Acute Myelogenous Leukemia: Early Indication that Lenalidomide May Help Subset of Elderly Patients

2011 ◽  
Vol 33 (12) ◽  
pp. 41-42
Author(s):  
Kurt Samson
Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4387-4387 ◽  
Author(s):  
Chandanda Thatikonda ◽  
James M. Rossetti ◽  
Richard K. Shadduck ◽  
John Lister

Abstract Background: Secondary acute myelogenous leukemia (AML) carries a poor prognosis when compared to de novo AML. Therapeutic options are typically limited as patients are often elderly with comorbidities that preclude intensive chemotherapy. Moreover, resistance to therapy is common. Studies have shown that methyltransferase inhibitors (MTI) have activity in myeloid malignancy. It is not known if addition of histone deacetylase (HDAC) inhibitors improves or prolongs the activity of MTI. We present our experience of 3 elderly patients with secondary AML treated with MTI (azacitidine or decitabine) in combination with an HDAC inhibitor (vorinostat). Methods: Patients include 2 males and 1 female, ages 78 yrs, 82 yrs and 71 yrs. All were initially diagnosed with high-grade myelodysplastic syndrome (MDS), which transformed to CD34+ secondary AML at 33, 14 and 4 months from diagnosis of MDS, respectively. One patient had trisomy 8. Patients received 8, 3 and 4 cycles of MTI before leukemic transformation, respectively. At transformation, one patient failed standard induction therapy and 1 patient failed arsenic trioxide. Both of these patients were then placed back on MTI as maintenance therapy. Vorinostat was added at a dosage of 400 mg daily at MTI cycles 8, 3 and 1 post transformation, respectively. The number of cycles of combination therapy was 6, 9 and 4. Gastrointestinal intolerance was an issue in 2 of these patients: nausea (n=2), diarrhea (n=2), vomiting (n=1) and loss of appetite (n=1). Dose reduction to 100mg in one patient and 300 mg in another resulted in some symptomatic relief. The addition of 5-HT3 antagonists or low dose prednisone allowed dose escalation. One patient had 50% reduction in marrow blasts, 1 had near clearance of the peripheral blasts and 1 had a transient minor platelet response. All 3 patients are alive at 14, 10 and 9 months post transformation (6, 8 and 7 months after addition of vorinostat) with no disease progression, respectively. Conclusion: The combination of MTI and HDAC could be an option in elderly patients with secondary AML without increasing morbidity and mortality. Treatment appears well tolerated when premedication with 5-HT3 antagonists is employed. As the treatment options are limited in high-risk elderly patients with secondary AML, larger studies are needed to investigate the utility of this combination.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4164-4164
Author(s):  
Heather L. Benjamin ◽  
James M. Rossetti ◽  
Aaron J. Lampkin ◽  
Christie Hilton ◽  
Entezam Sahovic ◽  
...  

