Clinical Activity of Azacitidine In Combination with the Oral mTOR Inhibitor Everolimus (RAD001) In Relapsed and Refractory AML: Interim Analysis of a Phase Ib/II Study

Abstract Abstract 3301 Background Although the demethylating agent azacitidine has an established role in myelodysplastic syndromes and encouraging activity in oligoblastic acute myeloid leukemia (AML), information regarding its role in relapsed and refractory AML is still emerging. The French ATU reported an overall response rate (ORR; CR/CRi+PR) in relapsed and refractory AML of 11% (Itzykson et al. ASH 2009 #1054). In a similar population, azacitidine salvage therapy produced a CR/CRi rate of 19% (Ayari S, et al. ASH 2009 #2044). Rapamycin, an inhibitor of the AKT downstream target mammalian Target Of Rapamycin (mTOR), is reported to specifically target leukemic stem cells and orally bioavailable rapamycin derivatives, such as everolimus (RAD001), are in active clinical development. Clinical responses with single agent everolimus in relapsed, refractory AML, however, have been modest (Yee et al, Clin Cancer Research 2006 and Boehm et al, European Journal of Internal Medicine 2009). Aim Building on our experience combining everolimus with low dose cytarabine (submitted to ASH, 2010), we have sought to investigate the feasibility and preliminary efficacy of combining everolimus with azacitidine in relapsed and refractory AML. Methods Phase Ib/II open label dose escalation study. Patients were treated with azacitidine 75 mg/m2 s.c. daily on days 1–5 and 8–9 of each 28-day cycle with either 2.5, 5 or 10 mg everolimus orally on days 5–21 for a maximum of 12 cycles. Results This preliminary analysis includes 20 patients (M 14, F 6), median age 64 years (range 17–76) receiving 2.5 mg (n=6), 5 mg (n=12) or 10 mg (n=2) everolimus. 9 (45%) had chemotherapy refractory and 11 (55%) relapsed AML after 1 (n=8), 2 (n=10) or 3 (n=2) previous lines of therapy. 7/17 (41%) had poor risk and 10/17 (59%) intermediate risk cytogenetics. 6/19 (32%) had secondary AML. The overall response rate (ORR) in 14 evaluable patients was 36% (2 CR, 3 PR). Stable disease (SD) was observed in 7 (50%) patients and 2 (14%) had progressive disease. Absolute bone marrow blast reductions from baseline in the 5 responders ranged from 9 to 88% (Figure 1). Grade 3/4 non-hematologic toxicities are summarized as follows: 2.5 mg everolimus cohort- septicemia (n=1) and mucositis (n=1, dose limiting toxicity; DLT), 5 mg everolimus cohort- septic arthritis (n=1, DLT). Febrile neutropenia during the first cycle of therapy was reported in 5/20 (25%). Safety analysis in the 10 mg everolimus cohort is ongoing. With a median follow up of 82 days, 30 day mortality was 0%. Enrolment continues to a planned 40 patients. Of interest, 2 out of 3 patients with FLT3-ITD+ AML refractory to high-dose cytarabine and antracyclines, had a striking reduction in bone marrow blasts after commencing azacitidine + everolimus (2.5 mg) therapy, with the absolute blast count falling from 95% to 16% and 92% to 5%, respectively, and lasting for at least 5 months in both. One of these patients has so far proceeded to allogeneic stem cell transplant (allo-SCT). Another patient with 3rd relapse of AML after failing allo-SCT, achieved CR after 3 cycles of treatment with azacitidine + everolimus (2.5 mg) and remains in CR after 157 days. Conclusion In relapsed and refractory AML, azacitidine in combination with the mTOR inhibitor everolimus was well tolerated and demonstrates substantial clinical activity in this advanced AML population. Further evaluation of this promising combination is ongoing. Disclosures: Wei: Novartis: Advisory board, Research Funding; Celgene: Research Funding. Off Label Use: AML therapy. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants.

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D.C.E.P. in Patients with Quad- or Penta-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117713 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2021-2021

Author(s):

Scott Goldsmith ◽

Mark A. Fiala ◽

Brandon B. Wang ◽

Mark A. Schroeder ◽

Tanya M. Wildes ◽

...

Keyword(s):

Multiple Myeloma ◽

Retrospective Study ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Cell Transplant ◽

