Report of a Phase II Study of Clofarabine and Cytarabine in De Novo and Relapsed and Refractory AML Patients and in Selected Elderly Patients at High Risk for Anthracycline Toxicity

Abstract Abstract 2188 Background: Treatment options for pts with refractory/relapsed (R/R) AML are limited. High dose cytarabine (A) containing regimens are still considered standard options for pts with AML relapsing after a first complete remission (CR) lasting more than 12 months. The combination of A with fludarabine (F) was found to be superior to A alone in this setting, particularly when administered twice daily (BID). In addition, gemtuzumab ozogamicin (GO) has been shown to be active in combination or as single agent in pts with R/R AML. Therefore, we conducted a phase II study assessing the efficacy and safety of BID FA-GO. Patients and Methods: Pts with R/R AML, de novo AML patients unfit for other medical therapies, intermediate-2 and high-risk MDS, and chronic myeloid leukemia in myeloid blast crisis (CML-BC), with a performance status (PS) of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive F 15 mg/m2 IV q12 hrs day 1 to 5 as well as A at the dose of 0.5 g/m2 IV over 2 hrs q12 hrs day 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1. Treatment course was shortened to 4 days in pts older than 65 years and to 3 days in pts with a PS of 3. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML were allowed to receive concomitant tyrosine kinase inhibitors. Results: Sixty-five evaluable pts were enrolled: 6 (9%) with de novo AML, 5 (8%) with AML in first relapse with a duration of 1st CR (CRD1) of ≥12 months, 21 (32%) with AML with CRD1 <12 months, 24 (37%) with AML in second relapse and beyond, 3 (5%) with MDS, and 6 (9%) with CML-BC. Median age was 60 years (range, 19 to 80); 58 pts (89%) had a PS ≥1. Cytogenetic analyses were abnormal in 63 % including chromosomes 5 and 7 abnormalities in 17%. The overall response (OR) rate was 31% including CR in 17 pts (26%) and CR without platelet recovery (CRp) in 3 (5%). The overall 4-week mortality rate was 8%. The OR rates for pts with de novo AML, relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage (S) were 43%, 60%, 35%, and 19%, respectively. The CR rates were 29%, 60%, 27%, and 19%, respectively. The 4-week mortality rates were 19% for pts with R/R AML beyond the first salvage and 0% for the rest (Table1). With a median follow-up of 8 months (range, 1 to 27), the 16-week event-free survival (EFS), overall survival (OS), and complete remission duration (CRD) rates were 25%, 61%, and 89%, respectively. The median EFS and OS for the responding pts were 27 weeks (4-31 weeks). When compared to historical match cohort pts treated at our institution, BID FA-GO was better, with an ORR rate of 60 % in pts with AML in first relapse with CRD1 ≥12 months compared to an expected rate of 50%, 19% in pts with relapsed AML with CRD1< 12 months compared to 11%, and 35% in pts with AML beyond the first salvage compared to 7% (Table 2). The treatment was well tolerated with only 3% of the pts experiencing grade 3 and 4 toxicities including mainly skin rash. The main toxicities were of gastro-intestinal origin and all were of grade 1 and 2. There was no case of veno-occlusive disease reported. Conclusion: BID FA-GO appears to be active with an ORR of 31% in heavily pre- treated population. This combination appears to be safe as well with a low rate of 4-week-mortality of 5%. Ongoing studies are exploring the role of the new generation of nucleoside analogues in this setting. Disclosures: Cortes: Pfizer: Consultancy, Research Funding.

