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

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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Clofarabine, Idarubicin, and Cytarabine (CIA) As Frontline Therapy for Patients Younger Than 61 Years with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v118.21.1550.1550 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1550-1550

Author(s):

Aziz Nazha ◽

Farhad Ravandi ◽

Hagop M. Kantarjian ◽

Guillermo Garcia-Manero ◽

Elias Jabbour ◽

...

Keyword(s):

Induction Therapy ◽

Research Funding ◽

Response Rate ◽

De Novo ◽

Phase Iii ◽

Molecular Profile ◽

Cell Transplant ◽

Newly Diagnosed ◽

Elevated Bilirubin

Abstract Abstract 1550 Background: Clofarabine is a second generation nucleoside analogue with activity in adults with AML. A recent randomized phase III study in AML relapse showed higher response rates and better event-free survival with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. We have also reported the feasibility and safety of the addition of idarubicin to CA (CIA) in a previous phase I and II study. To explore this combination further, we conducted a phase II study of CIA in pts</= 60 years with previously untreated AML. Patients and Methods: Patients (Pts) were eligible if they were </=60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 pts, induction therapy consisted of Clofarabine 22.5 mg/m2 iv daily (days 1–5), Idarubicin 6 mg/m2 daily (days 1–3), and Cytarabine 0.75 g/m2 daily (days 1–5). From pt 31 onward, induction doses were amended to Clofarabine 20 mg/m2 × 5, Idarubicin 10 mg/m2 × 3, and Cytarabine 1 g/m2 × 5. Pts who have not achieved a complete remission following the induction could receive one re-induction course. Pts in CR or CRp continued with up to 6 consolidation cycles with Clofarabine 22.5 mg/m2 × 3, Idarubicin 6 mg/m2 (days 1–2), and Cytarabine 0.75 g/m2 × 3, subsequently amended to Clofarabine 15 mg/m2 × 3, Idarubicin 8 mg/m2 × 2, and Cytarabine 0.75 g/m2 × 3. Supportive care was standard. Pts ≥ 50 yrs were admitted to a laminar air flow room for the duration of the induction. Results: From April 2010 until August 2011, 51 pts have been accrued with a median age of 49 yrs (range 19–59): 33 pts (65%) with de novo AML and 18 pts (35%) with secondary AML (18 related to MDS, 7 related to therapy). Three pts (5%) had a PS of 2. Median WBC at diagnosis was 3.4 × 109/L (0.6-92.3). Thirty-three (65%) pts had abnormal cytogenetics (21/33[64%] poor risk and 5/33 [15%] intermediate risk). Molecular profile: 6 pts (11%) had FLT3/ITD, 3 pts (6%) CEBPA, and 8 pts (16%) NPM1 mutations. Thirty-five pts (69%) achieved CR and 1 (2%) CRp for an overall response rate (ORR) of 71%. 61% pts (31/51) achieved CR following one induction cycle. 18% (9/51) pts required a re-induction and 44% (4/9) of them responded after the re-induction. Responding pts received a median of 2 courses (1–8) courses. With a median follow-up of 23 weeks (3–36+) median remission duration has not been reached with a 1-yr remission probability of 85%. Ten pts (19%) died on study including 2 (4%) who died < 28 days from treatment start (one from septic shock and multi-organ failure, and one from Steven Johnson syndrome). Median overall survival (OS) for responding pts has not been reached (2–36 weeks). One-yr survival probability is 65%. Sixteen pts (31%) proceeded with an allogenic stem cell transplant in CR1. Most toxicities were </= grade 2 and included rash (41 %), nausea (29%), diarrhea (23%), elevated transaminases (21%), and elevated bilirubin (17%). Toxicities > grade 2 included elevated bilirubin (4%), hypokalemia (4%), cellulitis (4%) and seizure (1%). Myelosuppression was ubiquitous but prolonged myelosuppression > 42 days was infrequent. 76 % (39/51) pts had neutropenic fever. Conclusion: Clofarabine, Idarubicin and Cytarabine achieve a response rate of 71% in patients </=60 yrs with previously untreated AML. Induction mortality was low and the toxicity profile was expected and manageable. Longer follow up and comparisons with standard induction therapy will be needed to further assess the role of this combination in AML therapy. Disclosures: Off Label Use: Clofarabine, use of 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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Decitabine Is Effective and Safe In Patients with Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v116.21.4032.4032 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4032-4032

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

A. Megan Cornelison ◽

Tapan Kadia ◽

...

