Azacitidine Treatment of Lenalidomide-Resistant Myelodysplastic Syndrome with Deletion 5q

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2774-2774 ◽  
Author(s):  
Rami S. Komrokji ◽  
Najla H Al Ali ◽  
Eric Padron ◽  
Jeffrey E Lancet ◽  
Alan F List
Keyword(s):  
Myelodysplastic Syndrome ◽  
Treatment Failure ◽  
Effective Treatment ◽  
Median Duration ◽  
Research Funding ◽  
Median Number ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Cancer Center ◽  
Duration Of Response

Abstract Abstract 2774 Background: Lenalidomide is a highly effective treatment for lower risk transfusion dependent myelodysplastic syndrome (MDS) patients with deletion 5q [del(5q)]. Approximately two thirds of patients become transfusion independent for a median duration of 2 years or longer (List et al, NEJM). Effective treatment alternatives after lenalidomide treatment failure are limited. We examined the response to treatment with azacitidine in del(5q) MDS patients after lenalidomide treatment failure. Methods: MDS patients with del(5q) who were treated with azacitidine after lenalidomide failure were identified through the Moffitt Cancer Center (MCC) MDS database and individual charts reviewed. Data collected included demographics, disease baseline characteristics, duration of response to lenalidomide, responses to azacitidine by international working group (IWG) 2006 criteria, transformation to acute myeloid leukemia (AML), and overall survival (OS). Descriptive statistics were used for analysis and Kaplan Meier estimates were used for OS and AML transformation. All analysis was conducted using SPSS version 19.0 statistical software. Results: Between July 2005 and June 2011, 18 del(5q) MDS patients treated with azacitidine were identified. The median age was 66 years (50–83), all patients were Caucasian, and male predominance (67%; 12 patients). ECOG performance status was 0–1 in 94% of the patients. The median duration of follow up from date of azacitidine initiation was 645 days. According to the WHO classification, 7 patients (38.9%) had MDS with isolated del(5q), 7 patients (38.9%) refractory cytopenia with multilineage dysplasia (RCMD), 2 patients (11.1%) refractory anemia with excess blasts 1 (RAEB-1), and 2 patients (11.1%) refractory anemia (RA).The international prognostic scoring system (IPSS) risk category was low in 2 (11.2%), intermediate 1 (int-1) in 14 (77.8%), and int-2 in 2 (11.2%) patients. Based on karyotype, 7 patients (38.9%) had isolated del(5 q), 9 (50%) del 5q +1 abnormality, and 2 (11.2%) with del 5q +2 or more cytogenetic abnormality. All patients were transfusion dependent. The median number of lenalidomide cycles prior to azacitidine was 12 (1–38), with median duration of response 319 days (17–1169). The median number of azacitidine cycles administered was 6 (2–23). The median duration of treatment was 183 days (43–592). The best response to azacitidine by IWG 2006 criteria was one (7.1%) complete response (CR), 2 (5.6%) marrow CR (mCR), 7 (38.9%) hematological improvement (HI), 4 (22.2%) had stable disease, and 4 (22.2%) had progressive disease (PD). The overall response rate was 56%.The HI cell lineage responses were 9 out of 18 (50%) erythroid, 3 out of 13 (23%) HI-P (Platelets), and 2 out 9 (22.2%) HI-N (neutrophils). The median OS was 749 days (95%CI 435–1063) from the time of starting azacitidine. The rate of AML transformation was 27.8% (n=5); median time to AML transformation from azacitidine start was 864 days (95%CI 360–1368). Conclusion: To our knowledge this is the first report demonstrating the activity of azacitidine in patients with del(5q) MDS after lenalidomide treatment failure. Response rates are similar to those reported in non-del(5q) patients providing azacitidine as an effective option for salvage treatment. Larger cohort of patients is needed to confirm these findings. Disclosures: Komrokji: Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy.

scholarly journals Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure

2011 ◽  
Vol 29 (24) ◽  
pp. 3322-3327 ◽  
Author(s):  
Thomas Prébet ◽  
Steven D. Gore ◽  
Benjamin Esterni ◽  
Claude Gardin ◽  
Raphael Itzykson ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Treatment Failure ◽  
Clinical Care ◽  
Standard Of Care ◽  
Analysis Data ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Current Standard ◽  
Investigational Agents

Purpose Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described. Patients and Methods Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program). Results The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care. Conclusion Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.