Abstract Abstract 4164 BACKGROUND Effective treatment of the elderly patient with acute myelogenous leukemia (AML) remains a challenging task. Elderly patients with AML usually respond poorly to standard induction chemotherapy. Response rates in elderly patients are in the range of 30–50% compared to 80–90% in younger patients. Moreover, prolonged hospitalization with treatment related mortality as high as 30% is typical in this older population. In a prior retrospective analysis done at our institution, azacitidine showed an overall response rate of 60% with limited toxicity when administered to patients older than 55 years of age with AML. We present an interim analysis of the first 13 patients enrolled in our prospective, phase II open label study using single agent azacitidine for elderly patients with AML. METHODS This is a prospective, phase II open label study using azacitidine in patients ≥ 60 years with AML. Inclusion criteria: Newly diagnosed AML (de novo or secondary, WHO criteria) and ECOG≤ 2. Promyelocytic (M3) phenotype was excluded. Patients with circulating blast count ≥ 30,000/mcl were treated with hydroxyurea until < 30,000/mcl. Azacitidine was given at a dose of 100 mg/m2 subcutaneously for 5 consecutive days every 28 days until disease progression or significant toxicity. G-CSF was given to patients with neutropenia (ANC < 1000/mcl) during all cycles excluding cycle one. RESULTS Thirteen patients have been enrolled to date. The mean age of patients is 75 years (range: 66–84). The mean baseline ECOG performance score was 1 with a mean during treatment of 1. Mean baseline bone marrow blast count was 57% (range: 21–100%). Overall response rate using the NCI response criteria (IWG criteria for patients with hematological improvement (HI) only) was 46% (6/13): complete response (CR; n=3; 23%), partial response (PR; n=1; 8%), and HI (n=2; 15%). One additional patient had a 94% reduction in marrow blasts, but failed to achieve transfusion independence. The mean number of days on treatment was 171+ (range: 13–606). The mean number of days hospitalized for diagnosis plus treatment or disease related complication was 21 (range: 7–72) with the majority of therapy being given in the outpatient setting. One patient required prolonged hospitalization after going on to allogeneic transplantation. The mean overall survival from diagnosis for all patients was 246+ days (range: 13–606). The mean overall survival for responders was 399+ days (range: 212–606). One patient continues on therapy with azacitidine at 606 days (CR). Of the other responders, one progressed at 420 days and is considering other options (CR), one died from an intra-cranial hemorrhage after receiving Mylotarg for disease progression at 454 days (CR), one progressed at 119 days and went on to another clinical trial (PR), and two died with disease at 212 and 347 days (HI). Non-hematological toxicity was limited to mild injection site skin reaction and fatigue in 77% (10/13) each. No treatment related deaths were observed. The dose and schedule of therapy remained constant in all but three patients: One patient required a 25% dose reduction after cycle 3 followed by another 25% reduction after cycle 11 due to drug induced marrow suppression, one patient required a 25% dose reduction after cycle 2 due to drug induced marrow suppression, and one patient required and tolerated a 25% dose escalation to recapture a CR after cycle 15. CONCLUSION This interim analysis suggests that the administration of subcutaneous azacitidine in an accelerated dosing schedule to elderly patients with acute myelogenous leukemia is a feasible and well-tolerated alternative to standard induction chemotherapy. Disclosures: Benjamin: Celgene Corporation: Research Funding. Off Label Use: Use of azacitidine in AML.. Rossetti:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Sahovic:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Abdulhaq:Celgene Corporation: Research Funding. Shadduck:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Lister:Celgene Corporation: Research Funding.


2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 7026-7026 ◽  
Author(s):  
G. J. Schiller ◽  
D. DeAngelo ◽  
N. Vey ◽  
S. Solomon ◽  
R. Stuart ◽  
...  

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6620-6620
Author(s):  
Cyrus Khan ◽  
James M. Rossetti ◽  
Christie Hilton ◽  
Santhosh Sadhashiv ◽  
Sanaullah Khalid ◽  
...  

6620 Background: Effective alternative treatment of elderly patients (aged ≥ 60 years) with acute myelogenous leukemia (AML) remains challenging. Elderly patients with AML respond poorly to standard induction regimens and have high treatment related mortality. In a prior retrospective analysis of elderly patients with AML performed at our institution, azacitidine (AZA) showed an overall response rate (ORR) of 60% with limited toxicity. Methods: This is a prospective, phase II open-label study using AZA in patients ≥60 years with AML. Inclusion criteria: Newly-diagnosed non-M3 AML and ECOG ≤ 2. Patients with circulating blast count ≥30,000/mcl were treated with hydroxyurea until < 30,000/mcl. AZA was administered at 100 mg/m2 subcutaneously for 5 consecutive days every 28 days until disease progression or significant toxicity. Results: In all, 15 patients were enrolled last follow-up being 8/2/11. The mean age of patients is 74 years (range: 64–82). Mean ECOG score was 1. Mean baseline bone marrow blast count was 52% (range: 25–92%). ORR was 46% (n=7) with complete response (CR) in 3 (20%) patients and partial response (PR) in 2 (13%) patients according to NCI response criteria, and hematologic improvement (HI) in 2 (13%) patients according to IWG response criteria. The mean number of days on treatment was 198 (range: 13–724). The mean time to best response among responders was 95 days (range: 44-279). The mean number of days hospitalized for diagnosis plus treatment or disease-related complication was 19 (range: 5–56), with the majority of therapy administered in an outpatient setting. Mean overall survival (OS) from diagnosis for all patients was 355 days (range: 13–908) and mean OS for responders was 532 days (range: 120–908). Non-hematological toxicity was limited to mild injection site skin reaction and fatigue in 73% (11/15). No treatment-related deaths were observed. The dose and schedule of AZA remained constant in a majority of the patients. Conclusions: This study suggests that a 5-day schedule of SC AZA at 100 mg/m2 to elderly patients with newly-diagnosed AML is a feasible, well-tolerated and effective alternative to standard induction chemotherapy.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4041-4041 ◽  
Author(s):  
George Labban ◽  
James M. Rossetti ◽  
Richard K. Shadduck ◽  
Entezam Sahovic ◽  
Haifaa Abdulhaq ◽  
...  