Keyword(s):

Median Survival ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Chronic Myelomonocytic Leukemia ◽

Phase Iii ◽

White Blood Count ◽

Survival Duration ◽

Overall Response ◽

Myelomonocytic Leukemia

Abstract Abstract 4032 Background: Chronic myelomonocytic leukemia (CMML) is a rare yet indolent disease. The median survival duration in CMML is 12 to 18 months and patients with poor prognostic features do even worse, with median survival time ranging 3 to 6 months. Activity with decitabine in CMML has been previously reported. We sought to analyze the clinical experience of 17 adults with a diagnosis of CMML treated on two decitabine studies. Methods: A subset of patients with CMML from a pivotal phase III 3-day dosing and an open-label trial of 5-day dosing were identified and reviewed to determine the overall response rate (ORR, based on IWG 2006 criteria), duration of response, time to response, and overall survival (OS). Results: A total of 17 patients with CMML were included in this review. Mean age at diagnosis was 71 years (range, 47 to 81 years) with a mean time from diagnosis of 406.4 days. The majority of CMML patients had de novo (94.1%), good risk cytogenetics (58.8%) with an IPSS classification of Intermediate-1 (64.7%). Baseline mean white blood count (WBC), hemoglobin (HGB), and platelets (plts) were 7.5 × 103/μ L, 14.6 g/dL and 81.9 × 103/μ L, respectively. A larger proportion of CMML patients at baseline were plt and RBC transfusion independent. Objective response rate (ORR) was 41% [17.6% complete response (CR) and 23.5% marrowCR (mCR)]; Hematologic improvement (HI) was observed in 11.7% and stable disease in 29.4% of patients. Median survival was 391 (95% CI 239, 678) days and 2 (11.7%) patients progressed to AML. The adverse event profile was similar to observations in previous trials with myelosuppression and infectious complications. Conclusions: This retrospective review of responses in CMML patients supports previous findings of decitabine experience in this population. In this analysis an overall response rate of 41.4% was achieved. Decitabine provided anti-CMML activity with an acceptable safety profile. Disclosures: Jabbour: Eisai Inc.: Editorial and statistical support from Eisai Inc., Honoraria. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy. Ravandi:Eisai Inc.: Research Funding; Eisai Inc.: Honoraria. Borthakur:Eisai Inc.: Research Funding. Cortes:Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding.

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Interim Results of An Ongoing Clinical Study Suggests Efficacy and Improved Toxicity Profile with Once a Week Bortezomib with Dexamethasone In Newly Diagnosed Multiple Myeloma Patients with Older Age and Co-Morbidities

Blood ◽

10.1182/blood.v116.21.3061.3061 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3061-3061 ◽

Cited By ~ 1

Author(s):

Nikhil C. Munshi ◽

Saem Lee ◽

Suman Kambhampati ◽

Abid Mohiuddin ◽

Michal Rose ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Overall Response Rate ◽

