scholarly journals Validation of Kantarjian (2010) Model for Intensive Chemotherapy in Older Adults with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5258-5258
Author(s):  
Shawn Tahata ◽  
Annie Im ◽  
Michael Boyiadzis ◽  
Daniel Normolle
Keyword(s):  
Older Adults ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Historical Data ◽  
Performance Status ◽  
Risk Groups ◽  
Intensive Chemotherapy ◽  
Ecog Performance Status ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) carries a poor prognosis in older adults. Limited clinical trial data exist to support the use of conventional cytarabine-based regimens in this population, and practice standards have been extrapolated from studies in younger patients. Intensive chemotherapy in older adults is associated with high rates of treatment-related mortality and poor overall survival. In 2010, Kantarjian and colleagues developed a risk model for 8-week mortality using adverse prognostic risk factors, including age ≥80 years, complex karyotype (≥3 abnormalities), poor performance status (ECOG score ≥2), and serum creatinine >1.3 mg/dL. This study validates the Kantarjian model for progression-free survival (PFS) and overall survival (OS) in older patients with AML treated with intensive chemotherapy. Methods: Adults aged ≥70 years with AML (≥20% blasts in bone marrow or peripheral blood) who received intensive chemotherapy at UPMC Hillman Cancer Center between 2000 and 2011 were evaluated. Patients were stratified into low, intermediate, and high-risk groups according to the Kantarjian (2010) model and analyzed for PFS and OS using the Kaplan-Meier method. Differences in PFS and OS between risk groups were assessed with the log-rank test. ECOG performance status was estimated using historical data at the time of diagnosis. Additional variables, including AML type (primary vs. secondary), percent blasts at diagnosis, percent CD34-positive blasts, hemoglobin, leukocytes, platelets, LDH, AST, ALT, total bilirubin, albumin, and Charlson comorbidity index (CCI) were tested for added prognostic value when incorporated into the model, using Cox proportional-hazards regression for PFS and OS. Results: Clinical data were collected for 68 patients. Of these, 26 patients, all of whom were diagnosed prior to 2003, were excluded from the final analysis due to insufficient electronic health records. The remaining 42 patients were used for the validation study. Median age at diagnosis was 73 years (range: 70-87). Twenty-seven patients (64%) had primary AML, whereas 10 (24%) had AML evolving from another hematologic disorder and 5 (12%) developed AML after radiation or chemotherapy for another malignancy. Eleven (26%) patients had ≥3 karyotypic abnormalities and the remaining 31 (74%) had fewer than 3. Thirty-three (79%) patients had an ECOG performance status of 0 or 1, and the remaining 9 (21%) did not have sufficient historical data to estimate ECOG score and were given a score of 0. In total, there were 23, 16, and 3 patients categorized into the low, intermediate, and high-risk groups, respectively. These groups had non-overlapping PFS and OS curves (p <0.001 for both endpoints). The low, intermediate, and high-risk groups had median PFS of 9.6, 5.1, and 2.1 months and median OS of 14.0, 6.3, and 2.1 months, respectively. None of the additional variables were found to add significant prognostic value to the existing model. Discussion: The Kantarjian (2010) model is a valid method of risk-stratifying older adults with respect to PFS and OS, and may be useful when weighing the risks and benefits of intensive chemotherapy in these patients. In this study, we did not identify other disease characteristics or measures of organ function that significantly improved the model, although our analysis is limited by small sample size. We note that all patients in our study had an ECOG score of 0 or 1, implying selection of healthier patients for induction chemotherapy at our institution. Our results suggest that patients in the intermediate and high-risk groups may not derive significant PFS and OS benefit from intensive chemotherapy when the risks of morbidity and mortality from treatment are considered. Disclosures No relevant conflicts of interest to declare.