Advisory Committees ◽

Salvage Regimen ◽

Overall Response

Abstract Introduction: Despite the recent introduction of novel agents for multiple myeloma (MM), the disease remains incurable and invariably progresses through these new therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (refractory to an anti-CD38 monoclonal antibody as well) are left with few treatment options and poor prognoses. The chemotherapy regimen of dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) has demonstrated efficacy in the treatment of relapsed/refractory MM. We and others employ DCEP as a salvage regimen, however, few outcomes data exist in this heavily pretreated population. Methods: We conducted a retrospective study to identify all patients who received DCEP for quad- or penta-refractory MM at our institution between 2013 and 2018. Disease response and refractoriness were defined by IMWG criteria. The primary endpoint was overall response rate (ORR) defined as PR or better. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). Results: We identified 31 patients who received DCEP, 8 (26%) for quad-refractory and 23 (74%) for penta-refractory MM (Table 1). Twenty-eight (90%) had at least one autologous stem cell transplant, and one had a prior allogeneic transplant. Sixteen (52%) were female, 27 (87%) were white, and median age at DCEP was 60. Median number of prior treatment regimens was 8. All patients received dexamethasone (40mg/day), cyclophosphamide (400mg/m2/day), etoposide (40mg/m2/day), and cisplatin (10mg/m2/day) on days 1-4 (Lazzarino et al. 2001). Cycles were generally 28 days in length, but doses were delayed in cases of cytopenias or other toxicities. Dose reductions occurred in cases of renal impairment or prolonged cytopenias. Twenty patients (65%) received more than one cycle (range: 1-5). The overall response rate was 35%. One patient achieved CR allowing him to proceed to a second autologous transplant. One patient achieved a VGPR, 9 (29%) a PR. Four of the 8 (50%) quad-refractory patients responded compared to 7 of the 23 (30%) of the penta-refractory patients. Eleven (35%) were primary refractory to DCEP, and two patients died after one cycle prior to response assessment. The overall median PFS was 2.7 months (95% CI 1.5-3.8) and median OS was 6.2 months (95% CI 4.4-7.8). For responders, median DOR was 4.2 months (95% CI 3.0-5.4) and median OS was 9.0 months (95% CI 7.2-10.9). Conclusion: Quad- and penta-refractory MM carry a grim prognosis. In our retrospective study, DCEP led to a notable ORR of 35% (95% CI 19%-55%) in this very heavily-treated population, and suggests that it remains a reasonable salvage therapy. Furthermore, it supports prospective study of this regimen, possibly in combination or in comparison with other agents effective in quad- or penta-refractory MM. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients (pts) with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v124.21.385.385 ◽

2014 ◽

Vol 124 (21) ◽

pp. 385-385 ◽

Cited By ~ 4

Author(s):

Daver Naval ◽

Hagop M. Kantarjian ◽

Guillermo Garcia-Manero ◽

Naveen Pemmaraju ◽

Tapan M. Kadia ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Phase I ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Advisory Board ◽

Standard Chemotherapy ◽

Overall Response ◽

Board Membership

Background: Vosaroxin, is a first-in-class anti-cancer quinolone derived (AQD) DNA topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein, has limited toxicity, and is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts were eligible if they had AML or high-risk MDS (defined as having ³ 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG ² 2) and organ function. Pts younger than 60 who were unsuitable for standard chemotherapy were also eligible. In the phase I part of the study the first six pts received vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. This dose was well tolerated with no dose limiting toxicity identified and pts were then enrolled on phase II at this dose and schedule. However, due to mucositis in a few subsequent pts, the induction dose of vosaroxin was reduced to 70 mg /m2, starting with pt #25. The vosaroxin dose could be maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles, which were repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles. Dose adjustments and dose delays of one or both agents, were allowed based on toxicity. The primary endpoint was to determine the overall response rate including complete response (CR) + CR without platelet recovery (CRp) + CR with insufficient hematological recovery (CRi). Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality. Results: To date, 35 pts (32 AML, 3 high-risk MDS) with a median age of 71 years (range, 41-78) have been enrolled; 34 (97%) pts were older than 60 years. They included 15 (43%) pts with diploid cytogenetics, 12 (34%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 8 (23%) with other miscellaneous abnormalities. 13 (37%) pts with AML had antecedent hematological disorders (AHD) including 7 (20%) with MDS, 4 (11%) with myeloproliferative neoplasm and 2 (6%) with MDS/MPN. Three pts with AHD had received prior therapy including 5-azacytidine (n=1), ruxolitinib + 5-azacytidine (n=1), and lenalidomide (n=1). Additionally, 5 (15%) pts had therapy-related disease with prior exposure to chemotherapy or radiation therapy. Median bone marrow blast %, median white blood cell, hemoglobin, & platelet counts were 40% (9-97), 4.1 x 109/L (0.4-57.0), 9.4 g/dL (6.8-11.5), and 40 x 109/L (7-333), respectively. 34 pts were evaluable for response; 17 (50%) achieved CR, 6 (18%) CRp, and 3 (9%) CRi for an overall response rate of 77%. One pt is too early for response assessment. Responses by age, cytogenetic and molecular characteristics are shown in table 1. The median follow-up is 5.1 months (range, 0.9-11.0). Pts have received a median of 2 (1-6) treatment cycles with the median number of cycles to response being 1 (1-4). Three pts have relapsed and the median duration of CR/CRp/CRi has not been reached (0.5-9.9+ months). Four (12%) pts have proceeded to allogeneic stem cell transplant (ASCT). 4-week and 8-week mortality were 0% and 14%, respectively. The regimen is well tolerated with the main grade ³ 3 toxicity being mucositis in 9 (26%) pts and liver enzyme elevation in 3 (9%). Conclusion: Combination of vosaroxin and decitabine is effective and feasible in older pts with AML and high-risk MDS. Enrollment is ongoing. Table 1: Response by baseline characteristics Parameter Category N Overall response Too early to evaluate Age* 60-70 16 14/16 (88%) 0 >70 18 12/17 (71%) 1 Cytogenetics Diploid 15 11/14 (79%) 1 -5/-7/other adverse 12 8/12 (67%) 0 Miscellaneous 8 5/8 (63%) 0 Mutation Status IDH2 7 7/7 (100%) 0 IDH1 5 1/4 (25%) 1 TP53 9 6/9 (67%) 0 RAS 9 4/9 (44%) 0 *1 pt below the age of 60 years was unsuitable for standard chemotherapy and was enrolled on study. Disclosures Naval: Sunesis: Advisory board membership Other, Research Funding. Off Label Use: Vosaroxin (Qinprezo) has not been approved for AML. In this clinical trial we are evaluating the efficacy and safety of vosaroxin (Qinprezo) in combination with decitabine in elderly patients with AML. . Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Borthakur:Tetralogic Pharmaceuticals: Research Funding. Jabbour:Ariad, Novartis, BMS, Pfizer, and Teva: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Craig:Sunesis: Employment. Ravandi:Sunesis: Advisory board membership Other, Research Funding.