Response Rate ◽

Previous History ◽

Cell Transplant ◽

Newly Diagnosed ◽

Advisory Committees ◽

Current Time ◽

Overall Response

Abstract Abstract 3061 The current bortezomib schedule involves administration of the drug twice a week at 1.3 mg/m2 for 2 weeks every 21 days. This regimen although effective is inconvenient and associated with side effects including neuropathy and gastrointestinal toxicities that limits its use in a proportion of patients. Therefore, to improve convenience and compliance, we have investigated efficacy and safety of a weekly regimen of bortezomib. In this one-stage phase II multi-center, open-label single-arm study bortezomib is administered once a week at 1.6 mg/m2 in combination with dexamethasone in newly-diagnosed multiple myeloma patients not considered for autologous stem cell transplant in participating Veterans Hospitals nationwide. The objective is to evaluate overall response rate and toxicity of this regimen. Patients received bortezomib at 1.6 mg/m2 IV weekly for 4 weeks followed by 1 week off and dexamethasone 40mg PO on the day of and day after each dose of bortezomib. Patients may receive 6 such 5-week cycles. At the current time 32 patients (median age - 73; range 50–88) have been enrolled at 11 Veterans Administration Hospital across the U.S. Patients had significant co-morbidities including 61% with cardiovascular problems, 58% with diabetes and/or hyperlipidemia, 58% with elevation of serum creatinine, 26% with respiratory problems and 23% with previous history of cancer. All patients were at least on 5 daily medications. Of the 32 patients enrolled, 25 patients have received at least one cycle of therapy and were evaluable for toxicity and efficacy, while 6 patients have received less than one cycle of therapy and one patient has inadequate data. With a median of 4 cycles administered, this regimen was well tolerated. None of the patients have developed grade 3 neuropathy, while grade 1 neuropathy was observed only in 2 patients and one patient with grade 1 neuropathy at diagnosis had increase to grade 2. Dexamethasone dose was reduced in 29% patients while 6% required reduction in bortezomib dose to 1.3 mg/m2. Additionally, Grade ≥1 asthenia was observed in 42%, diarrhea in 35%, and thrombocytopenia in 26%. Four patients have died of co-morbidities which were considered unrelated or probably unrelated to the treatment with bortezomib. The partial response or better was achieved in 68% patients receiving at least 1 cycle of therapy; 20% patients achieved CR/nCR and additional 12% achieved VGPR. Including MR in the analysis, overall response was observed in all evaluable patients. On intent to treat analysis including all 32 patients, overall response rate (≥ MR) was observed in 78% patients and PR or better in 53% patients. These preliminary results suggest that the once a week bortezomib regimen is effective and tolerable with reduced toxicity even in this older patient population with significant co-morbidities. Disclosures: Munshi: Millennium: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roodman:Millennium: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria.

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AOP2014, a Novel Peg-Proline-Interferon Alpha-2b with Improved Pharmacokinetic Properties, Is Safe and Well Tolerated and Shows Promising Efficacy in Patients with Polycythemia Vera (PV)

Blood ◽

10.1182/blood.v120.21.175.175 ◽

2012 ◽

Vol 120 (21) ◽

pp. 175-175 ◽

Cited By ~ 3

Author(s):

Heinz Gisslinger ◽

Robert Kralovics ◽

Bettina Gisslinger ◽

Daniel Lechner ◽

Veronika Buxhofer-Ausch ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Phase Iii ◽

