Clofarabine Plus Low-Dose Cytarabine Induction Followed by Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine as Frontline Therapy for Patients (pts) with Acute Myeloid Leukemia (AML) ≥ 60 Years (yrs).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2058-2058
Author(s):  
Sameer A Parikh ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Low Dose ◽  
Single Agent ◽  
Disease Free Survival ◽  
Response Rates ◽  
High Response ◽  
Multiple Drugs ◽  
Low Dose Cytarabine

Abstract Abstract 2058 Poster Board II-35 Therapy of AML for elderly pts (≥ 60 yrs) remains challenging with low response rates, short durability of responses, and high toxicity rates following conventional therapy with standard-dose ara-C/anthracycline combinations. Clofarabine is a novel deoxyadenosine nucleoside analogue with single agent activity in frontline AML for older pts with ≥ 1 unfavorable prognostic factors. We have recently reported results of a randomized study suggesting higher response rates and comparable safety profile with the combination of clofarabine plus low-dose cytarabine over clofarabine alone. We have designed the current study of clofarabine plus low-dose cytarabine induction followed by consolidation with clofarabine plus low-dose cytarabine alternating with decitabine to maintain high response rates and improve disease-free survival based on the following hypotheses: 1) to extend duration of therapy by administering lower doses of the agents; and 2) to provide multiple drugs with different mechanisms of action to decrease risk of resistance. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days in a laminar air flow room. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during consolidation courses 1-2, 6-8, 12-14) alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3-5, 9-11, and 15-17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Forty pts have been enrolled with a median age of 70 yrs (range 60-80) of whom 22 (55%) had secondary AML (antecedent hematologic disorder in 11 pts). Two pts had received previous azacitidine for MDS. Fourteen pts (35%) had abnormal cytogenetics of whom 10 (25%) had monosomy 5, 7, or both. Four patients (10%) had a FLT3/ITD mutation. Of the 34 pts evaluable for response, 20 (59%) achieved CR and 2 (6%) CRp for an OR rate of 65%. Only 2 pts required 2 courses to CR. The OR rate for patients with diploid versus abnormal cytogenetics was 80% vs 50%; for pts with prior MDS versus no prior MDS 76% and 50%; and 75% for patients with FLT3 mutation. The median time to CR/CRp was 38 days (range 27-103). With a median follow up of 3.5 months (range 0.7-8.1), 2 pts relapsed (CR duration of 3.3 and 4.2 months, respectively); responses are ongoing in the remainder. Three pts (9%) died during induction therapy (one during re-induction) before a response could be established. The median number of consolidation cycles received by pts in CR was 3 (range 1-5). Most toxicities were ≤ grade 2 and included nausea/vomiting, diarrhea, rash, headache and mucositis. Six pts developed grade 3 elevations in serum transaminases which resolved at the end of induction therapy. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression was rare. In conclusion, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in elderly pts with previously untreated AML. Time-to-event parameters will be provided with more extensive follow up. Disclosures: Off Label Use: Clofarabine and Decitabine in AML. Kantarjian:Genzyme: Consultancy, Research Funding. Faderl:Genzyme: Consultancy, Research Funding; Eisai: Research Funding, Speakers Bureau.

Frontline Therapy for Older Patients (pts) with Acute Myeloid Leukemia (AML): Clofarabine Plus Low-Dose Cytarabine Induction Followed by Prolonged Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 336-336 ◽  
Author(s):  
Stefan Faderl ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Xuelin Huang ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Median Overall Survival ◽  
Low Dose ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
Prolonged Consolidation ◽  
Low Dose Cytarabine

Abstract Abstract 336 Standard therapy (e.g. “3+7”) of newly diagnosed older pts (≥ 60 yrs) with AML is characterized by low response rates, short response durations, and substantial toxicities. New approaches are therefore actively explored in clinical trials. Clofarabine is a second generation deoxyadenosine nucleoside analogue with activity in older pts with frontline AML and presence of unfavorable prognostic factors. In our experience, the combination of clofarabine with low-dose cytarabine achieved higher response rates at no increase of toxicity compared with clofarabine alone (Faderl S et al. Blood 2008). Based on the initial experience, we have designed a combination of lower-dose clofarabine plus low-dose cytarabine induction followed by a prolonged consolidation of these drugs alternating with decitabine to improve survival and maintain the high response rates from the earlier study. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during courses 1–2, 6–8, 12–14 alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3–5, 9–11, and 15–17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Fifty-nine pts have been accrued with a median age of 70 yrs (range 60–81), of whom 17 pts (29%) were ≥ 75 yrs. Eleven pts (19%) had a PS of 2. Seven pts (12%) had a WBC of > 20,000/mcl at diagnosis. Thirty pts (51%) had abnormal cytogenetics. Molecular profile: FLT3/ITD 5 pts (9%), FLT3/D835 2 (4), NPM1 6 (13), Ras 2 (4). Thirteen pts (22%) had prior MDS (4 pts prior azacitidine; 2 pts prior lenalidomide) and 17 pts (29%) had secondary AML (Hx of prior chemo and/or XRT). Of 57 pts evaluable for response, 35 (61%) achieved CR and 4 (7%) CRp for an ORR of 68%. Six pts (11%) required more than one course to response. The ORR for pts with diploid vs abnormal cytogenetics was 79% vs 57%; for pts with prior MDS 46% vs 82% for pts with neither MDS nor secondary AML. All 7 pts with a FLT3 mutation responded. With a median follow up of 11.6 months (1.1-20.2+), 16 pts relapsed. Responses (CR) are ongoing in 19 pts. Median CR duration is 14.1 mos (1.8-16.4). Six pts (10%) died on study. Only one pt suffered an early death ≤ 28 days from induction (C1D26). Deaths were due to myelosuppression-associated infectious complications. Median overall survival for all 59 pts was 18.1 mos (0.8-20.2+). Median overall survival for responding patients has not been reached. The median number of consolidation cycles received by pts in CR/CRp was 4 (0-14). Fifteen of these pts have so far received at least 6 consolidation cycles. Most toxicities were ≤ grade 2 and included rash (64%), nausea (61%), transaminase elevations (58%), bilirubinemia (51%), diarrhea (32%), mucositis, creatinine evelations, and headache (12% each). Among toxicities > grade 2, transaminase elevations (14%) and bilirubinemia (5%) were most frequent. One pt (65 yr old female) experienced renal failure and pulmonary edema shortly following start of the induction. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression in responders was rare. In summary, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in pts ≥ age 60 with previously untreated AML. Longer follow up and comparisons with conventional therapy will help establish whether or not this combination also has a survival advantage. Disclosures: Faderl: Genzyme: Honoraria, Research Funding; Eisai: Research Funding. Off Label Use: clofarabine and decitabine in AML. Kantarjian:Genzyme: Research Funding; Eisai: Research Funding.