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Activity of lenalidomide in a phase II trial for T-cell lymphoma: Report on the first 24 cases

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8524 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8524-8524

Author(s):

G. S. Dueck ◽

N. Chua ◽

A. Prasad ◽

D. Stewart ◽

D. White ◽

...

Keyword(s):

T Cell ◽

Overall Response Rate ◽

Response Rate ◽

Large Cell ◽

Median Number ◽

Clinical Activity ◽

Cell Transplant ◽

Overall Response ◽

T Cell Lymphomas ◽

Common Grade

8524 Background: Novel therapies are needed to improve outcomes in T-cell lymphomas. We report the interim results of a prospective multicenter trial evaluating lenalidomide in T-cell lymphomas. Methods: Patients with relapsed and refractory T-cell lymphomas other than mycosis fungoides were prescribed oral lenalidomide (25mg daily) on days 1 to 21 of each 28 day cycle, with standardized dose reductions for toxicity. Treatment continued until disease progression, death or unacceptable toxicity. The primary endpoint was overall response rate, and secondary endpoints were complete and partial response rates, progression-free and overall survival (PFS, OS), and safety. The two-stage design allows for up to 40 patients. Results: At the time of this interim analysis, 24 patients were enrolled in this study and 23 were evaluable for response. The median age was 65 years. ECOG PS was 0–1 (n=15), 2 (n=7), 3 (n=2). The histology was peripheral T-cell unspecified (PTCL-u, n=10), angioimmunoblastic (n=7), anaplastic large cell (n=5), enteropathic T-cell (n=1) and hepatosplenic gamma/delta (n=1). Median number of prior therapies was 1 (range, 0–4), and three had prior autologous stem cell transplant. Four patients were previously untreated and not candidates for combination chemotherapy. Median time from completion of prior therapy to the start of lenalidomide was 8 months (range, 1–48 months). The overall response rate was 7/23 (30%); all were partial responses. Two patients had stable disease (SD) for ≥3 cycles. Responses were seen in anaplastic, angioimmunoblastic, and PTCL-u histologies. Median PFS was 96 days (range, 8–696 days). Median OS was 241 days (range, 8–696+ days). Among the 9 patients with SD or better, median PFS was 168 days and median OS has not yet been reached with 241–696 days of follow-up. The most common grade 4 adverse event was thrombocytopenia (33.3%). The most common grade 3 adverse events were neutropenia (20.8%), febrile neutropenia (16.7%), and pain NOS (16.7%). Conclusions: In relapsed and refractory T-cell lymphomas, oral lenalidomide monotherapy has clinical activity and toxicity is consistent with the known profile of lenalidomide. Further study of lenalidomide in these diseases is warranted. [Table: see text]

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Phase 2 Study of 5 Days Azacytidine Priming Prior to Fludarabine, Cytarabine and G-CSF Combination for Patients with Relapsed or Refractory AML

Blood ◽

10.1182/blood-2018-99-114037 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5181-5181

Author(s):

Ibraheem H. Motabi ◽

Shahid Iqbal ◽

Syed Ziauddin A. Zaidi ◽

Belal Albtoosh ◽

Nawal Faiez Alshehry ◽

...