Molecular Response ◽

Overall Response ◽

Long Term Treatment

Abstract Abstract 175 AOP2014 is a next generation long-acting pegylated IFNa-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. AOP2014 has a distinct pharmacokinetic and pharmacodynamic profile which may potentially allow reduced dosing frequencies compared to other pegylated IFNs. This is being expected to result in improved tolerability, better compliance, and, finally, favorable long-term treatment outcomes. AOP2014 is a designated Orphan Drug in EU for treatment of patients with PV. The maximum tolerated dose (MTD), long term safety and efficacy of AOP2014, administered subcutaneously every 14 days, are the main objectives of the study. Patients with confirmed PV diagnosis, age equal or older 18 years, both naïve and cytoreduction pre-treated are eligible. After establishing the MTD, an extended cohort of 25 additional patients was planned to be recruited. European LeukemiaNet criteria were used for response assessment. 34 patients, treated by March 31, 2012 were included into this analysis: 25 in Phase I (dose-finding) and 9 in the Phase II (cohort extension). Median time from diagnosis was 24 months (range 0–180). 12 patients (35%) were HU pre-treated (mean past duration of HU pre-treatment 39 months, mean daily HU dose 950 mg). Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–8), a total of 21 patients (62%) were regularly phlebotomized at least once in three months prior to study entry. 11 patients (32%) had a history of thrombotic complications. Median Hct at baseline was 42% (range 36–51). Median WBC and platelet counts were 10.6*109/l (range 3.9–20.4) and 452*109/l (range 141–1019), respectively. 17 patients (50%) had splenomegaly at baseline. The median reported treatment duration was 41 weeks (range: 1 day – 80 weeks), 11 patients completed 1 year on treatment. Doses from 50 to 540 ug every two weeks were tested, 540 ug has been concluded as MTD as the highest tested dose, since no DLTs occurred in the study. The mean administered dose (both Phase I and II patients) was 287 ug. After 28 weeks of treatment (21 evaluable patients), 71% of patients had hematological response (7 CR, 33%; 8 PR, 38%), at week 36 (19 evaluable patients) 8 patients (42%) achieved a CR and 8 patients (42%) a PR, overall response rate (ORR, CR+PR) was 84%. At week 52 (1 year; 11 evaluable patients), 5 patients (46%) had CR and 5 (46%) PR, ORR was 91%; 8 (73%) patients presented with completely normalized blood values, all evaluable patients were phlebotomy free at this timepoint. 4 patients (of 12 evaluable for this measurement, 33%) had still enlarged spleen at week 52. At week 76, 2 evaluable patients were complete responders. At week 52, 1 patient (of 9 evaluable, 11%) developed partial molecular response, at week 68 3 patients (of 7 evaluable, 43%) had partial molecular response. One patient with allelic burden of 22% at baseline developed complete molecular response at week 36 (still ongoing). Mainly grade 1 and 2 adverse events were reported. A total of 358 adverse events occurred. 27 patients (79%) suffered from drug-related adverse events. 9 patients (26%) developed serious adverse events; 4 SAEs were considered to be treatment related. 5 patients (15%) discontinued their study participation prematurely, 3 of them due to adverse events (deterioration of underlying disease and two cases of depression). Acceptable tolerability and durable clinical benefits have been demonstrated in PV patients measured as overall response rate of above 90% with CRs of 46% at one year after treatment start. Phlebotomy independence and normalization of hematological parameters could be seen in most of the patients. The study continues to recruit and collect long term follow up information. Presented data support further development of AOP2014 in PV, a Phase III study is planned to start early 2013. Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding; Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Lechner:AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Tarmann:AOP Orphan Pharmaceuticals AG: Employment. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.

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Lenalidomide and Rituximab For The Treatment Of Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results Of Planned Interim Analysis

Blood ◽

10.1182/blood.v122.21.5299.5299 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5299-5299 ◽

Cited By ~ 1

Author(s):

Michael Y. Choi ◽

Januario E. Castro ◽

Sheila Hoff ◽

Hongying Li ◽

Laura Rassenti ◽

...

Keyword(s):

Partial Response ◽

Interim Analysis ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Free Survival ◽

