A Randomised Comparison of Clofarabine Versus Low Dose Ara-C As First Line Treatment for Older Patients with AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 889-889 ◽  
Author(s):  
Alan K Burnett ◽  
Nigel H. Russell ◽  
Mary Frances McMullin ◽  
Jonathan Kell ◽  
Sahra Ali ◽  
...  
Keyword(s):  
Overall Survival ◽  
Patient Group ◽  
Older Patients ◽  
Low Dose ◽  
Response Rate ◽  
De Novo ◽  
Remission Rate ◽  
Final Analysis ◽  
Median Number ◽  
Grade 3

Abstract Abstract 889 Introduction There is no adequate standard of care for older patients with AML who are not considered fit for intensive treatment. In recent years a number of potential novel agents have been tested in single arm studies, but have not been validated in a randomised assessment. Clofarabine is a novel nucleoside analogue which has shown encouraging activity in this patient group in single arm studies [1,2]. As part of our “Pick a Winner” (PaW) trial programme, Clofarabine (CLO) 20mg/m2 IV days 1 to 5 was compared to Low Dose Ara-C (LDAC) 20mg bid SC days 1 to 10, each for up to 4 courses, with patients deriving benefit allowed to continue on treatment. The rules of PaW [3] required a confidential interim analysis after 50 & 100 randomised patients per arm to confirm that the aim of doubling the CR rate to >30% was likely to be achieved, in order to proceed to phase 3 with overall survival as the primary endpoint. Methods Between August 2006 and April 2011, 406 patients entered the randomised comparison from 109 centres in the UK, Denmark and Australia with a median age of 74 yrs (range 51–90). Sixty-two per cent had de novo disease, 24% secondary AML and 14% high risk MDS (>10% blasts): 2% had favourable cytogenetics, 72% intermediate and 26% adverse. By Wheatley Score [4], 3% were good; 46% standard and 51% poor risk; 13% had WHO performance score >2. Results Overall 28% entered CR/CRi and 28% and 13% were alive at 12 and 24 months respectively. The median number of courses given was 2.0 (range 0–8) in both arms. Of the remitters 34% are alive at 2 years compared with 4% of non-remitters. At the two interim analyses 34% and 41% were in CR in the CLO arm compared with 15% and 21% in LDAC. The trial therefore recruited to full accrual. In the final analysis the CLO arm had a superior response rate (CR + CRi) of 38% vs 20% (CR 22% vs 12%, CRi 16% vs 8%; OR 0.41 (0.26-0.62); p<0.0001). The 30 and 60 day all-cause mortality was higher in the CLO arm (18 vs 13% and 32% vs 26%). RFS (2 yrs) was non-significantly better in the CLO arm (20% vs 8%, HR 0.76 (0.49-1.19), p=0.2) but for those achieving CR the survival was non-significantly better in the LDAC arm (44%vs 26% HR 1.19 (0.74-1.91), p=0.5), which is partly explained by a significantly superior survival from relapse in the LDAC arm (8% vs 0%, HR 1.91 (1.10-3.31), p=0.02). The lack of OS benefit in the CLO arm is also partially explained by a better survival for those in the LDAC arm who did not achieve initial CR (HR 1.37 (1.06-1.76), p=0.02). The CLO arm had more reported grade 3/4 toxicities of nausea, diarrhoea and liver biochemistry in course 1 & 2, while LDAC had more reports of grade 3/4 cardiac toxicities. The increased myelosuppression in the CLO arm was reflected in an increased use of RBC and platelet transfusions, and more days on antibiotics and in hospital. In an analysis stratified by demographic, cytogenetic and molecular (FLT3/NPM1) subgroups, clofarabine consistently resulted in a superior remission rate. However, with respect to overall survival, there was no evidence of any subgroup benefit. Conclusion Clofarabine was shown to double the response rate in older patients compared with LDAC, but did not result in an improvement in survival overall, or in any demographic or risk subgroup. CR may not serve as a reliable surrogate for overall survival in this patient group Acknowledgments: This study received research support from Genzyme and Cancer Research UK. Disclosures: Burnett: Genzyme: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Clofarabine in treatment of AML. Hills:Genzyme: Consultancy.