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Low-Dose 5-Aza-2′-Deoxycytidine, a DNA Hypomethylating Agent, for the Treatment of High-Risk Myelodysplastic Syndrome: A Multicenter Phase II Study in Elderly Patients

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.5.956 ◽

2000 ◽

Vol 18 (5) ◽

pp. 956-956 ◽

Cited By ~ 421

Author(s):

P. Wijermans ◽

M. Lübbert ◽

G. Verhoef ◽

A. Bosly ◽

C. Ravoet ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Myelodysplastic Syndrome ◽

Survival Time ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Response Duration ◽

Multicenter Phase ◽

Dna Hypomethylating Agent

PURPOSE: 5-Aza-2′-deoxycytidine (decitabine; DAC) is a DNA hypomethylating agent that has shown a 50% response rate in a small phase II study in elderly patients with high-risk myelodysplastic syndrome. We performed a second, multicenter phase II study in a larger group of patients to confirm our findings and to study the toxicity of DAC. PATIENTS AND METHODS: Between June 1996 and September 1997, 66 patients (median age, 68 years) from seven centers received DAC 45 mg/m2/d for 3 days every 6 weeks. For patients in whom a complete response (CR) was reached after two courses, two further cycles were administered as consolidation therapy. In case of a stable disease situation, improvement, or a partial response (PR), a maximum of six cycles was administered. The primary end points were response rate and toxicity. The secondary end points were response duration, survival from the start of therapy, and overall survival. RESULTS: The observed overall response rate was 49%, with a 64% response rate in the patients with an International Prognostic Scoring System (IPSS) high-risk score. The actuarial median response duration was 31 weeks, with a response duration of 39 weeks and 36 weeks for patients who reached a PR or CR, respectively. The actuarial median survival time from the time of diagnosis was 22 months and from the start of therapy was 15 months. For the IPSS high-risk group, the median survival time was 14 months. The median progression-free survival time was 25 weeks. Myelosuppression was rather common, and the treatment-related mortality rate was 7% and was primarily associated with pancytopenia and infection. Significant responses were observed with regard to megakaryopoiesis, with increases in platelet counts having already occurred after one cycle of DAC therapy in the majority of the responding patients. CONCLUSION: We were able to confirm our previous observation that DAC therapy was effective in half of the studied patients with high-risk myelodysplastic syndrome and is especially active in the patients with the worst prognoses. Myelosuppression was the only major adverse effect observed.

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Phase II Study of Clofarabine and Cytosine Arabinoside in Adult Patients with Relapsed AML and in Elderly Patients with Untreated AML Who Are at High Risk of Anthracycline Toxicity.

Blood ◽

10.1182/blood.v108.11.1951.1951 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1951-1951 ◽

Cited By ~ 3

Author(s):

Edward Agura ◽

R. Brian Berryman ◽

Laura Brougher ◽

Barry Cooper ◽

Andrew De Leon ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Phase Ii ◽

Response Rate ◽

De Novo ◽

High Risk Patient ◽

Early Death ◽

Poor Response ◽

Adult Patients ◽

Open Label

Abstract PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in adult patients with refractory or relapsed acute myeloid leukemia and in selected elderly patients with untreated AML and heart disease. PATIENTS AND METHODS: In a phase II, open-label trial, 23 patients with de-novo AML, AML evolved from MDS or relapsed AML received a 5 day regimen consisting of clofarabine 40 mg/m2 intravenously over 1 hour followed within 4 hours by Ara-C 1000 mg/m2. The median age was 68 years (range 39–79 years). Fifteen (65%) had received at least one prior cytotoxic regimen (excluding 5-AZA). Significant cardiovascular disease (history of myocardial infarction, bypass grafting, cardiomyopathy) was present in 52% (12/23) prior to therapy. RESULTS: 22/23 received at least one cycle of therapy and 5 received 2 cycles. One early death was due to disease progression. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 20 patients are evaluable for response. The histologic response rate (defined as marrow blasts <5%) is 60% (12/20) consisting of 10 (50%) complete remissions and 2 (10%) partial responses. Complete cytogenetic remissions occurred in 9 patients. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation. CONCLUSION: Clofarabine (40mg/m2) and Ara-C (1000mg/m2) x 5 days is an active and well tolerated regimen in myeloid malignancies including “elderly AML”—a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are being explored for use in allogeneic transplant regimens and with other high-risk patient groups.