Safety And Efficacy ◽

Overall Response ◽

Grade 3

Abstract Based on data previously presented by our group demonstrating the safety and efficacy of lenalidomide (L) and rituximab (R) in the upfront setting, we are conducting an open-label, phase 2 trial single center trial to evaluate this combination as treatment for patients with relapsed or refractory CLL. Methods Patients started L at 5 mg per day and could escalate to 25 mg/day if tolerated. Patients received L for 21 of 35 days for cycle 1, then 21 of 28 days for cycles 2 to 7. Rituximab was started at the end of C1 at 50 mg/m2 on Day 29, 325 mg/m2 on day 31 and 33, then 375mg/m2 weekly x4 for cycle 2, and on day 1 for cycles 3-7. Patients who achieved a response but had residual disease after 7 cycles were given the option to continue single-agent L in a consolidative manner for 6 additional cycles. All patients received allopurinol 300mg daily and aspirin 81mg daily, unless contraindicated. The primary endpoint was overall response rate by iwCLL guidelines following 7 cycles. This abstract reports on the planned interim analysis of the safety and efficacy. Results By April 2013, 24 patients were enrolled and received treatment. 63% of patients were male (15/24). The median age at the start of study treatment was 67 years (range 53-83), with median 2.5 prior therapies (range 1-7). 75% (18/24) had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 25% (6/24) had unfavorable cytogenetics (del 17p or del 11q). 5 patients stopped therapy early due to toxicity. 2 patients stopped treatment due to grade 3 tumor flare reaction. 1 patient developed grade 4 tumor lysis requiring hemodialysis. 1 patient had grade 4 neutropenia within days of starting L. 1 patient developed a deep vein thrombosis during cycle 2 while off aspirin for transient thrombocytopenia. These patients tended to have a higher baseline absolute lymphocyte count, but this association did not meet statistical significance. Treatment was otherwise well tolerated. Neutropenia was the most common adverse event (AE), with grade 4 (by CTCAE 4) in 9 patients, and grade 3 in 6 patients out of 21 evaluable patients. There was a single instance of grade 4 thrombocytopenia, and 4 patients had grade 3 thrombocytopenia. 3 patients had grade 3 anemia. The only other grade 3 or higher AE was fatigue (5%). Of note, grade 2 superficial thrombophlebitis occurred in 3 patients. Out of the 20 patients whose primary endpoints were assessed, the overall response rate (ORR) was 70% (14/20) with 15% nodular partial response (3 patients) and 55% partial response (PR) (11 patients). 30% (6/20) were non-responders (NR). Only 1 of the 6 patients with NR had objective progressive disease (PD). The other 5 patients stopped treatment early due to toxicity and were designed as non-responders. Of the responder patients, 8 elected to receive an additional 6 months of consolidation lenalidomide. All maintained the same response without meeting objective criteria for either PD or complete response. After a median follow-up of 17 months from the start of treatment, there have been no deaths among the 24 patients. For the 20 evaluable patients, the median progression free survival (PFS) was 18.4 months and the median treatment free survival was 13.5 months.We did not find any significant association between response, toxicity, or PFS and any demographic or prognostic variable analyzed, including age, ZAP-70, IgVH mutation, cytogenetics, splenomegaly, or CLL cell immunophenotype. Conclusions The combination of lenalidomide and rituximab is an effective regimen for the treatment of patients with relapsed or refractory CLL with an ORR and PFS that rivals novel CLL therapies, especially for patients continued on lenalidomide consolidation therapy. The median PFS for all patients is in excess of 1.5 years after a median follow-up of 17 months. A subset of patients encountered adverse events requiring early treatment cessation, but only 1 patient progressed on treatment. Continued accrual will facilitate the identification of biologic or clinical factors that may predict such outcomes. Disclosures: Choi: Celgene: Research Funding. Castro:Celgene: Research Funding. Kipps:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation

Blood ◽

10.1182/blood-2011-02-338665 ◽

2011 ◽

Vol 118 (5) ◽

pp. 1231-1238 ◽

Cited By ~ 134

Author(s):

Gareth J. Morgan ◽

Faith E. Davies ◽

Walter M. Gregory ◽

Nigel H. Russell ◽

Sue E. Bell ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Response Rate ◽

Response Rate ◽

Autologous Transplantation ◽

Progression Free Survival ◽

Initial Therapy ◽

Newly Diagnosed ◽

Free Survival ◽

Overall Response ◽

Depth Of Response

Abstract As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

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A Phase 2 Study to Assess the Feasibility and Tolerance of the Combination of Elotuzumab, Lenalidomide, and Dexamethasone (ERd) in the Induction, Consolidation, and Maintenance Treatment of Transplant-Eligible Patients Newly Diagnosed with Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2019-130277 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 603-603 ◽

Cited By ~ 4

Author(s):

Jesus G. Berdeja ◽

Tara K. Gregory ◽

Suman Kambhampati ◽

Bertrand M. Anz ◽

Stefano R. Tarantolo ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Research Funding ◽

Maintenance Treatment ◽

Overall Response Rate ◽

Response Rate ◽

Survival Rates ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Overall Response