The Addition of Gemtuzumab Ozogamicin to Low Dose Ara-C Improves Remission Rates but Not Survival: Results of the UK LRF AML14 and NCRI AML16 “Pick a Winner” Comparison

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 18-18 ◽  
Author(s):  
Alan Burnett ◽  
Robert Hills ◽  
Ann Elizabeth Hunter ◽  
Donald Milligan ◽  
William J. Kell ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Older Patients ◽  
Low Dose ◽  
Remission Rate ◽  
Significant Proportion ◽  
Gemtuzumab Ozogamicin ◽  
Fixed Dose ◽  
The Uk

Abstract Abstract 18 In a significant proportion of older patients with AML intensive chemotherapy is not considered a viable option[1]. Such patients may receive low-dose Ara-C (LDAC), best supportive care (BSC) with hydroxyurea or an experimental agent but outcomes are poor. We have shown that LDAC is superior to BSC [2], but only in patients who enter CR (fewer than 20%).[2]. There is therefore scope to improve outcomes in these patients, and a number of possible treatments have been evaluated in the randomised UK NCRI AML16 trial, one of which is gemtuzumab ozogamicin (GO), which we have shown to benefit the majority of younger patients when given in conjunction with standard chemotherapy[3]. In AML16 novel agents or combinations are tested in untreated older patients with AML or high risk MDS (marrow blasts >10%) using a “pick a winner” design. The design allows unpromising treatments to be identified early (typically after 50 or 100 patients per arm): only those arms which show promise will continue to a trial with OS and DFS as endpoints. The aim is to at least double the remission rate from 15% to 30%, and thus improve overall survival. We now report the results of LD Ara-C (20mg bd days 1–10 for 4 courses) versus LDAC combined with GO (at a fixed dose of 5mg on day 1 of each course for 4 courses at 6–8 week intervals). Patient Details: The comparison opened as part of the UK LRF AML14 trial and was carried forward to AML16 unchanged. Between June 2004 and June 2010, 495 patients were randomised, 249 to LDAC plus ATO, 246 to LDAC. The median age was 75 years (range 54–90); 83% of patients were aged over 70 years, and 61% were male. To be eligible patients’ LFTs had to be less than twice ULN. Treatment arms were balanced for age, gender, performance status, de novo/secondary AML/high risk MDS, presenting WBC and cytogenetic risk group. Follow-up is complete to 1st January 2010, with median follow up of 21 months. Survival and remission data is available on 412, 404 patients respectively. Treatment Results: The trial passed through both stopping hurdles based on CR/CRi rates and therefore continued to full accrual, with overall survival as primary outcome measure. The table shows the distribution of outcomes: there was no heterogeneity by recruitment period (AML14 vs AML16). The causes of death (316) were:- There were no significant interactions between treatment and any of the baseline variables on either remission or survival outcomes. Likewise there were no major toxicity implications, although resource usage tended to be higher in patients given GO. Discussion: While the addition of GO significantly improves CR rate, achieving the 30% response originally sought, this does not translate into survival. This is predominantly due to an increase in relapse, indicating that if GO is to have a role in this setting, it will require effective treatment to maintain remission. [1] Juliusson G et al. Blood 2009; 113: 4179 – 4187 [2] Burnett et al. Cancer 2007 109: 1114–1124 [3] Burnett et al. JCO 2010 to appear. Disclosures: Off Label Use: Mylotarg (gemtuzumab ozogamicin).