Keyword(s):

Bone Marrow ◽

Overall Response Rate ◽

Response Rate ◽

Complete Response ◽

Refractory Disease ◽

Curative Therapy ◽

Overall Response ◽

Remission Status ◽

The Mean ◽

Refractory Aml

Abstract Background: Acute Myeloid Leukemia (AML) is a group of heterogeneous clonal disorder of myeloid progenitor cells. Relapsed and refractory AML represent a clinical and therapeutic challenge to hematologist because of chemotherapy resistant disease and are associated with poor outcome. Allo-SCT is the only potentially curative therapy for such patients and is only possible after achieving second remission. FLAG is used more commonly and is associated with around 50%. We hypothesize that pretreatment with azacytidine will improve the overall response rate and remission status. Objectives : The primary objective of this study is to evaluate the overall response rate (ORR) of pretreatment with azacytidine followed by FLAG for the treatment of relapsed/refractory AML. Methods: This is prospective phase II study of patients with diagnosis of refractory/relapse AML at King Fahad Medical City, Riyadh, Saudi Arabia between January 2015 and July 2018. Patient confirmed to be relapse/refractory AML based on bone marrow biopsy results were included. Eligible patients received pretreatment with azacytidine for 5 days (days -5 to -1). The FLAG protocol was started on the next day after the completion of 5-azacytidine. G-CSF was started on day 0 (24 hours after last 5-azacytine dose) and continued for a total of seven days (days 0 to 6). Fludarabine and cytarabine was started on next day after G-CSF start day and continued daily for 5 days (days 1 to 5). Patients were followed up with daily clinical examination and labs until next bone marrow examination at count recovery up to day 35. The bone marrow sample was analyzed for cell cycle and global DNA methylation status before and after azacytidine treatment. The ORR is the proportion of the treated patients who achieved CR or Cri. The toxicity was graded base on the frequency of Adverse Events (the NCI-CTCAE version 4.0 scoring system). Results: Sixteen refractory/relapsed AML patients (5 females; 11 males) admitted to our Center from January 2105 to July 2018 were included in the study. Twelve patients were evaluable after exclusion of three patients from analysis based on exclusion criteria. One patient died during induction. The mean age was 39.38 ± 15.11 years. The mean WBC, hemoglobin, platelets, peripheral blood blasts, bone marrow blasts were 26.44 ± 23.15, 7.43 ± 1.55, 61.81 ± 85.20, 49 ± 30.36, and 57.36 ± 29.23 respectively at diagnosis. The mean bone marrow blasts were 42.09 ± 29.75 at relapse/refractory disease. Seven patient had normal Cytogentics. One patient had BCR (9q43), PML (15q22), RUNX1T1(8q22) & MLL (11q23) genes. Another one had EGR1 (5q31) deletion, while t(8;21) was found in another patient. One patient was positive for 7q31 deletion. Four out of twelve patients had abnormal molecular cytogentics including FLT3 -ITD, CEBPA, FLT3 -TKD mutation and KITD816V. No patient has extramedullary disease at diagnosis or relapse settings. Seven out of twelve patients had primary refractory disease while five patients had relapsed disease with 6 months' median duration of remission (Range 1.25-84). Nine patient received 3+7 induction regimen at diagnosis while three had ICE protocol. Eight out of twelve patients showed complete response (67%). Four out of five relapsed patients achieved complete response (80%) whereas four out of seven (57.14%) achieved complete response in refractory disease. Eight patients were referred for stem cell therapy. The most common toxicity was cytopenia and bacterial infections. One patient has left arm cellulitis whereas one had arthritis with myositis. All patients were successfully treated with antibiotics, one patient died during study period because of severe invasive fungal infection. Conclusion Our phase II study preliminary results indicate that the addition of Azacitidene prior to standard therapy can improve the overall response rate and remission status in relapsed/refractory AML. This may provide an opportunity to responding patients to proceed to curative therapy with stem cell transplant. Disclosures No relevant conflicts of interest to declare.

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Bendamustine in Patients with Quad- and Penta-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-112258 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5627-5627

Author(s):

Scott Goldsmith ◽

Mark A. Fiala ◽

Brandon B. Wang ◽

Mark A. Schroeder ◽

Tanya M. Wildes ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Salvage Regimen ◽

Overall Response

Abstract Introduction: Despite significant advances in multiple myeloma (MM) therapy, disease progression through multiple novel treatments is often inevitable. Quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide), or penta-refractory MM (refractory to an anti-CD38 monoclonal antibody as well) portends a poor prognosis, with few subsequent lines of treatment currently available. We and others have used bendamustine combined with corticosteroids as a salvage regimen, but there is a paucity of outcomes data in this heavily pretreated population. Methods: We conducted a retrospective study to identify all patients who received bendamustine with corticosteroids for quad- or penta-refractory MM at our institution between 2013 and 2018. Disease response and refractoriness were defined by IMWG criteria. The primary endpoint was overall response rate (ORR) defined as PR or better. Secondary endpoints included overall survival (OS) and duration of response (DOR). Results: Twenty-seven patients were identified; 5 patients were quad-refractory, and 22 penta-refractory (Table 1). Twenty-two (81%) patients had at least one prior autologous stem cell transplant and 1 had a prior allogeneic. The median age at time of bendamustine was 61, 52% were female, and 85% were white. All patients received bendamustine at a dose of 90mg/m2 on days 1 and 2 of a 28 day cycle. Twelve patients (44%) received more than one cycle (range: 1-8). The overall response rate was 26%. While no patient achieved CR, 4 achieved VGPR and 3 a PR. Two of the 5 (40%) quad-refractory patients responded compared to 5 of the 22 (23%) penta-refractory. Sixteen (59%) were primary refractory to bendamustine and one patient went onto hospice prior to response evaluation. Overall the median PFS was 1.4 months (95% CI 1.1-1.6) and median OS was 8.7 months (95% CI 2.3-15.0). For responders (≥PR), median DOR was 6.6 months (95% CI 0.0-13.7) and median OS was 14.0 months (95% CI 0.6-27.4). Conclusion: The prognosis of quad- and penta-refractory MM remains poor. In this heavily pre-treated population, bendamustine demonstrates a 26% ORR (95% CI 11%-46%). The DOR and OS of the patients was poor but highly heterogeneous. Those who did respond to bendamustine had notably improved OS. Given the limited available options for quad- and penta-refractory MM, bendamustine remains a reasonable salvage therapy. Prospective trials are warranted perhaps including additional agents that are effective in penta-refractory patients. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Clofarabine, Idarubicin, and Cytarabine (CIA) As Frontline Therapy for Patients <= 60 Years with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v120.21.43.43 ◽