Background: The introduction of novel agents such as proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) with and without corticosteroids has revolutionized treatment (tx) and improved survival rates for MM. IMID/PI triplets such as VRD (bortezomib, lenalidomide, dexamethasone), VTD (bortezomib, thalidomide, dexamethasone), or KRD (carfilzomib, lenalidomide, dexamethasone) are preferred inductions for transplant-eligible patients (pts). Unfortunately, the PI often has unique safety events such as peripheral neuropathy (PN) or cardiac issues that can impact the quality of life. Elotuzumab is a mAb with a dual mechanism of action (tagging MM cells and activating NK cells by binding SLAMF7). The combination of elotuzumab, lenalidomide, and dexamethasone (ERd), is active, well-tolerated, and approved by the FDA for pts with relapsed MM. In this study, we will determine the feasibility of incorporating ERd into a transplant-eligible pt population. Methods: Pts with newly diagnosed MM requiring chemotherapy planning to undergo autologous stem cell transplantation (ASCT) were enrolled. Induction of elotuzumab at 10 mg/kg was administered IV on days (D) 1, 8, 15, 22 of the 1st 2 28-day cycles and days 1, 15 of the third and fourth 28-day cycles. Lenalidomide was dosed at 25 mg orally on D 1-21 of each 28 day induction cycle. Dexamethasone was administered IV concurrent with elotuzumab (28mg orally 3-24 hours prior to infusion and 8 mg IV with elotuzumab), with 40 mg orally administered on D 8 and 22 of cycles 3 and 4. After completion of the 4 induction cycles, pts proceeded to mobilization and ASCT though pts who refused transplantation were allowed to proceed directly to consolidation and maintenance if the investigator believed the pt was deriving benefit. 70-120 days after ASCT, 4 cycles of consolidation were administered (dosing similar to cycles 3-4 of induction but with lenalidomide at 15mg). Pts then went on to maintenance with elotuzumab 20 mg/kg IV on D 1, oral lenalidomide 10mg +/- 5 mg D 1-21 and dexamethasone 28mg oral/8 mg IV prior to elotuzumab infusion were dosed in 28-day cycles for up to 24 months. The primary endpoint was the induction feasibility rate (IFR) defined as the percentage of pts successfully completing 4 cycles of induction tx with ERd and able to start ASCT. Secondary end points were complete response rate (≥nCR), overall response rate (≥PR), progression-free survival (PFS) and overall survival (OS). AEs were assessed according to CTCAE V4 and responses were assessed using the revised IMWG criteria. Results: 52 pts were enrolled: 56% male, median age 61 ys, 12% RISS III, 21% high-risk cytogenetics [17p del, t(4;14), and/or t(14;16)]. To date, 26 (50%) pts remain on active tx. 4 pts refused transplantation despite being eligible and were excluded from the IFR calculation. The IFR was 69% and the best overall response rate (ORR) was 92% (69% ≥ VGPR). With a median follow up of 20 mos, median PFS and OS for all pts were not reached. The 18 mo PFS and OS were 83% and 89% respectively. The most common AEs were fatigue (59.6%), diarrhea (42.3%) and nausea (42.3%). PN was seen in 29%, and all events were ≤ G2. There were 28 SAEs in 20 pts, including 12 tx-related SAEs. There was 1 tx-related death due to heart failure in a pt with no history of prior cardiac issues who had subsequent therapy. 29% of pts met the high-risk (HR) criteria (defined as RISS III or high risk cytogenetics) and 29% of pts were considered standard-risk (RISS I and no high-risk cytogenetics). The best ORR was 87% (67% ≥ VGPR) for HR pts and 93% (53% ≥ VGPR) for SR pts and the IFR was 57% for HR pts and 64% for SR pts. The median PFS and OS were 20.5 mos and 22.0 mos respectively for HR pts and have not been reached for SR pts. Conclusions: ERd induction, consolidation and maintenance was feasible and well tolerated in conjunction with ASCT in transplant-eligible pts. Despite high ORR for all pts, HR patients had inferior PFS and OS. This study supports the continued evaluation of this regimen in SR pts. Disclosures Berdeja: Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; Poseida: Research Funding; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding. Gregory:Takeda: Speakers Bureau; Celgene: Speakers Bureau; Poseida: Research Funding; Amgen: Speakers Bureau. OffLabel Disclosure: Yes, this was an investigational clinical study of the combination of elotuzumab, lenalidomide, and dexamethasone in the induction, consolidation, and maintenance treatment of transplant-eligible patients newly diagnosed with multiple myeloma.

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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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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

Blood ◽

10.1182/blood.v116.21.3301.3301 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3301-3301

Author(s):

Andrew H Wei ◽

Sonali Sadawarte ◽

John Catalano ◽

Anthony P. Schwarer ◽

Sharon Avery ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Overall Response Rate ◽

Mtor Inhibitor ◽

Response Rate ◽

Clinical Activity ◽

Cell Transplant ◽

Phase Ib ◽

Overall Response ◽

Refractory Aml

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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