelet count ≥30×109/L and at least 2-fold increase of the baseline platelet count and absence of bleeding; CR: platelet count ≥100×109/L), duration of response (DOR), bleeding scores, and adverse events (AEs). Results Between June 2015, and July 2018, 300 patients were randomly allocated into either ATRA plus HD-DXM (n=150) or HD-DXM monotherapy (n=150). At the 6-month follow-up, the proportion of patients with SR was significantly higher in the ATRA plus HD-DXM group than in the HD-DXM monotherapy group (61% vs 37%, p= 0.009). So far, the increase of almost one quarter is very encouraging. The combination of ATRA and HD-DXM resulted in a higher incidence of early OR at day 14 compared with HD-DXM monotherapy (83% vs 67%, P=0.031), and the CR rate was 60.0% (ATRA+HD-DXM) vs 40.6% (HD-DXM) (P=0.015). Throughout the follow-up period, overall DOR was greater in the combination group, estimated by the Kaplan-Meier analysis. Fewer patients in the combination group than in the monotherapy group relapsed during follow-up (p< 0.001), and the median time to relapse was 75 days (ATRA+HD-DXM) vs 48 days (HD-DXM). Bleeding was more effectively controlled in the ATRA plus HD-DXM arm, with fewer bleeding events and lower bleeding scores. There was no difference between the 2 groups in terms of rescue treatments. All subjects tolerated the treatment well, and no grade 4 adverse events or treatment-related death were reported. No statistically significant differences were observed in the incidence of treatment-related AEs between the two groups. Conclusions ATRA plus HD-DXM is an effective and safe treatment for ITP as a first-line therapy that can provide a sustained prolonged response in adults. This therapy could be a new treatment option for ITP subjects. Disclosures No relevant conflicts of interest to declare.

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High-Dose Dexamethasone (HD-DXM) Plus Oseltamivir Versus High-Dose Dexamethasone for Treatment of Adult Primary Immune Thrombocytopenia: Interim Analysis of a Prospective, Multicenter, Randomized, Controlled Trial

Blood ◽

10.1182/blood-2019-121825 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 900-900 ◽

Cited By ~ 1

Author(s):

Lu Sun ◽

Xinguang Liu ◽

Hai Zhou ◽

Hongguo Zhao ◽

Chenglu Yuan ◽

...

Keyword(s):