Azacitidine Treatment for Lenalidomide (LEN)-Resistant Myelodysplastic Syndrome (MDS) with Del 5q

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3833-3833 ◽  
Author(s):  
Rami S. Komrokji ◽  
Cecile Bally ◽  
Raphael Itzykson ◽  
Sylvain Thepot ◽  
Eric Padron ◽  
...  
Keyword(s):  
Stem Cell ◽  
Treatment Failure ◽  
Effective Treatment ◽  
Median Duration ◽  
Stable Disease ◽  
Response To Treatment ◽  
Cancer Center ◽  
Cell Transplant ◽  
Best Response ◽  
Baseline Characteristics

Abstract Abstract 3833 Background: LEN is a highly effective treatment for lower risk transfusion dependent (TD) MDS patients with chromosome 5q deletion [del(5q)]. Effective treatment alternatives after LEN treatment failure are limited and outcome reported to date is poor. With decitabine, Lubbert et al reported responses among 4/5 patients with del (5q) and > 5% myeloblasts (one patient had isolated del (5q)) and Kantarjian et al in 2/16 higher risk del (5q) MDS patients. We assessed the response to treatment and outcome with azacitidine (AZA) in del(5q) MDS patients after LEN treatment failure. Methods: Patients with del(5q) MDS who were treated with AZA after LEN failure were identified through the Moffitt Cancer Center (MCC) MDS and the Groupe Francophone des Myelodysplasies(GFM) database. Individual charts were reviewed. Data collected included baseline characteristics, duration of response to LEN, responses to AZA by IWG 2006 criteria, and overall survival (OS). Descriptive statistics were used for analysis and Kaplan Meier estimates were used for OS. Results: Thirty six del(5q) MDS patients treated with AZA after LEN failure were identified. The median age was 68 years (48–93), with M/F :20/16. The median duration of follow up from date of AZA initiation was 848 days. Table-1 summarizes baseline characteristics. The median duration of LEN therapy prior to AZA was 13 mo (1–58 mo), The median time between end of LEN treatment and start of AZA treatment was 2.5 mo (0–30 mo). The median duration on AZA treatment was 7 month (1–25 mo). The best response to AZA by IWG 2006 criteria was CR in 2 patients (6%), 3 (8%) marrow CR (mCR), 2 (6%) partial remission (PR),11 (31%) stable disease with hematological improvement (HI), 9 (25%) had stable disease without HI (SD) and 7 (19%) had progressive disease (PD); response data was not available for 2 (5%) patients. Overall response rate was 50%. HI lineage responses included erythroid (HI-E) 12 of 28 (46%), HI-P (Platelets) 8 of 23 (35%), and HI-N (neutrophil) 4 of 19 (21%). The median duration response (HI or better) was 12 mo (95%CI 5–19 mo). Median OS was 22 mo (95%CI 13–31 mo) from the time of AZA initiation, whereas median OS among patients with HI or better response to AZA was 32 mo (95%CI 20–44 mo) vs. 13 mo (95% CI 4–22 mo) in those with SD/PD. (p=0.001). Patients with blast <5% at time of starting azacitidine therapy had better median OS (28 mo versus 17 mo) (p=0.04) compared to those with ≥ 5%. Patients with isolated del(5q) or int-1 risk IPSS prior to AZA had a trend for better OS (Table-2). Only 3 patients proceeded to allogeneic stem cell transplant with median OS 24 mo. Among all patients, 33% (12/36 patients) progressed to AML. Conclusion: To our knowledge this is the largest cohort evaluating the activity of AZA in patients with del(5q) MDS after LEN treatment failure. Response rates are similar to those reported in non-del (5q) patients, indicating that AZA is an effective option for salvage treatment. Given the poor outcome among AZA non-responders patients should be considered for allogeneic stem cell transplantation. Disclosures: Komrokji: Celgene: Honoraria, Speakers Bureau. List:Celgene: Consultancy. Fenaux:Celgene: Honoraria, Research Funding.