2012 ◽

Vol 120 (21) ◽

pp. 43-43

Author(s):

Aziz Nazha ◽

Farhad Ravandi ◽

Hagop M. Kantarjian ◽

Xuelin Huang ◽

Sangbum Choi ◽

...

Keyword(s):

Induction Therapy ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Hepatic Function ◽

Phase Iii ◽

Cell Transplant ◽

Newly Diagnosed ◽

Free Survival ◽

Overall Response

Abstract Abstract 43 Background Clofarabine is a second generation nucleoside analogue with activity in adults with AML. A recent randomized phase III study in relapsed AML showed higher response rates and better event-free survival (EFS) with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. A phase I/II trial of CIA in patients with relapsed/refractory AML had shown an overall response rate (ORR) of 38% (21% CR; 11% CRp). To explore this combination further, we conducted a phase II study of CIA in patients </= 60 years with previously untreated AML. Patients and Methods Eligible were patients >18–60 years with newly diagnosed AML and adequate renal and hepatic function. Patients were excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 patients, induction therapy consisted of Clofarabine (C) 22.5 mg/m2 iv daily (days 1–5), Idarubicin (I) 6 mg/m2 daily (days 1–3), and Cytarabine (A) 0.75 g/m2 daily (days 1–5). From patients 31 onward, induction doses were amended to C 20 mg/m2 × 5, I 10 mg/m2 × 3, and A 1 g/m2 × 5. Patients who did not achieve CR following induction could receive one re-induction course. Patients in CR/CRp/CRi continued with up to 6 consolidation cycles (C 22.5 mg/m2 × 3, I 6 mg/m2 × 2, and A 0.75 g/m2 × 3, subsequently amended to C 15 mg/m2 × 3, I 8 mg/m2 × 2, and A 0.75 g/m2 × 3). Results From April 2010 until February 2012, 59 patients were enrolled (Table 1). Fifty-seven patients were evaluable. Forty-two patients (74%) achieved CR and 3 (5%) CRp for an overall response rate of 79%. Ten patients required a re-induction {4/10 (40%) patients achieved CR, 2/10 (20%) achieved CRp). All patients received a median of 2 cycles (1–8 cycles), 24 (42 %) patients proceeded with an allogeneic stem cell transplant in first remission. With a median follow up of 10.9 months (1.6 - 23.1), the median OS was not reached, the median EFS was 13.5 months, and the median relapse free survival was not reached. Most toxicities were < grade 2. Toxicities > grade 2 included nausea (47%), rash (39 %), diarrhea (25%), elevated transaminases (23%), and elevated bilirubin (12%). Myelosuppression was ubiquitous but prolonged myelosuppression > 42 days was infrequent. Four week mortality was 2%. The response rate and toxicity were similar in both dose schedules. In subgroup analysis, patients < 40 years had better OS (HR 0.12, 95%CI, 0.02–0.90, P = 0.04) and EFS (HR 0.12, 95%CI, 0.02–0.93, P = 0.04) compared to patients > 40 years old. Compared to a historical group of patients who were treated with IA combination (I 12 mg/m2 IV daily × 3 plus A 1.5 g/m2 IV daily × 4) and after controlling for age, cytogenetics and other important clinical factors, the OS and EFS were significantly higher (P = 0.005, 0.0001, respectively) for CIA treated patients. Furthermore, in multivariate analysis, CIA retained its superior impact on OS (HR 0.53, 95% CI, 0.29 to 0.97, P =0.03) and EFS (HR 0.40, 95% CI, 0.22 to 0.73, P =0.003) compared to IA. Conclusion CIA is an active combination for patients </= 60 years with newly diagnosed AML. Patients < 40 years had significantly better OS and EFS. Compared to IA alone, CIA achieved significantly longer OS and EFS. A randomized comparison with standard induction therapy will be needed to further assess the role of CIA in frontline AML therapy of younger patients. Disclosures: Off Label Use: Clofarabine in AML. Ravandi:Genzyme: Research Funding. Kantarjian:Genzyme: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Lenalidomide, Bortezomib, and Dexamethasone (RVD) in Combination with Vorinostat As Front-Line Therapy for Patients with Multiple Myeloma (MM): Results of a Phase 1 Study