Abstract BACKGROUND: Effective treatment of the elderly patient with acute myelogenous leukemia (AML) remains a challenging task. Elderly patients with AML usually respond poorly to standard induction chemotherapy. Response rates in elderly patients are in the range of 30–50% compared to 80–90% in younger patients. Moreover, prolonged hospitalization with treatment related mortality as high as 30% is typical in this older population. In a prior retrospective analysis done at our institution, azacitidine showed an overall response rate of 60% with limited toxicity when administered to patients older than 55 years of age with AML. We present an interim analysis of the first 8 patients enrolled in our prospective, phase II open label study using single agent azacitidine for elderly patients with AML. METHODS: This is a prospective, phase II open label study using azacitidine in patients ≥ 60 years with AML. Inclusion criteria: Newly diagnosed AML (de novo or secondary, WHO criteria) and ECOG ≤ 2. Promyelocytic (M3) phenotype was excluded. Patients with circulating blast count ≥ 30,000/mcl were treated with hydroxyurea until &lt; 30,000/mcl. Azacitidine was given at a dose of 100 mg/m2 subcutaneously for 5 consecutive days every 28 days until disease progression or significant toxicity. G-CSF was given to patients with neutropenia (ANC &lt; 1000/mcl) during all cycles excluding cycle one. RESULTS: Eight patients have been enrolled to date. The mean age of patients is 74 (range: 64–82 years). The mean baseline ECOG performance score was 1 with a mean during treatment of 1. Mean baseline bone marrow blast count was 53% (range: 21–92%). Overall response rate using the NCI response criteria was 75% (6/8): complete response (CR; n=2; 25%) and partial response (PR; n=4; 50%). The mean number of days on treatment was 117 (range: 4–247 days). The mean number of days hospitalized during therapy was 18 (range: 7–51 days) with the majority of therapy being given in the outpatient setting. The mean overall survival time from diagnosis for all patients was 180 days (range: 23–403). The mean overall survival time for responders was 200 days (range: 36–403). Three patients continue on therapy at 146 (PR), 153 (CR) and 247 (PR) days. Of the other responders, one went on to receive an allogeneic PBSCT, one died at 36 days from complications of a strangulated hernia, and one removed himself from study at 82 days (unconfirmed CR) to receive treatment closer to home. All patients were red blood cell (RBC) transfusion dependent at the start of the therapy. To date, two of the six responders (33%) became independent of RBC transfusion. Four patients were transfusion dependent for platelets at the start of therapy with two being non-responders and two achieving a PR. Non-hematological toxicity was limited to mild injection site skin reaction and fatigue in 63% (5/8) each. No treatment related deaths were observed. The dose and schedule of therapy remained constant in all patients except one who required a 25% dose reduction after cycle 3 due to drug induced marrow suppression. CONCLUSION: This interim analysis suggests that the administration of subcutaneous azacitidine in an accelerated dosing schedule to elderly patients with acute myelogenous leukemia is a feasible and well-tolerated alternative to standard induction chemotherapy.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1040-1040
Author(s):  
Stuart L. Goldberg ◽  
Aisha Masood ◽  
Jayshree Shah ◽  
Jack W. Hsu ◽  
Neelesh Rastogi ◽  
...  