Investigate the efficacy of immunotherapy for treatment of pancreatic adenocarcinoma (PDAC) with mismatch repair deficiency (dMMR).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 415-415
Author(s):  
Arish Noor ◽  
Luis E. Aguirre ◽  
Kirsten Blue ◽  
Trenton Avriett ◽  
Estrella M. Carballido ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Metastatic Disease ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Complete Response ◽  
Median Number ◽  
Cancer Center ◽  
Duration Of Response

415 Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.

Paclitaxel Is Safe and Effective in the Treatment of Advanced AIDS-Related Kaposi's Sarcoma

1999 ◽  
Vol 17 (6) ◽  
pp. 1876-1876 ◽  
Author(s):  
Parkash S. Gill ◽  
Anil Tulpule ◽  
Byron M. Espina ◽  
Suzanne Cabriales ◽  
Jocelyn Bresnahan ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Median Duration ◽  
Systemic Therapy ◽  
Kaposi's Sarcoma ◽  
Single Agent ◽  
Kaposi’S Sarcoma ◽  
Duration Of Response ◽  
Previously Treated ◽  
Prior Systemic Therapy ◽  
Grade 3

PURPOSE: Liposomal anthracyclines are the present standard treatment for advanced AIDS-related Kaposi's sarcoma (KS). No effective therapies have been defined for use after treatment failure of these agents. A phase II trial was thus conducted with paclitaxel in patients with advanced KS to assess safety and antitumor activity. MATERIALS AND METHODS: A regimen of paclitaxel at a dose of 100 mg/m2 was given every 2 weeks to patients with advanced AIDS-related KS. Patients were treated until complete remission, disease progression, or unacceptable toxicity occurred. RESULTS: Fifty-six patients with advanced AIDS-related KS were accrued. Tumor-associated edema was present in 70% of patients and visceral involvement in 45%. Forty patients (71%) had received prior systemic therapy; 31 of these were resistant to an anthracycline. The median entry CD4+ lymphocyte count was 20 cells/mm3 (range, 0 to 358). A median of 10 cycles (range, 1 to 54+) of paclitaxel was administered. Fifty-nine percent of patients showed complete (n = 1) or partial response (n = 32) to paclitaxel. The median duration of response was 10.4 months (range, 2.8 to 26.7+ months) and the median survival was 15.4 months. The main side effects of therapy were grade 3 or 4 neutropenia in 61% of patients and mild-to-moderate alopecia in 87%. CONCLUSION: Paclitaxel at 100 mg/m2 given every 2 weeks is active and well tolerated in the treatment of advanced and previously treated AIDS-related KS. The median duration of response is among the longest observed for any regimen or single agent reported for AIDS-related KS. Paclitaxel at this dosage and schedule is a treatment option for patients with advanced AIDS-related KS, including those who have experienced treatment failure of prior systemic therapy.

Oral Clofarabine in the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 118-118 ◽  
Author(s):  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Zeev Estrov ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Optimal Dose ◽  
Oral Formulation ◽  
Median Number ◽  
Infectious Complications ◽  
Molecular Characteristics ◽  
Number Of Cycles ◽  
Almost All