Blood ◽

10.1182/blood.v120.21.336.336 ◽

2012 ◽

Vol 120 (21) ◽

pp. 336-336 ◽

Cited By ~ 6

Author(s):

Jonathan L. Kaufman ◽

Jatin J. Shah ◽

Jacob P. Laubach ◽

Alaina R. Mitchell ◽

Cathy Sharp ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Cardiopulmonary Arrest ◽

Hematologic Toxicity ◽

Cell Transplant ◽

Newly Diagnosed ◽

Advisory Committees ◽

Overall Response

Abstract Abstract 336 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate (Richardson et al, Blood 2010; Kumar et al, Blood 2012). The addition of a novel targeted agent to RVD may improve depth of response as reflected by an increase in complete remission (CR) rate. Preclinical studies have demonstrated that vorinostat (Vor), a histone deacetylase inhibitor, is synergistic with bortezomib, immunomodulatory compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study was to determine the tolerability and activity of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (pts) received the classical RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5–8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. Dose limiting toxicity (DLT) (Grade (G) 3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of neutrophils to 1,000/μL or platelets to 50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified European Group for Blood and Marrow Transplantation and Uniform Criteria. Pts with partial remission (PR) or better could proceed to autologous transplant after 4 cycles. After completion of 8 cycles, patients could continue maintenance with lenalidomide +/− bortezomib, with Vor not administered during maintenance therapy. Results: Thirty pts (median age 56 years [range 40–76], 63% men) were enrolled with 4 pts in cohort 1 (Vor 100mg), 15 pts in cohort 2 (Vor 200mg), 8 pts in cohort 3 (Vor 300 mg) and 3 pts in cohort 4 (Vor 400mg). The maximum tolerated dose was determined to be 200 mg Vor with RVD. Including maintenance, the median number of cycles completed was 4 (range <1 to 41) with 5 pts completing less than 4 cycles, 4 because of toxicity and one for non-compliance. Ten patients completed 4 cycles and discontinued study therapy and proceeded to autologous stem cell transplant. Eleven pts completed 8 cycles with 8 pts remaining on study having completed between 4 and 41 cycles. Five DLTs have occurred, one in cohort 1 (syncope), one in cohort 2 (venous thromboembolism [VTE]) and 3 in cohort 4 (reversible G4 thrombocytopenia without bleeding; G3 reversible, asymptomatic elevated transaminases and G5 cardiopulmonary arrest, suspected to be due to VTE but not confirmed). The most common G1 or higher toxicities included thrombocytopenia (n=30), constipation (n=25), diarrhea (n=20), fatigue (n=19), nausea (n=16), and neuropathy (n=8). Grade 3 toxicities that occurred in 10% or more of pts were thrombocytopenia (n=8), fatigue (n=5), neutropenia (n=3), cardiovascular (n=3) and neuropathy (n=3). The overall response rate (PR or better) was 100% for the 29 evaluable pts, with a very good PR (VGPR) or better of 52% and a CR rate of 28%. For those pts who completed 4 cycles, VGPR and CR rates were 60% and 32% respectively and for pts who completed 8 cycles, the rates were 64% (VGPR) and 55% (CR). At a median follow up of 11.5 months (range 1 – 31 months) there has been only one pt with progressive disease (asymptomatic relapse from CR). Conclusion: The combination of RVD with vorinostat using the classical dose and schedule proved most tolerable at 200mg Vor dosing D1-14 every 21 days. The remarkably high VGPR/CR rate after 4 cycles and favorable progression free survival suggest that this combination is very effective. Alternative dosing and schedule of Vor may improve tolerability and so enhance clinical benefit, thus warranting further study. Disclosures: Kaufman: Onyx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Merck: Research Funding. Off Label Use: use of vorinostat in myeloma; use of lenalidomide as induction. Shah:Novartis: Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harvey:Celgene: Research Funding. Heffner:Millenium: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck; all < $10,000 per year and disclosed to my institution: Consultancy.

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SDX-105 Demonstrates a High Response Rate as a Single-Agent with Acceptable Safety in Rituximab-Refractory, Relpased Indolent or Transformed Non-Hodgkin’s Lymphoma (NHL).

Blood ◽

10.1182/blood.v104.11.2480.2480 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2480-2480 ◽

Cited By ~ 1

Author(s):

Jonathan Friedberg ◽

Philip Cohen ◽

Robert O. Kerr ◽

K. Sue Robinson ◽

Andres Forero-Torres ◽

...