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A phase II study of R-COMP14 in elderly patients with high-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high “life threat” impact cardiopathy.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.8058 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 8058-8058

Author(s):

G. Corazzelli ◽

F. Frigeri ◽

M. Arcamone ◽

A. Lucania ◽

G. Capobianco ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

B Cell ◽

Phase Ii ◽

Phase Ii Study ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Life Threat ◽

Large B Cell

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Final Results of a Phase II Study of Sequential R-CHOP and Yttrium-90 Ibritumomab Tiuxetan (RIT) for Elderly High Risk Patients with Untreated Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽

10.1182/blood.v116.21.1793.1793 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1793-1793 ◽

Cited By ~ 6

Author(s):

Paul A. Hamlin ◽

Maria Alma Rodriguez ◽

Ariela Noy ◽

Carol S. Portlock ◽

David Straus ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

B Cell Lymphoma ◽

Phase Iii ◽

Ibritumomab Tiuxetan ◽

Grade 5 ◽

Yttrium 90

Abstract Abstract 1793 Introduction: Elderly patients (pts) with high risk DLBCL are one of the fastest growing demographics of pts, but advances over RCHOP21 have not been realized. These pts are often under-represented in clinical trial secondary to comorbidity, ageism, and eligibility requirements. By the age adjusted international prognostic index (aaIPI), pts >60 years (yrs) with high-intermediate (HI) and high (H) risk disease had 5 yr survival (OS) rates of 37% and 21%. Even in the RCHOP era, high risk elderly patients have event-free-survival of roughly 50%. We report the mature data from a phase II study investigating sequential RCHOP followed by yttrium-90 ibritumomab tiuxetan radioimmunotherapy (RIT) in an effort to improve these results. Methods: Untreated ASCT-ineligible pts >60 yrs, with aaIPI HI and H risk DLBCL were eligible for study. Pts received RCHOP21 × 6 cycles at standard doses with prophylactic GCSF and darbepoetin alfa. Pts with responding (CR/PR) or stable disease post RCHOP received RIT, given 6–9 weeks post chemotherapy at 0.4 mCi/kg for platelets (plt) ≥150K and 0.3 mCi/kg for plt 100–149K. Weekly CBCs were performed for 12–13 weeks or until count resolution. Rituximab levels were assessed pre-RIT in a subset of pts. Primary end-points were PFS and OS, with intent-to-treat (ITT) analysis performed for all patients. Statistics anticipated 2/3 of pts (n=43) receiving RIT, with power to demonstrate a 20% improvement in PFS/OS at 2 yrs. Results: 65 pts were consented, with 2 pts having progression prior to a single cycle on protocol, leaving 63 evaluable pts. The median age was 75 (62-86), median KPS 70% (50-100%), Stage III/IV 23/74%, LDH>ULN 91%, ENS>1=45%, BM positive=11%; aaIPI HI/H 45%/55%. Moderate or greater comorbidity was present in 86% of pts (n=65) by NIA/NCI scale. 86% of pts completed RCHOP, with overall response rate (ORR) of 83% (CR/Cru 75%, PR 8%) (Cheson 1999). Fifty pts by ITT were eligible for RIT following RCHOP chemotherapy, with 44 pts ultimately treated. Reasons for discrepancy included low bone marrow cellularity (2pt), AFIB/CHF post day 0 (1 pt), abnormal baseline FISH/cytogenetics (2 pts), withdrawal of consent (1pt). Rituximab levels in 30 pts are available pre-RIT: mean 112 mcg/ml (range 41–196) and did not correlate with outcome. The RIT dose was 0.4 mCi/kg in 38 patients and 0.3 mCi/kg in 6 patients. No patient had altered biodistribution on imaging. RIT was generally well tolerated with expected hematologic nadirs at weeks 6–7. Grade 3/4 non-heme toxicity during RIT included neutropenic fever (2), transient EF decline >20% (1), hip fracture (1), anthracycline induced cardiomyopathy (grade 5), suspected CNS bleed (grade 5). Response post RIT (n=44) was CR/CRu 86%, PR 2%. Response improvement (PR->CR or CRu->CR) occurred in 7 pts (16%). Median followup for surviving pts is 42 months, with median OS and PFS not reached (0.5-74.4). KM estimates of OS and PFS at 42 months by ITT: 64% and 62% respectively. OS and PFS at 42 months for RIT treated pts (n=44): 83.5% and 74.5%. There have been only two relapse >12 months after RIT. The aaIPI (HI vs H) predicted outcomes: OS 75% vs. 49% (p=.008), PFS 68% vs. 45% (p=.01). Conclusion: Sequential RCHOP21 × 6 cycles followed by RIT in an elderly, high comorbidity, high risk DLBCL cohort is associated with very encouraging outcomes by ITT and specifically in the RIT treated pts with long term follow-up. Therapy was well tolerated in this age group and given lack of late relapses, one may hypothesize RIT is addressing minimal residual disease typically associated with recurrence. Outcome is very favorable when compared to historical controls. A prospective Phase III study is needed to confirm these results. Disclosures: Hamlin: Genentech: Honoraria, Speakers Bureau; Biogen Idec: Honoraria, Speakers Bureau; Spectrum: Consultancy, Research Funding; CTI: Consultancy, Research Funding. Off Label Use: Y-90 ibritumumab tiuxetan is not approved for use in DLBCL; it is FDA approved for NHL/indolent lymphoma. Rodriguez:CTI: Research Funding. Noy:Spectrum: Consultancy. McLaughlin:Spectrum: Consultancy. Pandit Tasker:CTI: Research Funding; Spectrum: Research Funding. Zelenetz:GSK: Consultancy; CTI: advisory board.