scholarly journals Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 890-890
Author(s):  
Andrew Wei ◽  
Stephen A. Strickland ◽  
Gail J. Roboz ◽  
Jing-Zhou Hou ◽  
Walter Fiedler ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Intensive Chemotherapy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Treatment Naïve ◽  
Equity Ownership ◽  
Low Dose Cytarabine

Abstract Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of &gt;60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, &lt;1 to 21 months). Thirty-eight (62%) of these patients achieved CR/CRi with a median duration of CR/CRi of 14.9 months (95% CI, 5.6 months to not reached [NR]; Figure). Best responses were 26% CR, 36% CRi, and 2% PR. Median OS was 11.4 months (95% CI, 5.7-15.7 months); the observed 12-month OS was 46% (95% CI, 33-58%). Only 1 patient has subsequently undergone bone marrow transplantation. Treatment-emergent grade 3/4 AEs (in ≥20% of 61 patients) were thrombocytopenia (59%), neutropenia (46%), febrile neutropenia (36%), anemia (28%), and decreased WBC count (26%). One case (2%) of tumor lysis syndrome occurred. Serious AEs (in ≥3 of 61 patients) were febrile neutropenia (20%), malignant neoplasm progression (13%), lung infection/pneumonia (13%), and sepsis (7%). The 30-day mortality rate was 3%; causes of death were disease progression (n=1) and lung infection (n=1). Common recurrent mutations in 53 patients who received VEN 600 mg are shown in the Table. All patients with an NPM1 mutation (including 3 with a co-mutation in FLT3-ITD) achieved CR/CRi. Patients with DNMT3A, FLT3-ITD, and SRSF2 mutations had CR/CRi rates of ≥75%, whereas those with TP53 mutations had the lowest CR/CRi rates of 44%. For patients with CR/CRi, median OS was 18.4 months (95% CI, 13.5 months to NR). The 12-month OS rate for patients in the 600-mg VEN cohort who achieved CR/CRi was 70.4% from Kaplan-Meier estimates, with 11 deaths. Among 19 patients who received study treatment ≥12 months, 17 remain alive. The longest, ongoing, disease-free follow-up after treatment completion is 12 months. Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Figure Figure. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

scholarly journals Single Centre Experience in Treating Elderly Patients with Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndrome with a Combination of Low Dose Cytarabine, Venetoclax and Fluconazole (VeLDAC-F)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5220-5220 ◽  
Author(s):  
Lauren Child ◽  
Henry Chan ◽  
Ross Alistair Henderson ◽  
Anna Elinder ◽  
Eileen Merriman ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Low Dose ◽  
Complete Response ◽  
Event Free Survival ◽  
Free Survival ◽  
Haematological Response ◽  
Tumour Lysis ◽  
Low Dose Cytarabine