The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 388-388 ◽  
Author(s):  
Gautam Borthakur ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Low Dose ◽  
Response Rate ◽  
Median Number ◽  
Highly Active ◽  
Flt3 Inhibitor ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Low Dose Cytarabine

Abstract Background: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity. In a phase I and II studies the composite response rate (CRR) was approximately 50% among patients with FLT3-ITD. There is in-vitro synergy between quizartinib and 5-AZA or LDAC. We hypothesize that adding quizartinib to a hypomethylating agent such as 5-azacitidine (AZA) or cytarabine may improve the response rate expected from the use of either agent alone. Objectives: The primary objective of phase I part is to determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of the combination of quizartinib (AC220) with either AZA or low-dose cytarabine (LDAC); for phase II is to determine the clinical activity of both combinations. This planned interim analysis reports on the recommended phase II dose (RP2D) and first futility analysis. Methods: For phase I, patients with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or AML were eligible irrespective of FLT3 mutation and salvage status. For phase II, presence of FLT3-ITD is a requisite. Phase II enrollment is limited to patients >60 years with untreated MDS/CMML/AML, or any age receiving first salvage treatment. Additional eligibilities include performance status ECOG ≤2, adequate organ function, normal electrolytes (potassium, calcium and magnesium). Important exclusions include QTcF> 450 mSec, concomitant drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers with the exception of antibiotics, antifungals, and antivirals that are used as standard of care. Treatment cycle is defined as 28 days. Treatment comprises of AZA 75 mg/m2 subcutaneously (SQ) or intravenously (IV) for 7 days of every cycle (Days 1-7), or cytarabine 20 mg SQ twice daily for 10 days of every cycle (Days 1-10) along with quizartinib at two planned dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2) uninterrupted. Patients are assigned to AZA or LDAC arm by physician choice or slot availability. Planned accrual for each arm in phase 2 is 26 pts each and an ORR of ≥50% will be considered favorable. Accrual of 26 pts will give a 95% credible interval for overall response rate of (0.32, 0.68). The study will be stopped for toxicity (>30%) and/or futility (ORR <50%) at interim analysis for each arm. Results: Twenty-six (Phase I=12, phase II=14) pts have been enrolled: 18 to AZA arm and 8 to LDAC arm. Median age is 62 years (range, 25-79 years), 7 (27%) are female. Cytogenetics are diploid=14, +8=2, -7=2, miscellaneous=6, 11q and t(8;21)= 1 each. Median number of prior therapies is 2 (range, 0-7), 7 patients received prior FLT3 inhibitor. For both schedules quizartinib 60 mg daily was identified as the recommended phase II dose (RP2D) based on emerging results from separate dose-finding study. Eighteen [5 in LDAC arm (63%) and 13 (72%) in AZA arm; all with FLT3-ITD mutation without D835 mutation] of 26 total pts (69%) have responded (CR=1/ CRp=3/ CRi=2/ MLFS=10/PR=1/HI=1). Among patients with FLT3-ITD (N=22), ORR is 82%. Four of 7 (57%) patients with prior FLT3 inhibitor exposure responded. Median number of days to respond is 57 days (range, 25-102 days). Among responders two patients died (MLFS=1, PR=1): one with gastro-intestinal bleeding and other with progressive pneumonia. Three additional responders have discontinued therapy for stem cell transplant (1), withdrawal of consent (1), and loss of response with emergence of D835 mutation (1). Nine responders (CR=1, CRi=1, CRp=1, PR=1, MLS=5) had >50% reduction of FLT3-ITD allelic burden and 2 additional pts (CR=1, CRi=1) had no detectable FLT3-ITD at response. Number of pts with treatment emergent grade 3/4 toxicities irrespective of attribution include hypokalemia (15), hypophosphatemia (5), hyponatremia (4), hypocalcemia (4), hyperbilirubinemia (3), increase in ALT (1), hypernatremia (1hyperglycemia (1), hypotension (1), QTcF prolongation (1, grade 3). Conclusion: Combination of quizartinib and AZA or LDAC is highly active among patients with AML/MDS/CMML with FLT3-ITD . Response rates appear higher than expected with either agent alone. Clinically significant QTcF prolongation is infrequent. Accrual to both arms of the current trial continues. Disclosures Cortes: Ambit Biosciences: Research Funding.