Safety and Efficacy of Bendamustine and Idarubicin in Combination Therapy for Patients Age ≥50 with Untreated Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome – Results From a Phase I/II Adaptive Design Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2622-2622
Author(s):  
Mazyar Shadman ◽  
Jack M. Lionberger ◽  
Raya Mawad ◽  
Ravinder K Sandhu ◽  
Carol Dean ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Posterior Probability ◽  
Performance Status ◽  
Outpatient Setting ◽  
Ecog Performance Status ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 2622 Background: Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS with 10–19% blasts) are associated with higher mortality in the elderly population. This poor outcome is in part attributed to therapy resistance and therefore, using combinations of agents with different mechanisms of action may improve outcomes. The nitrogen mustard Bendamustine combines unique alkylating characteristics with putative anti-metabolite activity while Idarubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs. In this single-arm adaptive phase I/II dose-escalation trial, we assessed increasing doses of Bendamustine in combination with a uniform dose of Idarubicin. We used a Bayesian approach to determine whether there was a dose of Bendamustine which, together with Idarubicin can provide a complete response (CR) rate of at least 40%, with minimal (<30%) grade 3–4 extramedullary toxicity in untreated AML or high-risk MDS patients age > 50. Methods: Eligible patients were age 350 with untreated AML or high-risk MDS, had an ECOG performance status <3 and creatinine and bilirubin each less <2.0. Patients received 1 of 3 doses of Bendamustine (45, 60 or 75 mg/m2 daily days 1–5) together with Idarubicin (12 mg/m2 days 1–2). Response was assessed according to the International Working Group (IWG) criteria (Cheson et. al., JCO, 2003) and non-hematologic toxicities according to the NCI CTCAE v.3. After each cohort of 3 patients at a given dose had been evaluated for toxicity and response, Bayesian posterior probabilities based on the data and non-informative prior probabilities were computed. If no Bendamustine dose was associated with a >95% posterior probability of both grade 3–4 extramedullary toxicity <30% (between the 1/6 and 2/6 of the conventional 3+3) and CR rate >40%, the study stopped. Otherwise, the study would continue at the highest dose that met the above criteria until 45 patients had been treated. Treatments were administered in the outpatient setting and patients were admitted to the hospital only if medically indicated. Results: Between October 2010 and May 2012, 39 patients were treated per protocol. The median age was 73 (range, 56–82). Patients had ECOG performance status of 1 (92%), or 2 (7%). AML patients comprised majority of the cases (34/39; 87%). Among AML patients, 35% (12/34) had primary AML, 47% (16/34) had AHD (antecedent hematologic disorders) and 18% (6/34) had secondary AML with a prior history of chemotherapy or radiation. None of the patients had favorable-risk cytogenetic (CG) and 19 (49%) had poor-risk CG including 9 patients (23%) with monosomal karyotype. None of the patients with normal CG had favorable molecular markers. Treatment was given in 1, 2, and 3 cycles in 25 (64%), 7 (18%) and 7(18%) patients, respectively. The number of patients in each cohort and the treatment efficacy and toxicity is reported in the table below. The MTD (maximum tolerated dose) was established at 60 mg/m2 of Bendamustine as two grade 3 toxicities were seen at the dose of 75 mg/m2 (congestive heart failure and mucositis in one patient each). Patients were treated as outpatients but hospitalization was required in 90% of the patients (35/39; 90%). The leading cause of admission was febrile neutropenia (26/35; 74%) followed by fungal infections (4/35; 11%). Conclusion: The combination of Bendamustine (60 mg/m2 (for 5 days) with Idarubicin (12 mg/m2 for 2 days) can be delivered in the outpatient setting and had a <95% posterior probability of >30% toxicity. However, the posterior probability of a CR rate >40% was also <95%, suggesting that continued exploration of new therapeutic combinations is warranted in elderly patients with AML or high-grade MDS. Disclosures: Off Label Use: Bendamustine is indicated for the treatment of CLL and indolent non-Hodgkin's lymphoma. In our study we are using Bendamustine to treat AML.

Prognostic Value of Cytogenetics in Patients with Acute Myeloid Leukemia Aged More Than 60 Years at Diagnosis: Identification of Subgroups Taking Benefit from Intensive Chemotherapy. Results from a Large Single Center Retrospective Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3503-3503
Author(s):  
Nicolas Blin ◽  
Pascaline Talmant ◽  
Richard Garand ◽  
Francoise Accard ◽  
Philippe Moreau ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Rank Test ◽  
Intensive Chemotherapy ◽  
Secondary Aml ◽  
Log Rank Test ◽  
Group 3 ◽  
Standard Risk ◽  
Acute Myeloid