Abstract Introduction Acute myeloid leukaemia (AML), high risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukaemia (CMML) are bone marrow disorders that predominately affect the elderly population. The treatment options for this patient group have been limited and those unable to undergo intensive chemotherapy have historically had a poor prognosis. Low dose cytarabine (LDAC) is an accepted treatment option in patients who are ineligible for intensive therapy. LDAC has been shown to achieve a complete response (CR) and complete response with incomplete count recovery (CRi) in 11-18% of patients with a median overall survival of 5- 12 months. Recent evidence suggests that venetoclax (VEN) has a synergistic effect with LDAC with a phase I/II trial reporting a CR +CRi of 33/61 (54%) with this combination. Antifungal agents are commonly used in AML treatment protocols due to the increased risk of invasive fungal infections in this population. Fluconazole, a moderate CYP3A4 inhibitor, increases the maximum concentration (Cmax) of VEN resulting in a 2-5-fold increase in the area under the curve (AUC), thereby significantly increasing drug exposure. When using an azole antifungal, a dose reduction of VEN is recommended to maintain safe therapeutic levels. Here, we present our experience with using a lower dose of VEN in combination with fluconazole and LDAC (VeLDAC-F) in patients with AML, high risk MDS and CMML. Methods Patients with a diagnosis of AML, high risk MDS or CMML that required treatment but were not candidates for high intensity chemotherapy were offered the combination of VeLDAC-F. In cycle 1, VEN was started at 100mg daily and ramped up over the first 4 days to 200mg. This dose was continued from days 4-10. Fluconazole was started on day 3 and continued at 200mg until day 10. On subsequent cycles, VEN was administered at 200mg daily on days 1-10 with 200mg of fluconazole. Subcutaneous LDAC 20 mg/m2/day was given on days 1-10 of each cycle. Treatment cycles were repeated every 4-6 weeks. Patients were not routinely admitted for initiation of chemotherapy, unless the circulating blast count was high. Patients who received at least one dose of VeLDAC-F were included. Event-free survival was the time to either treatment termination, disease progression or death; overall survival was the time to death from all cause. Patients who achieved a haemoglobin > 100g/L, platelets >100 x 109/L and neutrophils > 1 x 109/L were said to have reached a modified haematological response (HR), and time to modified haematological response was analysed using competing risk model with death as the competing factor. All statistical analysis was done using IBM SPSS version 20 and R Statistics. Results Nineteen patients received at least one dose of VeLDAC-F between the 1st of June 2017 and the 1st of June 2018. The majority of patients were male (89.5%). 14/19 (73.7%) had an ECOG performance status of 0 or 1 and the median Charleston co-morbidity index was 6. The median age at diagnosis was 77 years (range 64.4- 87.7 years). The cohort included 9 patients with AML (47.4%), 7 with high risk MDS (36.8%) and 2 with CMML (15.8%). Twelve patients were still alive at the time of analysis (63.2%). The median follow-up was 182 days. Ten patients achieved a modified HR (52.6%). The median duration of response in these patients was 210 days and the 100 day probability of achieving a modified HR was 50.1%. The majority of patients who achieved a modified HR did so within 2 cycles of treatment with only one patient achieving a modified HR after 100 days. Seven patients died over the follow-up period (36.8%) with one patient dying within 30 days of commencing treatment (5.3%). Four patients died of progressive disease, 2 from sepsis and 1 from catastrophic bleeding. The median OS had not been reached at the time of analysis. The 180-day OS was 61%. The median event free survival was 217 days. There were no cases of clinical tumour lysis and three cases of biochemical tumour lysis (15.8%). Only 10 patients were admitted to hospital with neutropenic fever over the course of the follow up period (52.6%). Discussion The combination of VeLDAC-F appears to be an effective regimen for elderly patients with AML, high grade MDS and CMML who are otherwise ineligible for intense chemotherapy. The risk of tumour-lysis is low in this real-world cohort, but ongoing follow-up and further clinical trials are needed to establish the longer-term outcomes of this regime. Figure. Figure. Disclosures Chan: Amgen: Honoraria; Karyopharm: Research Funding. Simpson:Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; MSD: Honoraria; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding.

A Single-Center Retrospective Comparison of Post-Transplant Outcomes in Patients Receiving VRD Vs. VD Vs. RD As Initial Therapy Prior to ASCT for Newly Diagnosed Multiple Myeloma (MM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2042-2042
Author(s):  
Nathan C Nussbaum ◽  
Andrew Dougherty ◽  
Dan T. Vogl ◽  
Brendan M Weiss ◽  
David L Porter ◽  
...  
Keyword(s):  
Outcome Measures ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rates ◽  
Initial Therapy ◽  
Newly Diagnosed ◽  
Single Center ◽  
Free Survival ◽  
Disease Response

Abstract Abstract 2042 Background: The optimal pre-transplant induction therapy for newly diagnosed MM remains to be determined. Combinations of lenalidomide, bortezomib, and dexamethasone result in high response rates with acceptable toxicity in the majority of patients. The most commonly utilized regimens in the U.S. are lenalidomide and dexamethasone (RD); bortezomib and dexamethasone (VD); lenalidomide, bortezomib, and dexamethasone (VRD); and thalidomide and dexamethasone (TD). We sought to determine whether any of the common initial regimens is a superior first choice. Methods: This retrospective single center study examined MM patients < 70 who underwent their initial ASCT between 7/1/2008 to 6/30/2011. A chart review was conducted using the outpatient electronic medical record. Data was gathered on disease characteristics, induction regimens, disease response, and clinical course after ASCT. The primary outcome measures were progression-free survival (PFS), overall survival (OS), and event-free survival (EFS), all measured from day 0 of ASCT. The secondary outcome measures were number of distinct induction therapy regimens, time from start of induction therapy to ASCT, and disease response immediately prior to ASCT. Disease response was grouped as either ≥Very Good Partial Response (VGPR) or <VGPR. The observation period ended on 6/30/2012. Results: A total of 174 patients were included in the analysis. The initial regimen was RD for 80 patients (46%), VD for 43 patients (25%) and VRD for 30 patients (17%). Other regimens (mostly thalidomide-based) accounted for the remaining 12%. The TD regimen was inferior as initial therapy in terms of all outcome endpoints. The primary analysis, therefore, compared RD to VD to VRD. The baseline characteristics for these groups of patients (including gender, stage at diagnosis, serum creatinine at diagnosis) were similar for RD and VRD, but the VD group had more subjects with higher stage (p=0.018) and creatinine > 2 at diagnosis (p<0.001). Use of maintenance therapy after ASCT, usually with lenalidomide, was different between the groups (p<0.001), with more frequent use for patients who received VRD or RD as initial therapy (73% and 64% respectively) than for patients who received VD (26%). The frequency of changes in induction therapy was similar across groups (received > 1 induction regimen: RD 29%, VD 26%, VRD 17%, p=NS). The primary reason for a change in regimen was lack of response rather than toxicity. Response rates immediately before ASCT were not significantly different among regimens (≥VGPR: RD 51%, VD 63%, VRD 73%, p=0.08). EFS was similar for patients treated with the RD, VD, and VRD (EFS at 2 yr post-ASCT: RD 56%, VD 48%, VRD 70%, p=NS). With a median follow-up of 26.3 months after ASCT, there is no significant difference in PFS or OS (OS at 2 yr post-ASCT: RD 90%, VD 86%, VRD 96%). Conclusions: We compared three commonly used regimens for initial treatment of MM in the transplant eligible population to determine if one combination resulted in a better outcome than the others after ASCT. Although there was a trend towards higher pre-ASCT responses with VRD induction therapy, with approximately 2 years of median follow-up, survival was not significantly different when based on choice of initial therapy. These data support that in the current era of highly active induction regimens, choice among them can be made considering such factors as disease manifestations, potential toxicity and drug administration rather than response rates and survival differences. Longer follow-up of these patients as well as future prospective analyses will further clarify these results. Disclosures: Vogl: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Porter:Novatis: Patents & Royalties; Celgene: Honoraria; Genentech: Employment; Pfizer: Research Funding. Mangan:celgene: Speakers Bureau; millenium: Speakers Bureau. Stadtmauer:celgene: Consultancy; millenium: Consultancy.