Abstract Abstract 118 Clofarabine (CLO) is a second generation deoxyadenosine nucleoside analog with activity in patients (pts) with acute myeloid leukemia (AML). Early reports also suggestedactivity of iv CLO in myelodysplastic syndrome (MDS), but the role of CLO in MDS therapy remains largely undefined. Due to the molecular characteristics of CLO it can also be administered as an oral formulation with a bioavailability of around 50%. As an oral agent has obvious advantages over parenteral administrations, we designed a phase 2 study to evaluate the activity and safety of oral CLO in patients with MDS. Pts were eligible if they had MDS and ≥ 5% blasts (including RAEB-t by FAB) or IPSS intermediate-2 and high-risk, and CMML. Hematopoietic growth factor support prior to and during the study was permitted. Thirty-two pts (2 RA, 11 RAEB-1, 11 RAEB-2, 2 RAEB-t, 5 CMML-1, 1 CMML-2) were treated. Twenty-two pts (69%) had intermediate-2 or high-risk disease by IPSS. Median age was 70 yrs (range 53–86). Overall, ≥ 27 pts (84%) were older than 60 yrs. Thirteen pts (41%) had a history of a prior malignancy and 20 pts (66%) failed prior hypomethylator therapy (6 pts azacitidine, 12 pts decitabine, 2 pts both). Cytogenetics were intermediate and poor in 9 (28%) and 10 (31%) pts, respectively. The starting dose of CLO was 40 mg/m2 orally daily × 5 days every 4–6 weeks (6 pts), which was decreased due to toxicities to 30 mg/m2 orally daily × 5 days (19 pts), and eventually 20 mg/m2 orally daily × 5 days (7 pts). Twenty-eight pts (88%) received treatment in an outpatient facility and almost all pts (94%) received anti-infectious prophylaxis. Responses of 31 evaluable pts are summarized in the Table: Among 20 pts who failed prior hypomethylator therapy responses were CR in 2 (10%), HI in 2 (10%), and CB in 2 (10%). The median number of cycles to response was 1 (range 1–3). Of 10 pts who received further consolidation cycles, the median number was 1 (range 1–8+). No pts died within 6 wks of induction. Acute renal failure occurred in 4 pts (1 pt 40 mg/m2, 3 pts 30 mg/m2) in the context of myelosuppresssion-associated infectious complications; 4 pts died. Common adverse events were nausea/vomiting, rashes, reversible transaminase elevations and hyperbilirubinemia, and fatigue and were mainly ≤ grade 2. The most frequent ≥ grade 3 toxicity were reversible elevations of transaminases. Myelosuppression was ubiquitous, but prolonged myelosuppression (> 42 days) was rare in responding pts. Infectious episodes occurred in 16 pts and were more frequent in pts receiving CLO at 40 or 30 mg/m2. Oral CLO has an ORR of 46% in pts with higher-risk MDS. Responses are lower in pts failing prior hypomethylator therapy. The optimal dose and schedule to balance activity and toxicity remain to be defined. Disclosures: Faderl: Genzyme: Consultancy, Research Funding. Off Label Use: Clofarabine in MDS. Kantarjian:Genzyme: Consultancy, Research Funding.

Secondary Myelodysplastic Syndrome/Acute Myeloblastic Leukemia During Lenalidomide-Based Regimens in Relapsed and/or Refractory Multiple Myeloma Patients: Single Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1867-1867
Author(s):  
Rouslan Kotchetkov ◽  
Esther Masih-Khan ◽  
Chia-Min Chu ◽  
Young Trieu ◽  
Saima Dean ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myelodysplastic Syndrome ◽  
Median Duration ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Alkylating Agents ◽  
Myelogenous Leukemia ◽  
Median Baseline ◽  
Number Of Patients ◽  
Secondary Myelodysplastic Syndrome