Keyword(s):

Bone Marrow ◽

Dose Reduction ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Mitotic Catastrophe ◽

Hematologic Toxicity ◽

Overall Response ◽

Cell Death Pathway ◽

Grade 3

Abstract SDX-105 (Treanda™, Bendamustine HCl) is an alkylating agent that may exert its anti-tumor activity via mitotic catastrophe, an apoptosis-independent cell-death pathway, as well as, through apoptosis. Its cytotoxic potency is unattenuated in chemotherapy-resistant lymphoma cell lines. We initiated a multi-center Phase II trial to investigate the safety and efficacy of SDX-105 in patients with rituximab-refractory, relapsed indolent or transformed B cell NHL. Patients must have pathologically-confirmed disease that has been demonstrated to be rituximab-refractory (no response or progression within 6 months) or must be intolerant of rituximab. Other requirements include measurable disease, adequate renal, hepatic and bone marrow function (ANC ≥1K/mm3, platelet ≥ 100K/mm3, except in cases of >50% NHL in bone marrow), up to 3 prior chemotherapies, and no prior allogeneic transplant. Patients receive SDX-105, 120 mg/m2 IV over 30–60 min, days 1 and 2, every 21 days. Grade 4 hematologic toxicity during a cycle results in dose reduction for subsequent cycles (to 90 mg/m2 and then to 60 mg/m2). Patients achieving stable disease or better after 6 cycles may receive up to 6 more cycles. 49 patients have been accrued to date with data available on the first 15 patients. The median age is 69 yrs (range 47–84), 47% male, median 6 yrs since diagnosis with NHL. Histologies: 10 follicular (6 Grade 1, 3 Grade 2, 1 Grade 3), 2 SLL, 1 marginal zone and 2 transformed NHL. Other features include: 93% Stage III/IV, 20% with B symptoms, 87% with extranodal disease, median 2 prior chemotherapies with 40% not responding to last chemotherapy. 4 patients have required dose reduction to 90 mg/m2 and 2 patients have withdrawn prior to completing 6 cycles due to treatment-associated toxicity. The current overall response rate (ORR) based upon best response in the intent-to-treat population is 80% (CR/CRu 20%, PR 60%). Overall 73% of patients experienced a related non-hematologic adverse event (AE), of which 20% were Grade 3 and 0% Grade 4. The most frequent AEs were nausea (40%), vomiting (27%), fatigue (33%), anorexia (20%), and constipation (20%). Alopecia was not observed. Grade 3 or 4 hematologic toxicity was seen in 53% (neutropenia), 20% (thrombocytopenia), and 13% (anemia) of patients. 4 patients experienced serious AEs, including 1 patient with baseline renal insufficiency who died on study from renal failure and pulmonary edema; other events include admissions for fever and anemia, urinary tract infection, and dehydration. Based upon these preliminary findings, SDX-105 demonstrates a high overall response rate with acceptable hematologic toxicity and modest non-hematologic toxicity in a relapsed lymphoma patient population, many of whom are refractory to rituximab-chemotherapy combinations. An additional study evaluating the combination of SDX-105 and rituximab in patients with relapsed indolent NHL who are rituximab-sensitive is also ongoing.

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Phase II Trial of the mTOR Inhibitor RAD001 in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: The Dana Farber Cancer Institute Experience.

Blood ◽

10.1182/blood.v112.11.1011.1011 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1011-1011

Author(s):

Irene M. Ghobrial ◽

Stacey Chuma ◽

Amy Sam ◽

Renee Leduc ◽

Marybeth Nelson ◽

...

Keyword(s):

Phase Ii ◽

Overall Response Rate ◽

Mtor Inhibitor ◽

Response Rate ◽

Significant Activity ◽

Waldenström Macroglobulinemia ◽

Overall Response ◽

Dana Farber Cancer Institute ◽

Waldenstrom Macroglobulinemia ◽

Grade 3

Abstract INTRODUCTION: Previous studies have demonstrated the clinical activity of the mTOR inhibitor RAD001 in low- grade lymphomas. Our preclinical studies demonstrated activity of mTOR inhibitors in Waldenstrom Macroglobulinemia (WM) cell lines and patient samples. This phase II study aimed to determine safety and activity of the oral mTOR inhibitor RAD001 (Novartis Pharmaceutical, MA) in patients with relapsed or refractory WM. METHODS: Patients who had at least one previous therapy for WM, and who had symptomatic relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received daily RAD001 at 10 mg. A cycle was considered 28 days. Patients were allowed to stay on therapy until progression of disease or excessive toxicity. This study was conducted in a collaborative effort between Dana Farber Cancer Institute (DFCI) and Mayo Clinic College of Medicine. Here, we report the data on the patients accrued at DFCI. RESULTS: 19 pts (15 men and 4 women) have been treated to date. All patients had symptomatic disease and required therapy. The median number of lines of prior treatment was 3 (range 1 – 5) including included rituximab, nucleoside analogues (fludarabine or 2-CDA), combination chemotherapy (e.g. CHOP, CVP), chloramucil, and bortezomib. The median IgM at baseline was 3330 mg/dL (range 1010– 7410). The median follow on RAD001 was 8 months (range 3 – 22 months). Eighteen pts are currently evaluable for response. Best responses to RAD001 after 2 cycles using IgM monoclonal protein were as follows: partial remission in 8 (44%), minimal response in 5 (28%). Progressive disease occurred in 4 (22%) and stable disease occurred in 1 (6%). The overall response rate (PR+MR) was 72%. The median duration of response has not been reached (3–22+ months). Patients tolerated therapy well without significant toxicities. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 1 patient, grade 3 pneumonia in 1 patient, grade 3 hyperglycemia in 1 patient and grade 3 mucositis in 1 patient. Other adverse events of grade 2 or lower included nail cracking, mucositis, diarrhea, and fatigue. Attributable toxicities otherwise proved manageable with appropriate supportive care, and RAD001 was generally well tolerated. One patient enrolled on the study withdrew consent and changed to hospice care within 3 weeks of therapy, and passed away due to disease progression. CONCLUSIONS: The use of the oral RAD001 single agent RAD001 in patients with relapsed or refractory WM was welltolerated and demonstrated significant activity achieving an overall response rate in 72% of patients. Future studies of combination of this agent with rituximab and bortezomib are currently being planned.