Long-Term Follow-up and Analysis of Dose Groups with Ibrutinib in Relapsed Follicular Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2706-2706 ◽  
Author(s):  
Nathan Fowler ◽  
Thomas E Boyd ◽  
Jeff P. Sharman ◽  
Sonali M. Smith ◽  
Fong Clow ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Dose Group ◽  
Low Dose ◽  
Single Agent ◽  
High Dose Group ◽  
Fixed Dose ◽  
High Dose ◽  
Grade 3

Abstract Introduction: As outcomes in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) remain suboptimal, new, effective treatment options with a favorable safety profile are needed. Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), a key component of B-cell signaling involved in B-cell survival, proliferation and function. In lymphomas, ibrutinib is FDA-approved for treatment of mantle cell lymphoma in pts with ≥1 prior therapy. A phase 1 dose-escalation study with ibrutinib showed single-agent activity in pts with R/R B-cell malignancies (overall response rate [ORR] 60%; complete remission [CR] in 16%) including FL (Advani JCO 2013). In this trial, the 560 mg/day fixed dose was well tolerated and led to full BTK occupancy. We evaluated the efficacy, safety, and tolerability of single-agent ibrutinib by low- vs. high-dose groups with longer follow-up in pts with relapsed FL. Methods: Data were analyzed for pts with R/R FL (N=16) treated with oral ibrutinib in the phase I study (PCYC-04753), where pts received escalating doses of ibrutinib 1.25-12.5 mg/kg/day per cycle (1 cycle = 28 days + 7 days rest) or continuous doses of ibrutinib 8.3 mg/kg/day or 560 mg/day fixed dose (1 cycle = 35 days). Pts with stable disease or better, who received therapy for 6 months, continued ibrutinib at a fixed dose of 560 mg/day in the extension study (PCYC-1103) until progression or unacceptable toxicity. Pt data categories included low-dose (1.25 mg/kg/day, 2.5 mg/kg/day, or 5 mg/kg/day) or high-dose (8.3 mg/kg/day or 12.5 mg/kg/day) groups. Results: Eight pts each were categorized into low-dose and high-dose groups. Baseline characteristics were similar, but median treatment duration was longer for the high-dose group (Table; 12 vs. 4 months). Increased ORR (63% vs. 25%) and CR rates (38% vs. 0%) were observed in the high-dose compared with low-dose group (Table). Median duration of response (DOR) was longer in the high-dose group (12 vs. 3 months), as was median progression-free survival (PFS; 24 vs. 9 months). Median overall survival (OS) was not reached (NR) in either group. Grade ≥3 adverse events (AEs) occurred in 3 pts in each group. Common grade ≥3 AEs reported in ≥3 pts in the combined groups included (low-dose, high-dose) diarrhea (n=2, 6), fatigue (n=3, 4), nausea (n=2, 4), cough (n=3, 2), myalgia (n=1, 3), headache (n=0, 3), muscle spasms (n=1, 2), pruritus (n=0, 3), and rash (n=0, 3). Serious AEs occurred in 3 pts in the low-dose and 1 pt in the high-dose group. AEs leading to treatment discontinuation occurred in 2 pts in each group. No fatal AEs occurred. Among 4 pts (high-dose group) receiving ibrutinib beyond 1 year (range, 18 to 61 months), no unexpected or increased AEs were observed; 1 pt experienced 2 grade 3 AEs (non-cardiac chest pain and vomiting), both within 60 days from start of treatment and lasting 1 day. No other grade ≥3 AEs occurred among these 4 pts. Conclusions: Higher doses of single-agent ibrutinib were associated with increased response rates and prolonged PFS in pts with R/R FL. A higher dose was not associated with increased AEs or with cumulative toxicity during extended therapy. In the current analysis, pts with FL derived the most benefit from ibrutinib doses at 8.3 mg/kg/day or higher. A study testing single-agent ibrutinib at 560 mg/day in pts with R/R FL is ongoing (Bartlett Blood 2014) as is a phase 2 study evaluating ibrutinib 560 mg/day in chemoimmunotherapy refractory FL. Table 1. Patient Characteristics and Efficacy Low dose(n=8) High dose(n=8) Median age, yrs (range) Age ≥ 70 yrs, n (%) 57 (48-70)1 (13) 62.5 (41-71)1 (13) Median no. of prior therapies (range) 3 (1-4) 2 (1-5) Ann Arbor stage III/IV disease, n (%) 6 (75) 6 (75) FLIPI score, % (low / intermediate / high)* 25 / 38 / 38 13 / 38 / 50 Median treatment duration, months (range) 3.8 (0.5-11.1) 12.4 (0.2-61.5) ORR, n (%) CR, n (%) 2 (25)0 (0) 5 (63)3 (38) Median DOR, months (range) n=2; 3.4 (1.8-4.9) n=5; 12.3 (4.8-51.3) Median PFS, months (95% CI) 9.2 (0.5, 13.4) 23.7 (2.2, NE) 10-month PFS, % 35.7 70 Median OS, months (95% CI) NR NR 10-month OS, % 100 100 *FLIPI scores from baseline data. NE, not estimable Disclosures Off Label Use: single-agent ibrutinib therapy in patients with relapsed FL. Boyd:Celgene: Research Funding, Speakers Bureau; Genentech: Research Funding; US Oncology: Research Funding; GSK: Research Funding. Sharman:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Janssen: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Calistoga: Honoraria. Smith:Pharmacyclics: Consultancy; Celgene: Consultancy. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment.