Abstract Abstract 1040 Poster Board I-62 Treatment of the elderly patient with acute myelogenous leukemia remains problematic as many have poor performance status precluding aggressive therapy and others have high risk features including abnormal cytogenetics. The success of 5-azacitidine among patients with advanced myelodysplastic syndromes in controlling blast cells and prolonging survival has led to its use in AML. However choosing between potentially curative hospital-based induction chemotherapy and palliative outpatient hypomethylating treatments is difficult. The availability of predictive comorbidity scores may aid in guiding patients in this decision. Methods: Patients with a new diagnosis of AML, ages 60 and older, were offered traditional in-patient induction therapy (7 days cytarabine 100 mg/m2 CI with 3 days idarubicin 12mg/m2) or out-patient therapy (5-azacitidine 75 mg/m2 IV 5 days per month). We report a retrospective review of clinical outcomes among patients treated between June 2003 and August 1, 2009. A review of presenting clinical features, placing patients into prognostic groupings by the Charlson Comorbidity Index (J Chronic Dis 1987; 40:373), Hematopoietic Cell Transplantation – Specific Comorbidity Index (Blood 2007; 110:4606), and the Myelodysplastic Syndrome – Specific Comorbidity Index (Blood 2008; 112: abstr 2677) was performed. Points for a diagnosis of leukemia were excluded from the indices. Results: 99 patients with AML were treated at our center, all with leukemic blasts >20% (median 48%). 75 chose traditional 7+3 and 24 chose 5-aza. The median age was younger for those choosing 7+3 (67 vs 77 years, p<0.001). The median survival for all patients was 340 days (95% CI 258, 422). The median survival was longer with 7+3 at 367 days (95% CI 306,428) compared to a median survival with 5-aza of 186 days (95% CI 122, 250) (p=0.07). Only one patient age <65 chose 5-aza. The median survival for pts with 7+3 was similar by age groups: <65 yrs (n=34) 367 days, 65-69 yrs (n=19) 340 days, and ≥70 yrs (n=22) 467 days (log-rank p=0.31). Cytogenetic features (SWOG criteria) at baseline correlated with survival: good risk (n=3) 186 days, intermediate risk (n=54) 604 days, and poor risk (n=28) 241 days. (p=0.03). Similarly, cytogenetic risk continued to remain significant regardless of treatment choice: 7+3: intermediate/poor risk karyotype 664 days vs 340 days, and 5-aza: intermediate/poor risk 604 days vs 67 days (p=0.03). All 3 examined comorbidity indices were able to predict overall survival for the entire cohort (n=99). Using the CCI, better scores led to improved outcome (log-rank p=0.007): Score 0 (n=41): 475 days; score 1 (n=23): 213 days; score 2 (n=25): 196 days; score 3 (n=8): 186 days; score 4 (n=2) 1404 days. Similar results were obtained using the HCTS-CI (log-rank p=0.01): Score 0 (n=33): 475 days; score 1 (n=24): 353 days; score 2 (n=13): 146 days; score 3 (n=17): 196 days; score 4 (n=5) 1113 days; score 5 (n=5) 337 days; score 8 (n=1) 1404 days. And using the MDS-CI (log-rank p=0.02) better scores predicted improved survival: Score 0 (n=64): 375 days; score 1 (n=18): 241 days; score 2 (n=13): 186 days; score 3 (n=3): 69 days; score 4 (n=1) 1404 days. In addition, patients who scored well on the CCI did better (p=0.005) than patients with poor scores by type of treatment (ie, a low score patient treated with 7+3 did better than a high score patient treated with 7+3, and a low score patient treated with 5-aza did better than a high score patient treated with 5-aza). Similar relationships were noted between scores on the HCTS-CI and MDS-CI and treatment choice. However, in all CCI score categories, 7+3 treatment was superior to 5-aza (score 0: 839 vs 298 days; score 1: 276 vs 69 days; score 2: 279 vs 106 days; score 3: 435 vs 90 days) (p=0.08). Similarly 7+3 treatment appeared superior to 5-aza by HCTS-CI score (p=0.02) and MDS-CI (p=0.05). Conclusions: Elderly patients with AML can achieve survivals approaching one year with current treatment options. 5-azacytidine is a reasonable option for patients declining aggressive hospital based treatments especially if cytogenetic features are favorable, however overall survival may be inferior to standard induction chemotherapy. Although comorbidity indices are able to stratify potential outcomes among elderly patients with AML choosing a particular treatment, in our series we could not identify a comorbidity score that would dissuade aggressive treatment in favor of less intensive therapy. Disclosures: Goldberg: Celgene: Speakers Bureau. Off Label Use: 5-azacytidine use in AML. Masood:Celegene: Speakers Bureau.


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