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High Overall Response Rate in Calcineurin Inhibitor-Free Treatment with the mTOR Inhibitor Everolimus in Advanced Extensive Chronic GvHD after Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v112.11.2210.2210 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2210-2210 ◽

Cited By ~ 3

Author(s):

Anne Klink ◽

Kristina Schilling ◽

Katrin Rapp ◽

Klaus Höffken ◽

Herbert G. Sayer

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Overall Response Rate ◽

Mtor Inhibitor ◽

Response Rate ◽

Complete Response ◽

Overall Response ◽

Free Treatment ◽

Unrelated Donors ◽

Grade Ii

Abstract Background: The mammalian target of rapamycin (mTOR) inhibitor Everolimus (RAD001, Certican®) is a new immunosuppressive drug and beside of sirolimus used and approved in solid organ transplantation. Recently, it was reported that mTOR-inhibitors in combination with calcineurin inhibitors (CNI) showed clinical responses in chronic graft-versus-host disease (cGvHD). In this single centre retrospective analysis, we report on 29 patients (pts) with severe cGvHD treated with Everolimus without CNI. Patients and Methods: Twenty-nine pts (17 AML, 3 CML, 4 ALL, 3 CLL, 2 NHL) with a median age of 44 years [range: 25–61] underwent allogeneic stem cell transplantation between September 1999 and August 2007. Myeloablative conditioning was used in 21 pts, reduced-intensity conditioning in 8 pts. Except for one patient receiving bone marrow, all pts received peripheral blood stem cells for transplantation. Family donors (2 non-fully HLA matched) were used in 7 pts (24%) and unrelated donors (7 non-fully HLA-matched) in 22 pts (76%). GvHD-prophylaxis consisted of CNI (cyclosporine or tacrolimus) in 4 pts, CNI+Methotrexate (MTX) in 8 pts, CNI+Mycophenolate (MPA) in 8 pts and CNI+MPA+MTX in 9 pts. Antithymocyte globulin (ATG) as in vivo T-cell depletion was used in 9 pts. Cytomegalovirus (CMV)-serostatus was positive in 14 pts, with seronegative donors in 5 pts. Acute GvHD occurred in 27/29 (93.3%), grade II-IV in 25 (86.2%). At the same time, CMV reactivation/infection was observed in 11 pts and thrombotic microangiopathy (TMA) in 3 pts. All pts developed severe cGVHD with extensive disease. Organ involvement included skin with scleroderma in 21 pts, mucous membranes in 22 pts, eyes in 22 pts, lungs in 8 pts, liver in 11 pts, gut in 9 pts and arthralgia in 6 pts. At the time of treatment start with everolimus (0.75 mg Certican ® twice a day orally), CNI medication was stopped. The intended plasma therapeutic levels of everolimus were 3–8 mg/l. In addition all pts received prednisone and in 18 pts (62%) MPA as third immunosuppressive agent was continued. Results: Median treatment duration was 8.4 months [range: 2.5–21.7]. None of the pts developed CMV disease or TMA. Adverse events were: arterial hypertension in 1 patient, atrial fibrillation in 1 patient, pneumonia in 1 patient, sinusitis in 1 patient, herpes labials infection in 1 patient, renal insufficiency grade II in 2 pts and myalgia in 2 pts. 96.6% are still alive, 1 patient (3.4%) died due to relapse of ALL. Two pts (6.9%) achieved a complete response of their cGvHD and 18 pts (62.1%) a partial response resulting in an overall response rate of 69.0% (n=20) according to the recent consensus NIH report (Biol. Blood Marrow Transplant. 2006 May; 12(5): 491–505). No change was observed in 3 pts (10.3%) and progression occurred in 6 pts (20.7%). Complete response in HLA-identical related donors was 20% (1/5) and with HLA-matched unrelated donors was 6.7% (1/15). 100% (n=2) of pts with a HLA-mismatched related donor achieved a partial remission and 85.7% (n=6) of pts with a HLA-mismatched unrelated donor. The gender of recipient or donor did not impair the observed responses with everolimus. Prednisone could be tapered in 62.1% of all pts (18/29). In the triple combination with MPA, MPA could be tapered in 22.2% (4/18) and could be stopped in 38.9% (7/18). Conclusions: A CNI-free treatment of advanced extensive cGvHD with everolimus seems to be feasible and effective with a high overall response rate of nearly 70 %. It should be emphasized that a low toxicity profile without TMA was observed. Our data supports further clinical and immunological investigations with m-TOR inhibitor everolimus in treating GvHD.

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