scholarly journals Clofarabine Plus Low-Dose Cytarabine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome (MDS) Who Have Been Relapsing after, or Are Refractory to, Hypomethylating Agent (HMA) Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3166-3166 ◽  
Author(s):  
Elias J. Jabbour ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Tapan M. Kadia ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Group Performance ◽  
Performance Status ◽  
Advisory Board ◽  
Cell Transplant ◽  
Complex Karyotype ◽  
Overall Response ◽  
Low Dose Cytarabine

Abstract Background: HMA therapy is standard of care for patients with MDS. Outcome post HMA failure is poor with a median survival of 4-6 months. Clofarabine is a second generation nucleoside analog with single agent activity in MDS. The objective of this phase II trial is to evaluate the safety and activity of the combination of clofarabine and low dose cytarabine in the treatment of patients with high risk MDS who failed prior HMA therapy. Methods: Eligible patients were adults older than 18 years with MDS intermediate-1 and higher by the IPSS, who have had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine. Patients were required to have an Eastern Cooperative Oncology Group performance status of </=2 at the time of study entry. Responses were defined according to International Working Group 2006 criteria. Induction therapy consisted of clofarabine 10-15 mg/m2 IV daily X 5 days (days 1-5) and cytarabine 20 mg SC twice daily X 7 days (days 1-7). Patients could receive up to 3 induction cycles as long as they tolerated the therapy and had stable disease. Responding patients proceeded with consolidation therapy with clofarabine 10-15 mg/m2IV daily X 3 days (days 1-3) and cytarabine 20 mg SC twice daily X 5 days (days 1-5) for a maximum of 12 cycles. Cycles were repeated every 4 to 8 weeks depending on hematopoietic recovery and resolution of toxicities. Results: From January 2012 to August 2015, 80 eligible patients were enrolled in this prospective study (NCT01444742) and received a median of 2 cycles (range, 1-12) (Table 1). The overall response rate (ORR) was 46% (16 [20%] achieved complete remission (CR), 17 [21%] marrow CR, 1 [1%] partial response (PR), 3 [4%] hematological improvement (HI)) with a median response duration of 7 months. The median time to response was 42 days (range, 9-191). By multivariate analysis, complex karyotype was the only independent factor predicting for response (hazard ratio [HR] 0.13; 95% confidence interval [CI]: 0.03- 0.62; p=0.01). Of the 37 patients with diploid karyotype, the overall response was 68% (7 [19%] achieved CR, 15 [41%] marrow CR, 1 [3%] PR, 3 [4%] HI). Nine of the responding patients received subsequent allogeneic stem cell transplant (ASCT). With a median follow-up of 24 months (range: 1-51 months), the median event-free survival (EFS) and overall survival (OS) times were 5 months (95% CI: 2.7-6.3) and 11 months (95% CI: 6.5-14.9), respectively (Figure 1). The median OS for responding and non-responding patients was 24 months (95% CI: 11.7-35.6) and 5 months (95% CI: 2.8-6.2), respectively (p<0.001). There was no difference in OS whether patients were censored or not at the time of ASCT (p=0.463). At last follow-up, 22 patients (28%) remained alive: 1 is receiving low-dose clofarabine and cytarabine, 5 are alive in response after ASCT, 9 are receiving salvage therapy, 1 went to hospice, and 6 were lost to follow-up. By multivariate analyses, complex karyotype, platelet count less than 30 x 109/L, and poor performance status were independently associated with poor survival. In addition, the response to the combination of low-dose clofarabine and cytarabine was independently associated with better OS (HR 0.17; 95% CI 0.09-0.36; p<0.001). Grade ≥ 3 therapy-related toxicity included infections (34%), increased liver functional tests (8%), acute renal failure (3%), skin rash (3%), syncope (1%), and rectal bleeding (1%). Twenty-two (28%) patients had clofarabine dose reduction after a median of 2 courses. After 47 patients were enrolled and several patients experienced infections during induction, the protocol was amended to reduce the dose of clofarabine to 10 mg/m2 per day for 5 and 3 days during the induction and consolidation phases, respectively. There was no difference in responses before and after the modification to the protocol's dosing schedule (p=0.314). Conclusion: The combination of low-dose clofarabine and cytarabine in patients with higher-risk MDS after HMA failure resulted in an ORR of 46% and median OS of 11 months and may be particularly effective in patients with diploid karyotype. Our results also indicate that the combination of low-dose clofarabine and cytarabine may be useful as a bridge to ASCT in eligible patients. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jain:Abbvie: Research Funding; Infinity: Research Funding; Servier: Consultancy, Honoraria; Incyte: Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Novimmune: Consultancy, Honoraria; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Clofarabine Plus Low-Dose Cytarabine For The Treatment Of Patients Withhigher-Risk Myelodysplastic Syndrome (MDS) Who Have Been Relapsing After, Or Are Refractory To, Hypomethylator Agent Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1525-1525 ◽  
Author(s):  
Aziz Nazha ◽  
Guillermo Garcia-Manero ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Complete Remission ◽  
Stable Disease ◽  
Low Dose ◽  
Liver Enzymes ◽  
Performance Status ◽  
Single Agent ◽  
Elevated Liver Enzymes ◽  
Elevated Bilirubin ◽  
Low Dose Cytarabine