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A phase II study of bexarotene + GM-CSF in refractory AML and high risk MDS.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.e13542 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. e13542-e13542

Author(s):

Kelly J. Norsworthy ◽

Richard J. Jones ◽

Erica D. Warlick ◽

Eunpi Cho ◽

William H. Matsui ◽

...

Keyword(s):

High Risk ◽

Phase Ii ◽

Phase Ii Study ◽

Gm Csf ◽

Refractory Aml

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Phase II study of clofarabine and cytosine arabinoside in adult patients with relapsed AML and in elderly patients with untreated AML who are at high risk of anthracycline toxicity

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7064 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7064-7064 ◽

Cited By ~ 2

Author(s):

E. D. Agura ◽

R. Berryman ◽

B. Cooper ◽

J. Fay ◽

H. Holmes ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Phase Ii ◽

Response Rate ◽

De Novo ◽

Poor Response ◽

Chromosome Analysis ◽

Open Label ◽

Elderly Aml ◽

History Of

7064 Purpose: To evaluate the efficacy/safety of a novel AML regimen in elderly patients with heart disease or in patients with a contraindication to ‘standard‘ anthracycline-containing regimens. Patients and Methods: Phase II, open-label design. Eligible pts had elderly de-novo or relapsed AML or would not benefit from 7+3 or simlar therapy. Treatment was CLOF 40 mg/m2, Ara-C 1,000 mg/m2. (d1–5). Results: Patients were accrued and treated from April 2005 through Oct 2006. All pts signed IRB-approved consents. The median age was 67 years (range 38–82 years). Twenty (67%) subjects had received at least one prior cytoxic regimen (excluding 5-AZA). Significant cardiovascular (history of MI, bypass grafting, cardiomyopathy) was present in 43% (13/30) prior to therapy. Thirty pts were enrolled and all recieved at least one day of therapy. 1 pt died within 24 hours of starting treatment due to disease progression. Of the remaining, 29/30 received at least one complete cycle of therapy and 5 received 2 cycles. None received more than 2 cycles. Toxicities were greater in those receiving a second cycle. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 25 patients survived >28 days and are evaluable for hematologic response. The histologic response rate (RR) is 68% (17/25) consisting of 14 (56%) complete remissions (marrow blasts <5%) and 3 (12%) partial responses (PR). There were 13 subjects with known cytogenetic abnormalities, 1 favorable and 12 unfavorable. Complete cytogenetic remissions (CytoCR) occurred in 4 of those patients, by chromosome analysis and/or FISH. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation. Conclusion: Clofarabine and Ara-C is an active and well tolerated regimen in myeloid malignancies including “elderly AML” a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are ongoing in hematopoietic transplant and other high risk subgroups. No significant financial relationships to disclose.

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