Platelet Count ◽

Controlled Trial ◽

Statistical Significance ◽

Initial Response ◽

High Dose ◽

Platelet Destruction ◽

Platelet Counts ◽

High Dose Dexamethasone ◽

Primary Immune Thrombocytopenia

Introduction: Primary immune thrombocytopenia (ITP) is an acquired hemorrhagic disorder caused by immune-mediated platelet destruction and insufficient platelet production. As the first-line treatment of ITP, corticosteroids enable the recovery of platelet count in 60% to 80% of cases. However, a large proportion of patients would relapse during steroid tapering or withdrawal. Recently, sporadic studies reported successful treatment of ITP with oseltamivir which decreased platelet destruction through inhibition of platelet desialylation, a possible mechanism leading to Fc-independent platelet phagocytosis by hepatocytes. We hypothesize that corticosteroids and oseltamivir might complement each other in terms of mechanisms and induce a better response in ITP. Therefore, a prospective randomized controlled trial was conducted to compare the efficacy and safety of high-dose dexamethasone (HD-DXM) plus oseltamivir with HD-DXM monotherapy in adult ITP. Here we report the interim analysis of this study. Methods: From February 2016 to May 2018, 80 newly diagnosed treatment-naïve ITP patients from 5 tertiary medical centers in China were screened in the trial (NCT01965626). Dexamethasone was administered orally at 40 mg daily to both arms for 4 days (days 1 - 4). If platelet counts remained < 30 × 109/L or there were bleeding symptoms by day 10, another course of HD-DXM was given (days 11 -14). For the combination arm, oral oseltamivir was given concomitantly at a dosage of 75 mg twice daily for the first 10 days (days 1 - 10). The primary endpoints were initial response and sustained response (SR). Platelet counts should be confirmed on two separate occasions at least 7 days apart when defining responses (CR: platelet count ≥ 100×109/L and absence of bleeding; R: platelet count ≥ 30 × 109/L but < 100 × 109/L and at least a doubling of baseline and absence of bleeding). Initial responses were assessed by day 14. Responders underwent follow-up for at least 12 months or until relapse. Response lasting for at least 6 consecutive months without additional ITP-specific intervention was regarded as SR. Secondary endpoints included time to response (TTR), bleeding scores, duration of response and adverse events (AEs). Platelet transfusion was permitted in patients with severe bleeding symptoms and recorded. Requirements for any additional ITP-specific intervention were considered as treatment failure. Results: Fifty-nine patients were enrolled, of whom 28 were randomly to receive HD-DXM plus oseltamivir and 31 to HD-DXM monotherapy. Demographics and baseline characteristics were balanced between the 2 arms (Table 1). Results showed that HD-DXM plus oseltamivir achieved a higher incidence of initial response than HD-DXM alone at day 14 (82.1% vs. 58.1%, P = 0.045). At the end of 6 months, SR rate in the HD-DXM plus oseltamivir arm was higher than that in the HD-DXM monotherapy arm even though it did not reach statistical significance (42.8% vs. 25.8%, P = 0.167). Relapse-free survival in the HD-DXM plus oseltamivir arm was significantly improved compared with the HD-DXM monotherapy arm during follow-up period (HR 1.96, Log Rank P =0.043), as estimated by the Kaplan-Meier analysis. There was no statistical difference in median TTR between the two arms (P > 0.05). Bleeding was well controlled in both arms, with comparable post-treatment bleeding events (7.1% vs.19.3%, P> 0.05) and lower bleeding scores in the HD-DXM plus oseltamivir arm (0 vs. 0, P = 0.036). Incidence of AEs was similar between the 2 arms (P > 0.05). A slight increase in gastrointestinal reactions was observed in the HD-DXM plus oseltamivir arm but it did not reach statistical significance. Most of the AEs were mild to moderate (grade 1 to 2) and usually resolved spontaneously after medication was completed. No previously undescribed AEs was observed. Conclusions: The combination of HD-DXM with oseltamivir significantly improved the initial response in newly diagnosed ITP patients. However, due to the limitation of sample size, the conclusion of SR superiority can hardly be drawn at the moment. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Oseltamivir, a sialidase inhibitor which is extensively used in the treatment of or prophylaxis against influenza virus A and B. It has been reported that the treatment of oseltamivir could concomitantly increase platelet counts, which was independent whether influenza was diagnosed. Along those lines, several studies showed successful treatment of ITP patients with oseltamivir. We hypothesize that HD-DXM and oseltamivir might complement each other in terms of the mechanisms and achieve better response rates in ITP patients.

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Standard-dose versus high-dose radiotherapy with concurrent chemotherapy in esophageal cancer: A prospective randomized study

South Asian Journal of Cancer ◽

10.4103/sajc.sajc_178_17 ◽

2018 ◽

Vol 07 (01) ◽

pp. 27-30 ◽

Cited By ~ 7

Author(s):

Navin Nayan ◽

M. Bhattacharyya ◽

Vikas K. Jagtap ◽

A. K. Kalita ◽

R. Sunku ◽

...

Keyword(s):

Esophageal Cancer ◽

Total Dose ◽

Standard Dose ◽

Randomized Study ◽

Complete Response ◽

Concurrent Chemotherapy ◽

Prospective Randomized Study ◽

High Dose ◽

Large Sample Size

Abstract Objective: The objective of this study is comparision of local and distant control rates with high-dose versus standard-dose radiotherapy along with concurrent chemotherapy in esophageal cancer – a prospective randomized study. Materials and Methods: Histologically proven Stage I–III patients with carcinoma esophagus were randomized into two groups. One group has been treated with standard-dose radiotherapy, i.e., a total dose of 50.4 Gy (1.8 Gy/day, 28#, 5 days/week). The other group (study arm) has received high-dose radiotherapy, i.e. a total dose of 64.8 Gy (1.8 Gy/day, 36#, 5 days/week). Both groups have received 2 cycles of 3 weekly concurrent chemotherapy (cisplatin 75 mg/m[2] on day 1 and 5-fluorouracil 750 mg/m[2] continuous intravenous infusion over 24 h on day 1–4). Follow-up response evaluation was done by both endoscopy and computed tomography scan after 6–8 weeks and after 2 months thereafter. Results: Out of a total of 28 patients, 68% showed a complete response, 14% showed partial response, and 18% patients developed progressive disease at first and subsequent follow up (median follow-up of 21 months). Among the complete response patients, rates were higher in high-dose group compared to standard-dose radiotherapy group (71% vs. 64%, P = 0.38). Treatment-related toxicities were acceptable in both groups. Conclusion: High-dose radiotherapy with concurrent chemotherapy seems to be more effective with acceptable toxicity in our study. However, further follow-up and large sample size may be required to validate the current study conclusion.

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