Abstract Background Treatment with hypomethylating agents (HMA) such as azacitidine and decitabine has changed the overall outcome of patients with MDS. Failure to responed to or relapse from treatment with HMA carries a poor outcome and no approved therapy for these patients exists. Clofarabine is a second generation nucleoside analog with single agent activity in MDS. Aim This is a phase II trial to evaluate the safety and activity of the combination of clofarabine and low dose cytarabine in the treatment of patients with high risk MDS who failed prior HMA therapy. Material and Method Eligible were adults older than 18 years with MDS who have had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine. Patients were required to have an ECOG performance status of </=2 at the time of study entry. Responses were defined according to IWG 2006 criteria. Induction therapy consisted of clofarabine 15 mg/m2 IV daily X 5 days (days 1-5) and cytarabine 20 mg SC twice daily X 7 days (days 1-7). Patients could receive up to 3 induction cycles as long as they tolerated the therapy and had stable disease. Responding patients proceeded with consolidation therapy with clofarabine 15 mg/m2IV daily X 3 days (days 1-3) and cytarabine 20 mg SC twice daily X 5 days (days 1-5) for a maximum of 12 cycles. Cycles were repeated every 4 to 8 weeks depending on hematopoietic recovery and resolution of toxicities. Results Between January 2012 and March 2013, 29 patients were enrolled. The clinical characteristics are summarized in Table 1. Twenty four patients were evaluable for response (5 patients were too early for response). The overall response rate (ORR) was 50% (8 [33%] achieved complete remission (CR)/ complete remission with incomplete platelets recovery (CRp)/marrow CR, and 4 [17%] had stable disease with hematological improvement). With a median follow up of 4.9 months (range, 1.9-16.7), the median overall survival (OS) was 4.8 months (range, 0.5-13.5). Most toxicities were grade </= 2 and included: elevated liver enzymes in 41% of the patients, elevated bilirubin (38%), rash (28%), nausea (31%), headache (24%), and febrile neutropenia (28%). Grade >/= 3 toxicities included: elevated liver enzymes (3%) and elevated bilirubin (3%). Four-week mortality was 12%. Conclusion The combination of clofarabine and low-dose cytarabine has an ORR of 50% in patients with MDS who failed prior therapy with HMA. The study continues to accrue and updated results with longer follow up will be presented at the meeting. Disclosures: Off Label Use: Clofarabine use in MDS. Faderl:Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Belantamab Mafadotin in Patients with Relapsed/Refractory AL Amyloidosis with Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1670-1670
Author(s):  
Yifei Zhang ◽  
Amandeep Godara ◽  
Stacey Pan ◽  
Denis Toskic ◽  
Teresa Fogaren ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Response Rates ◽  
Cardiac Response ◽  
Clinical Activity ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Renal Response

Abstract Introduction: Daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara/CyBorD) is the only FDA approved therapy for newly diagnosed systemic light-chain (AL) amyloidosis (N Engl J Med 2021;385:46). Belantamab mafodotin is a novel anti-BCMA immunoconjugate with humanized IgG1 anti-BCMA monoclonal antibody conjugated to a microtubule-disrupting agent, monomehtyl auristatin F (MMAF) via a non-cleavable linker (Blood 2014;123:3128). Phase I/II studies in heavily pre-treated multiple myeloma patients showed single agent clinical activity with overall response rates ranging from 30-60%, with majority of responses being durable at 13 months of follow-up. Toxicity profile included keratopathy, thrombocytopenia and anemia (Blood Cancer J 2019;9:37; Lancet Oncol 2020;21:207). Based on these results, belantamab mafadotin (BLM; Blenrep) was FDA approved for relapsed myeloma. A role for new agents such as BLM in AL has not been previously reported. Here we report outcomes of six patients who received BLM at different centers for relapsed refractory (RR) AL associated with myeloma. Methods: In this retrospective study we identified AL patients with RR disease who received at least one dose of BLM. In a multi-institutional collaboration we collected demographic, medical history, laboratory, pathologic and treatment/response data on patients with myeloma and biopsy-proven AL who had received BLM. Laboratory assessment including evaluations for hematologic and organ response was done as per standard criteria and toxicity assessed as per CTCAE v6.0. Results: We identified 6 patients, 3M/3F, from 4 centers; baseline characteristics and treatment data are provided in Table 1. Baseline median age was 61 years (range, 51-74) and median marrow plasmacytosis and iFLC were 40% (10-90) and 868mg/L (145-5324). Four patients had AL λ-type and 2 κ-type, and 5 of 6 had cardiac involvement while 3 had additional organ involvement (renal, GI, nervous system). Prior to initiating BLM the median number of lines of prior therapy was 6 (range, 5-10), including daratumumab, bortezomib and lenalidomide, and prior to initiating BLM marrow assessment showed a median plasmacytosis of 23%. BLM at 2.5 mg/kg was given as an intravenous infusion over the course of 30 minutes every three weeks after ophthalmologic exam clearance until discontinuation for progression or toxicity. At a median follow-up of 4.5 months, 5 patients (83%) achieved hematological responses (HR) with 3 (50%) achieving complete hematological responses (CR) by standard criteria (J Clin Oncol 2012;30:4541). Time to HR ranged from 3 to 150 days. Cardiac response was seen in all but 1 patient, with time to response ranging from 11 to 96 days. One patient had a renal response; response assessment is not yet available for 2 other patients with renal involvement. The most common toxicity was keratopathy (grade 1-2). BLM was held after the first dose in one patient who had been heavily pre-treated and had extensive cardiac and pulmonary AL and multiple sites of FDG-avid progressive myeloma bone disease. Two days after administration of the first dose of BLM, this 51-year-old man was admitted to hospital for dyspnea, developed atrial fibrillation and ventricular tachycardia, and briefly required cardiac resuscitation without intubation with return of spontaneous circulation after 6 minutes. This patient achieved a CR after one dose of BLM that has been stable for over 5 months with marked clinical improvement. A 62 year-old woman with cardiac and renal AL has achieved a CR durable for over 16 months with cardiac and renal responses. Conclusions: In this group of 6 patients with RR AL with myeloma, HR and cardiac response rates were impressive at 83% and 80%, respectively. One patient who had 24-hour urine protein evaluation also achieved a renal response. Time to response was rapid with 2 patients achieving HR within a week of starting treatment, and the rest within five months. Additionally, 3 of 6 patients achieved CR, 1 had no clonal plasma cells in the marrow and another clonal disease detectable only by MRD. In this retrospective multi-institutional cohort BLM resulted in rapid reduction of iFLC and induced critical organ responses. These data provide preliminary evidence for the clinical activity of BLM in RR AL. Results of the on-going phase 2 clinical trial in the European Myeloma Network (EMN27; NCT04617925) are awaited with great interest. Figure 1 Figure 1. Disclosures Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; SkylineDx: Consultancy. Comenzo: Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Kansagra: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Clofarabine Plus Low-Dose Cytarabine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndromes (MDS) Who Have Relapsed or Are Refractory to Hypomethylating Agent (HMA) Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 534-534
Author(s):  
Elias Jabbour ◽  
Koji Sasaki ◽  
Naval Daver ◽  
Naveen Pemmaraju ◽  
Nitin Jain ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Low Dose ◽  
Liver Enzymes ◽  
Performance Status ◽  
Intermediate Risk ◽  
Elevated Liver Enzymes ◽  
Elevated Bilirubin ◽  
Low Dose Cytarabine