Triplet chemotherapy (TC) with FOLFIRINOX regimen in metastatic colorectal cancer (mCRC): Experience of the Val d’Aurelle Center.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3633-3633
Author(s):  
Emmanuelle Samalin ◽  
Virginie Loriot ◽  
Simon Thézenas ◽  
Eric Assenat ◽  
Fabienne Portales ◽  
...  
Keyword(s):  
Overall Survival ◽  
Liver Metastases ◽  
Targeted Therapies ◽  
Primary Tumor ◽  
Response Rate ◽  
Objective Response ◽  
Complete Response ◽  
Median Number ◽  
Grade 3 ◽  
The Impact

3633 Background: TC is a treatment option for mCRC to improve the tumor response rate in selected patients (pts) and the conversion rate of initially non-resectable liver metastases. The aim of this study was to evaluate the impact and feasibility of FOLFIRINOX regimen in mCRC pts. Methods: All mCRC pts with non-resectable disease who have received FOLFIRINOX alone or combined with targeted therapies (bevacizumab or cetuximab) from October 2000 to December 2010 were selected for this analysis. Clinical data were collected in a mCRC specific data base and analyzed by the end of 2011. Results: Ninety two pts (52% of men), median age 59 yrs (range: 27-76) were treated with FOLFIRINOX (D1 oxaliplatin 85 mg/m² IV 2H then irinotecan 180 mg/m² IV 90 min and elvorin 200 mg/m², then 5FU 200 mg/m² and 2400 mg/m² by 46H infusion, D1=D15) alone (64%) or combined with cetuximab(30%) or bevacizumab (6%), as 1st-line in 82 pts (89%). Prophyllactic G-CSF was given in 58% of them. Primary tumor was located in colon (58%) or rectum (42%), and 64 (69%) of pts presented with synchronous metastases: liver 100%, lung 40%, peritoneum 17% and nodes 17%. Median number of cures was 8 (range: 1-12). There was 1 toxic death. Grade 3-4 toxicities were: diarrhea 22%, neuropathy 21%, cutaneous 12%, neutropenia 28%, febrile neutropenia 0%, thrombopenia 6%. Objective Response rate according to RECIST criteria was 72% [CI95% 61-81] including 10 pts with complete response (11%). The primary tumor was resected in 70 pts (76%) and 14% had KRAS mutated tumor. Among the pts with liver metastases, 63 (68%) pts were evaluated for secondary resectability by a multidisciplinary committee and 40 pts (43%) had resection achieved (70% R0). Median overall survival was 49 months [CI95%28-62]. Conclusions: These results confirm the feasibility of FOLFIRINOX regimen with or without targeted therapies and its efficacy in terms of response rate and overall survival as 1rst-line treatment in selected mCRC pts.

Phase II Trial of Bevacizumab Combined with Low Dose Dexamethasone and Lenalidomide (BEV/REV/DEX) for Relapsed or Refractory Myeloma (MM).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1173-1173 ◽  
Author(s):  
Martha Raschko ◽  
Stephanie Markovina ◽  
Shigeki Miyamoto ◽  
Walter Longo ◽  
Eliot Williams ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Low Dose ◽  
Plasma Cells ◽  
Response Rate ◽  
Myeloma Cell ◽  
Median Number ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Grade 3