Abstract Abstract 1867 Secondary myelodysplastic syndrome and acute myelogenous leukemia (2° MDS/AML) are well-known complications that can occur after alkylating agent therapy for multiple myeloma (MM) or other cancers. However, until recently, the survival of MM pts was relatively short, a feature which may have contributed to a relatively low reported incidence of this complication in MM. The introduction of novel agents has improved survival rates of MM pts; lenalidomide (len) + dexamethasone–currently approved for MM after one prior therapy– is one of the main regimens that has contributed to this finding. Since alkylating agents, either given orally or as part of high-dose melphalan + ASCT, still remain an important component of MM therapy, more pts may survive to be at risk for 2° MDS/AML. Using the MM database at PMH, we retrospectively reviewed the charts of patients with relapsed/refractory (rel/ref) MM treated with len-based regimens (>1 cycle) to determine the incidence and characteristics of 2° MDS/AML that developed during this therapy. Between 06/2006 and 08/2012 we identified 230 patients having received len-based therapy: len + corticosteroids 222 patients, len alone 8 patients, cyclophosphamide + len + prednisone (CPR) 32 patients. 2° MDS/AML developed in 9 patients (3.9%) at a median of 89.6 months (range 30–188) from the time of diagnosis of MM and 22.4 (2–56.6) months from the time of initiation of len regimens. The median follow-up from start of len was 1.6 years, and from the start of diagnosis 7.5 years. The median duration of len treatment was 9.4 months. The MDS/AML cytogenetic changes were variable, but four patients had deletions of all or part of chromosome 5. None of the 2° MDS/AML had translocation t(4;14), as compared to 5.9% in (−) MDS/AML subgroup. The characteristics of patients at the time of starting len, in those who later developed (+) or did not develop (−) 2° MDS/AML during therapy, are shown in Table 1. Cumulative incidence of 2° AML/MDS from time of diagnosis to time of 2° AML/MDS is 4.5% [95% CI 2.2–9.2%] at 15 years. Cumulative incidence of 2° AML/MDS from starting time of len to time of AML/MDS is 5% [95% CI 2.4–10.4%] at 5 years. The incidence of 2° MDS/AML among those who had prior oral alkylators (OA) and/or concomitant OA was 10.5% (2/19 patients), concomitant cyclophosphamide only 7.6% (1/13), prior OA only 1.9% (3/152), and 6.5% for those who did not receive prior/concomitant OA (3/46). Grade 3–4 neutropenia occurred during len in 44% versus 58% in those with and without 2° MDS/AML, respectively. G-CSF was used in 56% of pts who developed MDS compared with 53% who did not. We conclude: 1) The cumulative incidence of MDS/AML from starting len to time of 2° AML/MDS was 5% at 5 years; 2) patients who developed 2° MDS/AML while on len regimens were slightly older, had slight male predominance, higher beta-2-microglobulin, creatinine and platelet count, less often received prior ASCT, thalidomide, and bortezomib, but had longer exposure to len; 3) the relationship with OA is not entirely certain, but it appears that those with prior and concomitant exposure to OA have the highest incidence of this complication, which is most often seen in prolonged len treatment. Table 1. Patient characteristics (n=230) Feature ALL patients (+) MDS/AML (–) MDS/AML Number of patients 230 9 221 Median age, years 61 (31–80) 68 (53–76) 61 (3–80) Male 134 (58%) 6 (67%) 128 (56%) Median baseline ANC, × 109/L 2.8 (0.9–61.4) 3.0 (1.5–5.1) 2.8 (0.9–61.4) Median baseline β-2 microglobulin (nmol/L) 222 (43–1695) 300 (133–481) 222 (43–1695) Median baseline pl count, × 109/L 156 (5–479) 200 (43–277) 156 (5–479) Median baseline creatinine, μmol/L 87 (39–515) 97 (56–117) 86 (39–515) Median # prior regimens 2 (0–6) 2 (1–5) 2 (0–6) Prior alkylating agents (all) 218 (95%) 9 (100%) 209 (95%) Prior oral alkylators 167 (73%) 6 (67%) 162 (73%) Prior ASCT 187 (81%) 2 (78%) 180 (81%) Prior thalidomide 132 (57%) 3 (33%) 129 (58%) Prior bortezomib 109 (47%) 3 (33%) 106 (48%) Concomitant cyclophosphamide 32 (13.9%) 3 (33%) 29 (13%) G-CSF use 123 (53%) 5 (56%) 118 (53.39%) Median duration of Len (mo, range) 9.4 (0.1–67.2) 22.8 (6.6–56.6) 6.8 (0.1–67.2) Disclosures: Chen: Johnson & Johnson, Lundbeck, Celgene: Consultancy; Roche: Honoraria; Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Reece:Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding.