Abstract Background: Treatment with HMAs such as azacitidine and decitabine has changed the overall outcome of patients with MDS. Failure to respond to or relapse from HMA treatment is associated with poor prognosis without further approved therapy. Clofarabine is a second-generation nucleoside analog with single-agent activity in MDS. Aim: This is a phase II trial to evaluate the safety and activity of the combination of clofarabine and low-dose cytarabine in the treatment of patients with high-risk MDS who failed prior HMA therapy. Materials and Methods: Eligible patients were adults older than 18 years with MDS who had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine and an ECOG performance status of ≤ 2 at the time of study entry. Responses were defined according to IWG 2006 criteria. Induction therapy consisted of clofarabine 15 mg/m2 IV daily for 5 days (days 1-5) and cytarabine 20 mg SC twice daily for 7 days (days 1-7). Responding patients proceeded with consolidation therapy with clofarabine 15 mg/m2 IV daily for 3 days (days 1-3) and cytarabine 20 mg SC twice daily for 5 days (days 1-5) every 4 weeks for a maximum of 12 cycles. Overall survival (OS) was defined as the time between the date of the first dose of clofarabine and the date of death from any cause. Univariate (UVA) and multivariate analysis (MVA) related to response and survival were performed with Cox regression analysis. Results: Between January 2012 and December 2013, 56 patients were enrolled. Fifty-two patients were evaluable for response (4 patients had not been on-study long enough to evaluate). The median follow-up is 15.3 months (range, 1.2-27.7+), and the median age at enrollment was 71 years (31-83). Ten patients (19%) had prior chemotherapy and 12 (23%) had prior radiation therapy. Median bone marrow blast percentage was 15% (6-30%). Three patients (6%) had CMML-1, 4 (8%) had CMML-2, 7 (14%) had RAEB-1, 19 (37%) had RAEB-2, and 19 (37%) had RAEB-T. Eight (15%) patients had intermediate-1 risk, 23 (44%) had intermediate-2 risk, and 21 (40%) had poor risk by IPSS. By IPSS cytogenetic risk, 25 patients (48%) had low-risk cytogenetics, 15 (29%) had intermediate-risk, and 12 (23%) had high-risk. Mutational analysis detected 2 (4%) FLT3-ITD, 0 FLT3-D835, 7 (13%) RAS, 2 (4%) NPM1, and 2 (4%) JAK2 mutations. Thirty-nine patients (75%) received prior azacitidine therapy and 15 (29%) received prior decitabine therapy. The overall response rate (ORR) was 48% (9 [17%] achieved complete remission [CR], 3 [6%] complete remission with incomplete platelet recovery [CRp], 7 [13%] marrow CR, and 6 [12%] had stable disease with hematological improvement), and median duration of response was 12.0 months (range, 2.0-26.7+). Five patients (10%) went on to receive allogeneic stem cell transplantation. Of the 25 patients with low-risk cytogenetics, 16 (64%) achieved OIR, 5 (20%) CR, 3 (12%) CRp, 6 (24%) mCR, and 2 (8%) HI. Of the 15 patients with intermediate-risk cytogenetics, 5 (33%) had OIR, 4 (27%) CR, and 1 (4%) mCR. Of 12 patients with high-risk cytogenetics, 2 (17%) had OIR, 1 (8%), CR, and 1 (8%) HI. Median OS was 6.8 months (range, 0.4-27.7+). The median OS in patients with response and those without response was >12.4 months (range, 3.5-27.7+) and 3.4 months (range, 0.4-16.1), respectively. Most toxicities were of grade ≤ 2 and included elevated liver enzymes in 41% of patients, elevated bilirubin in 38%, rash in 28%, nausea in 31%, headache in 24%, and febrile neutropenia in 28%. Grade ≥ 3 toxicities included elevated liver enzymes (3%) and elevated bilirubin (3%). 21 (40%) patients had clofarabine dose reduction after a median of 2 courses (range, 1-8). UVA and MVA for survival identified performance status ≥2 (p=0.002; HR, 4.860; 95%CI, 1.784-13.244), stable disease or progressive disease after clofarabine (p<0.001; HR, 8.372; 95%CI, 3.233-21.677), thrombocytopenia <30 (/109L) (p=0.001; HR, 3.659; 95%CI 1.682-7.958), and complex cytogenetics (UVA, p<0.001; MVA, p= 0.110, HR, 2.329; 95%CI 0.826-6.564) as prognostic factors for poorer OS. Conclusion: The combination of clofarabine and low-dose cytarabine has an ORR of 48% in patients with MDS who failed prior therapy with HMA. The study continues to accrue, and updated results with longer follow up will be presented at the meeting. Disclosures Daver: Novartis: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Borthakur:Tetralogic Pharmaceuticals: Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Garcia-Manero:Epizyme, Inc: Research Funding.