Abstract The interaction between malignant plasma cells and non malignant bone marrow microenvironment has been recognized as both an important feature of MM propagation and a therapeutic target. One critical interaction appears to involve angiogenesis as evidenced by increased blood vessel density in areas of myeloma cell proliferation. The potent anti MM compound lenalidomide may work partly through down regulation of VEGF expression by bone marrow stromal cells. We hypothesized that the addition of the VEGF-A receptor inhibitor, bevacizumab, in combination with low dose weekly dexamethasone, would provide more complete blockade of VEGF activation and translate to increased activity in MM patients with relapsed or refractory disease. ELIGIBILTY: relapsed or refractory MM patients (pts), failing >1 therapy, with no previous exposure to lenalidomide, measurable M protein in serum and/or urine, no current history of unstable cardiovascular disease or uncontrolled thrombosis, no therapy for ≥28 days, and no contraindication to aspirin. METHODS: Each 4 week cycle consisted of lenalidomide 25 mg PO d1–21, bevacizumab 10 mg/kg IV over 2 hours every two weeks, and dexamethasone 40 mg PO q week. All pts received aspirin 325 mg PO daily. Prior to therapy pts underwent bone marrow biopsy and aspirate. MM and stromal cells were isolated for analysis of STAT 3 activation to assess the treatment’s effect on stromal/MM cell interactions. Clinical responses were assessed using IBMTR criteria. RESULTS: 17 pts have been enrolled, ages 53––89, with median number of previous regimens 3 (range 1–6). Two pts were taken off study during the first cycle, one due to GI perforation occurring d 6 of therapy, and one pt due to rapidly progressive disease during first week of therapy. Ten pts have completed ≥ 4 cycles and can be evaluated for response. Seven of 10 pts achieved a PR after a median of two cycles and have maintained that response. One pt progressed after completing one cycle, one pt progressed after 5 cycles, and one pt had stable disease after 6 cycles. Expected grade 3 toxicities included DVT in 2 patients (both of whom were on aspirin but received erythropoiesis stimulating agents) and 2 pts developed shortness of breath attributed to bevacizumab, with resolved after discontinuation of the drug; one patient developed atrial fibrillation which spontaneously converted. No patient developed hypertension or proteinuria. Most required a dose reduction of lenalidomide due to fatigue. Analysis of STAT3 DNA-binding in MM cells alone or in co-culture with MM-BMSCs revealed variable low levels of constitutive STAT3 activity and enhanced activity in co-culture. No additional effect of bevacizumab + revlimid on constitutive STAT3 activity was observed. CONCLUSIONS: the combination of lenalidomide, bevacizumab and low dose dexamethasone has activity in relapsed and refractory myeloma. The initial 70% response rate compares favorably with the 58% response rate reported by Stadtmauer et al (Blood 108:3552) in previously treated MM pts receiving lenalidomide and high dose dexamethasone. Toxicities of this regimen are predictable but manageable. The use of ESAs may contribute to the development of DVT and the protocol has been modified to preclude their use.

Low Dose Ara-C Versus Low Dose Ara-C and Tipifarnib: Result of the UK NCRI AML16 “Pick a Winner” Comparison

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2962-2962 ◽  
Author(s):  
Alan K. Burnett ◽  
Robert Hills ◽  
Donald Milligan ◽  
William J. Kell ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Low Dose ◽  
De Novo ◽  
Remission Rate ◽  
Performance Status ◽  
Randomised Trial ◽  
Age Distribution ◽  
Best Supportive Care ◽  
The Uk

Abstract Novel treatments are needed for older patients with AML who are not thought likely to benefit from standard chemotherapy. A recent randomised trial demonstrated that Low Dose Ara-C (LD Ara-C) was superior to best supportive care (BSC) (Burnett et al Cancer2007: 109: 1114–1124). The Farnesyl Transferase inhibitor, Tipifarnib, has produced encouraging responses in this patient group (Lancet 109; 1387–1394) although in a subsequent randomised comparison vs BSC it was not superior (Haroussea et al Blood1997:110,135a) The UK NCRI AML16 trial aims to test novel agents or combinations in untreated older patients with AML or high risk MDS (marrow blasts &gt;10%) following a “pick a winner” design. The intention is to randomise up to 50 patients per arm with the expectation that a “winner” will achieve a remission rate in excess of 30%, compared with 15–20% with LD Ara-C. If that is achieved randomisation will continue with OS and DFS as endpoints. We report our experience of LD Ara-C (20mg bd days 1–10 for 4 courses versus LD Ara-C combined with Tipifarnib (300mg bd days 1–21) for 4 courses at 6–8 week intervals. Patient Details: Sixty-five patients were randomised between December 2006 and October 2007. The median age was 74.4 years with 82% of patients over 70 years. There were no differences between the treatment arms with respect to age distribution, gender, performance status, de novo/secondary AML, high risk MDS presenting WBC or cytogenetic risk group. Because of concerns about excess deaths in the Tipifarnib arm and therefore the low probability that LD Ara-C + Tipifarnib would be superior to LD Ara-C alone, the DMEC recommended premature closure of the Tipifarnib arm. Conclusions: While other agents combined with Tipifarnib may continue to show promise, the combination with LD-Ara-C in this patient population was not beneficial.