Lack of Response of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) to Decitabine After Failure of Azacitidine

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3858-3858 ◽  
Author(s):  
Bhavana Bhatnagar ◽  
Dan P. Zandberg ◽  
Emily J. Vannorsdall ◽  
Alison P. Duffy ◽  
Michael L. Tidwell ◽  
...  
Keyword(s):  
Research Funding ◽  
Disease Free Survival ◽  
Initial Response ◽  
Median Number ◽  
Initial Therapy ◽  
Cancer Center ◽  
Disease Response ◽  
University Of Maryland ◽  
Demethylating Agents ◽  
Demethylating Agent

Abstract Abstract 3858 Background: Standard therapy for high-risk MDS consists of one of two FDA-approved demethylating agents, azacitidine or decitabine. AML patients considered unfit for intensive chemotherapy are also frequently treated with one of these agents, both of which have activity in AML and an acceptable toxicity profile. These agents are not considered curative, and responses are of variable duration. When azacitidine or decitabine is not effective, or is no longer effective, few options are available. In view of differences in pharmacological properties between these two agents, it is not uncommon to switch demethylating agents after failure of initial demethylating agent therapy. To date, only two small studies have addressed the outcome of this intervention, with conflicting results. In a study of 14 MDS patients treated with decitabine following failure of, or progression on, azacitidine, 4 patients (28%) responded (Borthakur et al, Leuk Lymph 2008), while a subgroup analysis of 10 evaluable patients treated with decitabine following azacitidine failure demonstrated no complete or partial responses (Prebet et al, J Clin Oncol 2011). Here we report outcomes in a retrospective analysis of 22 MDS and AML patients who received decitabine after azacitidine. Methods: Charts of 22 MDS or AML patients who were evaluated at the University of Maryland Greenebaum Cancer Center between January 1, 2008 and March 31, 2012 and who received decitabine after azacitidine were reviewed. Results: Patient and disease characteristics for 13 MDS patients and 9 AML patients are shown in Table 1. All patients were initially treated with azacitidine before being switched to decitabine following lack of response to initial therapy or disease progression after initial response. Five of 9 AML patients received azacitidine as frontline therapy, while four received it after other induction chemotherapy regimens. Disease responses following azacitidine 75mg/m2 for 5–7 days in 28-day cycles were variable as shown in Table 1. The median number of courses of azacitidine to disease response for MDS and AML patients who responded was 5 (range, 2–10), median disease-free survival (DFS) was 6.1 months (range, 2.3–16), and median number of courses of azacitidine received was 9 (range, 1 to 17). All 22 MDS and AML patients were refractory to, or progressed after, subsequent decitabine therapy after receiving a median of 2 courses (range, 1–6). Conclusions: Our study population represents the largest to date and the first in which AML disease responses to decitabine after failure of azacitidine have been studied. All MDS and AML patients were refractory to decitabine therapy following initial treatment with azacitidine. Thus this approach should generally not be employed. New therapies are needed for patients for whom demethylating agent therapy is, or becomes, ineffective, and these patients should be enrolled on clinical trials whenever possible. Disclosures: Baer: Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding.

Outcome Of Patients (pts) With Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 388-388 ◽  
Author(s):  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Lianchun Xiao ◽  
Al Ali Najla ◽  
Asmita Mishra ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Lower Risk ◽  
Research Funding ◽  
Complete Response ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Cancer Center ◽  
Primary Resistance ◽  
High Risk Disease