Clofarabine Plus Low-Dose Cytarabine Induction Followed By Clofarabine Plus Low-Dose Cytarabine Alternating With Decitabine Consolidation In Acute Myeloid Leukemia Frontline Therapy For Older Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3948-3948
Author(s):  
Aziz Nazha ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Xuelin Huang ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Single Agent ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Elevated Creatinine ◽  
Prolonged Consolidation ◽  
Low Dose Cytarabine

Abstract Background The outcome of elderly patients (pts) with acute myeloid leukemia (AML) treated with currently available therapies remains unsatisfactory. Clofarabine has single agent activity in AML. The combination of clofarabine with low-dose cytarabine produced higher response rates with a comparable safety profile compared with single-agent clofarabine. We previously reported a phase II study of clofarabine + low dose cytarabine followed by prolonged consolidation with clorarabine + low dose cytarabine alternating with decitabine in elderly patients with newly diagnosed AML (Faderl, Cancer 2012). The complete remission (CR) rate was 58%. With median follow up of 31.2 months, the median overall survival (OS) was 12.7 months, and the median relapse free survival was 14.1months. The combination was well tolerated with induction mortality of 3% (Early Death <28 Days), 7% at 8-weeks. Here we report the result with a larger patient population and longer follow up. Material and Methods Pts were eligible if they were >/= 60 years of age with newly diagnosed AML (based on World Health Organization [WHO] criteria) or high-risk myelodysplastic syndrome (MDS; >/=10% blasts or >/= intermediate-2 by the International Prognostic Scoring System) with Eastern Cooperative Oncology Group (ECOG) performance status of </= 2 and adequate organ function (serum total bilirubin </=2 mg/dL, alanine aminotransferase or aspartate aminotransferase </= 4 X the upper limit of normal, serum creatinine </= 2 mg/dL, and cardiac ejection fraction >40%). Induction therapy consisted of clofarabine 20 mg/m2 IV daily X 5 days (1-5) plus cytarabine 20 mg subcutaneously (SC) twice daily (BID) X10 days (1-10). All responses were defined as per IWG criteria (2003). Pts who did not achieve a CR could receive 1 re-induction cycle at the same dose after at least 28 days from C #1. Pts could receive up to 17 cycles of consolidation therapy. Consolidation was administered in blocks of 3 cycles where clofarabine 20 mg/m2 IV daily X 3 days (1-3) plus cytarabine 20 mg SC BID X 7 days (1-7) alternated with decitabine 20 mg/m2IV X5 days (1-5). Consolidation cycles were repeated every 4 to 7 weeks depending on hematopoietic recovery. Results Between 10/21/08 and 10/17/2011, a total of 118 patients were enrolled. The clinical characteristics are summarized in Table 1. The overall response rate (ORR) was 68% (71 [60%] CR, 9 [8%] CRp/CRi). Twenty two (19%) pts required re-induction, 16 (73%) achieved a response (12 achieved CR, 2 CRp, and 2 CRi). Median number of cycles received was 3 (range, 1-19). With median follow up of 31.2 months (range, 9.5-53.9), the median OS was 11.1 (range, 0.2-53.9), EFS 7.7 (range, 0.2-49.5), and relapse-free survival (RFS) 15.9 months (range, 0.3-48.3). The median OS among the responders was 21.1 months (range, 1.3-53.9). Four-week mortality was 3% and 8-week mortality 8%. Adverse events were predominantly grade 2 or less and included (>/= 10%): elevated liver enzymes (53%), elevated bilirubin (42%), diarrhea (19%), nausea (81%), rash (54%), hand and foot syndrome (10%), and elevated creatinine (10%). Grade 3 or more toxicities included: elevated creatinine (3%), rash (2%), vomiting (1%), and hand and foot syndrome (1%). No unexpected toxicities were observed. Conclusion Clofarabine plus low-dose cytarabine followed by prolonged consolidation alternating with decitabine is an active regimen with an ORR of 73% in older patients with newly diagnosed AML and high risk MDS. The regimen was well tolerated with low induction mortality. A randomized trail to compare this combination to best available therapy is needed to further asses the role of this combination in the treatment paradigm of elderly patients with AML. Disclosures: Off Label Use: Clofarabine and decitabine use in AML. Faderl:Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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