Randomized Phase 2 Trial of Two Different Doses of Ixazomib in Patients with Relapsed Multiple Myeloma Not Refractory to Bortezomib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3050-3050 ◽  
Author(s):  
Shaji K Kumar ◽  
Betsy R. Laplant ◽  
Craig B. Reeder ◽  
Vivek Roy ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Response Rate ◽  
Median Number ◽  
Phase 2 ◽  
Free Survival ◽  
Grade 3 ◽  
Randomized Phase 2

Abstract Background: Ixazomib is an experimental, orally bioavailable, proteasome inhibitor that has demonstrated anti-tumor activity in relapsed multiple myeloma (MM). In the dose escalation studies, ixazomib was tolerated up to a dose of 5.5 mg given every week as a single agent, while a dose of 4 mg was utilized in the combination studies with lenalidomide. We undertook this study to examine the efficacy and tolerability of the two doses of ixazomib in combination with dexamethasone in patients with relapsed MM. Patients and methods: This was a randomized phase 2 study of two doses of ixazomib (4mg; Arm A or 5.5 mg; Arm B) given weekly for three weeks with a week off along with weekly dexamethasone (40 mg) in patients with relapsed MM, who are proteasome inhibitor na•ve (including bortezomib) or have received less than 6 cycles of therapy with bortezomib and had a PR or better with no progression at the time of discontinuation. The primary objective was to determine the confirmed overall response rate (>=PR); secondary objectives included progression free and overall survival. A total of 71 patients were accrued from February 2013 to April 2015; one patient was ineligible. Results: Baseline characteristics were similar in the two arms; median age across the study was 70 years (46-84); 53% were male. Median number of prior therapies was 4 (range 2-6); 90% of the patients had prior IMiDs, 70% had prior transplant and 29% had prior bortezomib. At a median follow up of 10 months, 17 (49%) and 19 (54%) of patients had disease progression in arms A and B respectively with 12 (34%) patients in each arm still continuing on treatment. All patients in each arm were evaluable for response; the overall response rates were 31% in arm A (95%CI: 17-49) and 51% (95%CI: 34-69) in Arm B. The depth of response, event free survival and overall survival are outlined in Table 1. Among the patients with no prior bortezomib exposure the response rates were 38% for Arm A and 52% for Arm B. The treatment was well tolerated with 2 patients in each arm discontinuing treatment for adverse events; there were no on study deaths. A grade 3 or higher AE that was at least possibly related to treatment was seen in 21% and 54% in Arms A and B respectively; with 15% and 37% hematologic and 6% and 29% non-hematologic AEs. The most common attributable toxicities encountered included fatigue, thrombocytopenia, diarrhea and nausea with more grade 3 toxicities among Arm B. Peripheral neuropathy, possibly related to ixazomib, was seen in 55% (only grade 1 or 2) in arm A and 43% (2 patients with grade 3) in Arm B. Toxicities led to dose reduction of ixazomib in 17% and 43% of patients in Arm A and B respectively; the median number of cycles administered were 5 (1-24) and 5 (1-22) respectively. Conclusions: Ixazomib in combination with dexamethasone was well tolerated with significant anti-myeloma activity in this group of patients with relapsed MM. Deep responses including stringent CR were observed. The higher dose of ixazomib appears to be associated with a higher response rate but with higher rate of adverse events requiring dose reductions. Table 1. Treatment outcome in all patients Arm B (4 mg) (N=35) Arm C (5.5 mg) (N=35) Response Rate 31% (95%CI: 17-49) 51% (95%CI: 34-69)  No. of Responders 11 18   sCR 0 1   CR 1 0   VGPR 7 8   PR 3 9   MR 5 1 Median Overall Survival1 NA NA  6 Months 100% 100% Median Event Free Survival1,2 8.4 mos (95%CI: 4.3-13.2) 8.2 mos (95%CI: 3.8-16.3) %Event Free at 6 Months 60% (95%CI: 45-81) 60% (95%CI: 45-81) Median Duration of Response1 16.7 mos (95%CI: 9.3-22.0) 16.3 mos (95%CI: 7.0-20.1) Median Time to Response 1.1 mos (range: 0.8-3.6) 1.0 mos (range: 0.8-7.5) CI: confidence interval; mo: month; NA: not attained 1Kaplan Meier 2Event-free survival time is defined as the time from registration to the first of disease progression, death due to any cause, or subsequent treatment for multiple myeloma. Disclosures Kumar: Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