Abstract Background HMA are standard of care in pts with high-risk MDS and commonly used in pts with lower risk. Pts with high-risk disease post HMA failure have a poor prognosis with a median survival of 4-6 months. The prognosis of pts with low and intermediate-1 risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure is not known. Aims To assess outcome of pts with low and intermediate-1 risk disease post HMA failure that might benefit from specific strategies or investigational agents. Methods Data from 423 pts with low (n= 141, 33%) and intermediate-1 risk disease (n=282, 67%) by IPSS score treated with HMA at MD Anderson Cancer Center (MDACC; n=144) and Moffitt Cancer Center (MCC; n=279) between 2000 and 2011 were analyzed. Results Median age was 69 years. 294 (69%) pts had a diploid cytogenetic analysis. 63 (15%) pts had therapy-related MDS. 282 (67%) pts received azacitidine, 87 (21%) decitabine, and 54 (12%) both. Median number of cycles of HMA administered was 6 (range, 1-64) for a median duration of therapy of 7 months (range, 1- 74). Best response to HMA was complete response (CR) in 39 (9%) pts, partial response (PR) in 13 (3%), a bone marrow CR in 6 (1%), and hematologic improvement (HI) in 90 (21%) pts. Pts had discontinued HMA because of primary resistance in 198 (47%) pts, loss of response in 141 pts (33%), intolerance in 13 pts (3%) and other reasons in 71 pts (17%). At the time of HMA failure, 81 (19%) pts transformed into acute myeloid leukemia (AML). Of the 302 remaining pts evaluable by IPSS, 67 (22%) pts were of low-risk, 158 (53%) of intermediate-1 risk, 48 (16%) of intermediate-2 risk, and 29 (9%) of high-risk disease. By the revised IPSS (R-IPSS), the percentage of pts with low, very low, intermediate, high, and very high risk disease were 11%, 29%, 30%, 20%, and 10%, respectively. By the MDACC global prognostic scoring system (MDGPSS) 18%, 35%, 29%, and 18%, of the pts were of low-risk, intermediate-1, intermediate-2, and high-risk disease, respectively. After a median follow-up of 16 months from HMA failure, 117 (28%) pts remained alive. The median overall survival (OS) was 15 months (95% CI: 12-18) with estimated 1- and 3-year OS rates of 55% and 27%, respectively. Both, the R-IPSS and the MDGPSS were predictive of survival post HMA failure (Table 1 ). Conclusion In the largest cohort of lower risk MDS pts treated with HMA, the outcome after HMA failure is poor. Treatment of those patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population. Disclosures: Lancet: Celgene: Research Funding. Sekeres:Celgene: Consultancy; Amgen: Consultancy. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

A Phase II Open-Label, Multi-Center Study of Anti-CCR4 Monoclonal Antibody Mogamulizumab (KW-0761) in Patients with Previously Treated Peripheral T-Cell Lymphoma(PTCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1763-1763 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Bertrand Coiffier ◽  
John Radford ◽  
Dolores Caballero ◽  
Paul Fields ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Median Number ◽  
Advisory Board ◽  
Japanese Study ◽  
Duration Of Response ◽  
Previously Treated ◽  
Grade 3