scholarly journals Single arm, phase two study of low-dose metronomic eribulin in metastatic breast cancer

2021 ◽  
Author(s):  
Pavani Chalasani ◽  
Kiah Farr ◽  
Vicky Wu ◽  
Isaac Jenkins ◽  
Alex Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Peripheral Neuropathy ◽  
Clinical Benefit ◽  
Low Dose ◽  
Response Rate ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Free Survival

Abstract Background Treatment options for metastatic breast cancer (MBC) refractory to anthracyclines and taxanes are limited. In a phase III trial, eribulin demonstrated a significant improvement in overall survival compared to treatment of physician’s choice, but had limited tolerability because of neutropenia and peripheral neuropathy. Based on prior studies of alternative treatment schedules with other therapies, we hypothesized that a low-dose metronomic schedule of eribulin would permit patients to remain on treatment more consistently without treatment delays, resulting in longer time to progression, and improved toxicity profile. Methods We conducted a multi-site single arm, phase II trial patients with MBC. All patients were treated with metronomic eribulin (0.9 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle.) Treatment was continued until the patient developed disease progression, unacceptable toxicity, or chose to stop the study. Patients must have had prior taxane exposure. The primary endpoint was progression-free survival. Secondary end points were overall survival, response rate, and clinical benefit rate. Exploratory biomarkers were performed to analyze change in levels of circulating endothelial cells (CECs), circulating endothelial precursors, and carbonic anhydrase IX (CAIX) with response to therapy. Findings We consented 86 patients and 59 were evaluable for final analysis. Median age was 59 years; 78% had HER2 negative tumors. The median progression-free survival (PFS) was 3.5 months with overall survival (OS) of 14.3 months. Objective response rate was 15% with clinical benefit rate of 48%. Reported grade 3 neutropenia and peripheral neuropathy were 18% and 5%, respectively. Treatment discontinuation due to toxicity was seen in 3% of patients. Interpretation Metronomic weekly low-dose eribulin is an active and tolerable regimen with significantly less myelosuppression, alopecia, and peripheral neuropathy than is seen with the approved dose and schedule, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen.

Pentostatin and Cyclophosphamide: An Effective New Regimen in Previously Treated Patients With Chronic Lymphocytic Leukemia

2003 ◽  
Vol 21 (7) ◽  
pp. 1278-1284 ◽  
Author(s):  
Mark A. Weiss ◽  
Peter G. Maslak ◽  
Joseph G. Jurcic ◽  
David A. Scheinberg ◽  
Timothy B. Aliff ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Severe Nausea ◽  
Treatment Regimens ◽  
Purine Analogs ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

Purpose: Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs. Patients and Methods: We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m2. Seventeen patients received cyclophosphamide 600 mg/m2, and six patients received cyclophosphamide 900 mg/m2. Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy. Results: The cyclophosphamide 900 mg/m2 dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m2 as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy. Conclusion: Pentostatin 4 mg/m2 with cyclophosphamide 600 mg/m2 is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.

scholarly journals Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4188-4198 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Jessica Kohlschmidt ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
De Novo ◽  
Prognostic Significance ◽  
The Impact ◽  
Favorable Group ◽  
Acute Myeloid

AbstractLow MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene–embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.

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