Abstract Background CC chemokine receptor 4 (CCR4) is the receptor for macrophage-derived chemokine (MDC/CCL22) and thymus activation-regulated chemokine (TARC/CCL17). CCR4 is expressed on tumour cells in approximately 30-65% of patients with PTCL (Ogura, 2014). PTCL-NOS patients who are CCR4 positive have been reported to have a poorer prognosis compared to CCR4 negative patients (Ishida T CCR 2004). Mogamulizumab (KW-0761) is a defucosylated, humanized, IgG1 Mab with enhanced antibody dependent cellular cytotoxicity, that binds to CCR4. Mogamulizumab was evaluated in both phase 1 and 2 trials in Japanese patients. A phase II trial in PTCL and cutaneous T-cell lymphoma (CTCL) patients (Ogura, 2014) reported an overall response rate (ORR) of 35% in patients who relapsed after last systemic therapy (ORR was 34% in PTCL), leading to its approval in Japan in patients with previously treated CTCL and PTCL, in addition to its first indication, previously treated adult T-cell leukemia-lymphoma. Here we report the preliminary results of a European phase II trial of mogamulizumab in patients with relapsed/refractory PTCL. Methods A multi-center phase II study of mogamulizumab monotherapy was conducted to determine efficacy, safety and immunogenicity in patients with CCR4+ PTCL. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS) and overall survival (OS). At least 34 evaluable patients were needed to detect a significant improvement over 15% assuming 80% power and a 0.0240 alpha significance level (assumes 35% ORR for alternative). Patients received mogamulizumab once weekly for 4 weeks and subsequently once every 2 weeks until progressive disease (PD) or unacceptable toxicity at a dose of 1.0 mg/kg. Responses were assessed every 8 weeks according to IWG criteria (Cheson et al 2007). Results Based on a preliminary analysis of the data, a total of 38 patients received at least one administration of mogamulizumab and were evaluable for safety analysis; (Male/female 23/15 ;Median age 58.5 years (range 19-87)). Three patients are still ongoing in the study (1 complete response (CR) and 2 stable disease (SD)). ECOG performance status at baseline was 0 (32%); 1 (29%); 2 (39%) and 92% of patients had stage III (32%) or IV (61%) disease. The median number of prior treatments was 2 (range 1-8). Only 17 patients (49%) responded to the last treatment administered prior to study entry. The median number of mogamulizumab administrations was 6 (range 1-32). The majority of adverse events (AEs) were CTCAE grade 1-2. Skin rash related to drug was observed in 32% of patients (12/38) and related AEs > grade 3 occurred in 32% (12) of patients. Infusion related reactions occurred in 3 patients (2 were CTCAE grade 2 and 1 was grade 3). Thirty-five patients were evaluable for efficacy. The ORR rate was 11% and the stable disease rate was 34% with a SD or better rate of 46%. The response by histological subtype is specified in the table below. The median duration of response (including SD) is 2.9 months. The median PFS is 2.1 months. Two patients (ALCL-ALK-neg and PTCL-NOS) proceeded to allogeneic SCT. Although the ORR in this study was less than seen in the Japanese study, the PFS was comparable. There were differences in patient population/study conduct between the Japanese study and this study, respectively, which included: inclusion of only relapsed patients (100% vs 49%), ECOG PS 2 (0% vs 39%) and response assessments (after 4 and 8 weeks versus 8 weekly from week 8). Conclusions Based on preliminary data, mogamulizumab demonstrates a SD or better rate of 46% and an ORR of 11% with an acceptable safety profile in this phase II study of heavily pre-treated relapsed/refractory PTCL patients. TableBest Overall Response by Histological subtypeNo of subjectsCR/PR n (%)SDn (%)>SD n (%)PTCL-NOS152* (13%)6 (40%)8 (53%)AITL122 (17%)3 (25%)5 (42%)TMF301 (33%)1 (33%)ALCL-ALK neg402 (50%)2 (50%)ALCL-ALK pos1000Efficacy Evaluable Subjects354 (11%)12 (34%)16 (46%) *One patient had CR by CT scan but did not have bone marrow done for confirmation of CR Disclosures Zinzani: Sandoz: Consultancy; Celgene International Sàrl: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; MundiPharma International Ltd: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Pfizer Inc: Advisory Board Other, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited: Advisory Board Other, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Advisory Board Other, Honoraria; GlaxoSmithKline: Advisory Board, Advisory Board Other, Honoraria; Gilead: Advisory Board, Advisory Board Other; Bayer AG: Advisory Board Other, Consultancy. d'Amore:CTI Life Sciences: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda/Seattle Genetics : Speakers Bureau; Sanofi-Aventis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Kyowa-Kirin: Advisory Board Other. Haioun:Roche: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Morschhauser:Genentech: Honoraria; Bayer: Honoraria; Spectrum: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 305-308 ◽  
Author(s):  
Keichiro Mihara ◽  
Moniruddin Chowdhury ◽  
Nanae Nakaju ◽  
Sachiko Hidani ◽  
Akihiro Ihara ◽  
...  
Keyword(s):  
Molecular Marker ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
The Self ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Self Renewal ◽  
Precise Evaluation ◽  
Cd34 Cells ◽  
Patient Prognosis

Abstract The International Prognostic Scoring System (IPSS) has been widely used to predict the prognosis of patients with myelodysplastic syndrome (MDS). However, IPSS does not always provide a sufficiently precise evaluation of patients to allow the appropriate choice of clinical interventions. Here, we analyzed the expression of Bmi-1, which is required to regulate the self-renewal in CD34+ cells from 51 patients with cases of MDS and acute myeloid leukemia preceded by MDS (MDS-AML). Higher positivity rate of Bmi-1 was preferentially seen in refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), and MDS-AML compared with refractory anemia (RA) and RA with ringed sideroblasts (RARS). IPSS score was positively correlated with the percentage of Bmi-1 expression. Patients with RA and RARS with a higher percentage of Bmi-1+ cells showed disease progression to RAEB. Here, we propose Bmi-1 as a novel molecular marker to predict the progression and prognosis of MDS.

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