Abstract Cytogenetic analysis performed at diagnosis is known as the most important independent prognostic factor in adult acute myeloid leukemia (AML) treated with intensive chemotherapy. This major predictor of outcome has been mostly identified in younger patients who are categorized into three risk groups: favorable, intermediate and adverse. However, the prognostic value of chromosome abnormalities in elderly patients with AML aged 60 years or older has been evaluated in much fewer studies and overall prognosis remains very poor in this population with a very small number of long-term survivors using current standard chemotherapy. To further investigate the prognostic relevance of cytogenetic abnormalities in older patients, we reviewed 376 patients with de novo or secondary AML aged 60 years or more and available cytogenetic data at diagnosis. APL were excluded and no patient received allogeneic bone marrow transplantation. Of 376 patients, 280 (74%) received induction chemotherapy based on association with cytarabine (ara-C) and anthracyclins according to GOELAMS SA2, SA3, SA4 and SA2002 prospective trials between 1988 and 2005. Patients who were not treated with induction regimen received best supportive care or low dose ara-C. Overall complete remission rate was 42%, induction failure 38% and induction death 20%. With a median follow-up of 11.5 years for survivors, overall survival (OS) was 4.5% at 5 years (95% confidence interval [CI], 3.8%–5.8%) and disease free survival (DFS) was 4.3% at 5 years (95% CI, 3.7%–5.9%). Using a proportional hazards model with normal cytogenetics as reference group, 3 prognostic subgroups were identified for OS: low-risk (t(8;21) and inv(16)) in 20 of 280 patients (7%), standard-risk (+8, +11, −13/del(13q), t(11q23), +22, all in no complex karyotypes) in 175 of 280 patients (63%) and high-risk (−5/del(5q), −7/del(7q), −17/del(17p), −20/del(20q), +21, rare aberrations, complex≥3 and complex≥5) in 85 of 280 patients (30%). In multivariate analyses using a Cox model with backward selection procedure, high-risk cytogenetics (p<0.001), age>65 years (p=0.01), multilineage dysplasia on marrow at diagnosis (p=0.008) and white blood cell count (WBC) (p=0.03) appeared as independent prognostic factors on OS and DFS. Secondary AML did not appear as prognostic factor in multivariate analysis (p=0.18) but in a log-rank test, AML secondary to hematologic malignancy did significantly worse than AML secondary to solid tumors in both OS and DFS (p=0.01 and p=0.04, respectively). OS distribution between treated and untreated patients was compared using a log-rank test with homogeneous subgroups based on cytogenetic risk group and age. Three-years OS was significantly better in patients <70 years with standard-risk cytogenetics (p=0.008 if age<65years and p=0.02 if age <70 years). For high-risk cytogenetic group, 3-years OS was improved only in patients <65 years with WBC<30G/L (p=0.03). These results confirm the independent prognostic value of pretreatment karyotype, age >65 years, WBC and associated multilineage dysplasia in elderly patients with AML. Overall prognosis remains very poor and intensive chemotherapy does not improve OS in patients aged >70 years and high-risk cytogenetic groups.

scholarly journals Fitness in the elderly: how to make decisions regarding acute myeloid leukemia induction

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 339-347 ◽  
Author(s):  
Arati V. Rao
Keyword(s):  
Older Adults ◽  
Acute Myeloid Leukemia ◽  
Patient Population ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
The Elderly ◽  
Future Research ◽  
Strongly Correlated ◽  
Patient Will ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a disease of the elderly, but less than half of these patients are offered therapy despite the evidence of better survival with treatment in this patient population. Assessing fit, vulnerable, and frail older adults with AML remains a challenge for the treating oncologist. A majority of AML patients are elderly and often have significant comorbidities, lack of social support, and older caregivers. Performance status (PS), a subjective measure of how a patient will tolerate cancer chemotherapy, has been strongly correlated with mortality in older AML patients. However, a large portion of older adults have poor PS as a result of their underlying AML, and these patients may end up being undertreated. Conversely, some patients with excellent PS unexpectedly end up with excessive toxicity and mortality. The treating physician thus needs a more objective and comprehensive method to differentiate patients along the fit-frail spectrum irrespective of their chronological age. For more than a decade, comprehensive geriatric assessment has been shown to improve routine oncology assessment by adding information about the functional, emotional, cognitive, and social status of older patients with cancer. In addition to the chronological and functional age, there is an attempt to quantify a patient’s biological age to aid in better decision making. This chapter attempts to review the clinical challenges of AML treatment in the elderly population and to highlight the current literature and future research required to be able to assess fitness and maximize therapeutic options in this heterogeneous patient population.

scholarly journals Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4422-4429 ◽  
Author(s):  
Hagop Kantarjian ◽  
Farhad Ravandi ◽  
Susan O'Brien ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Eastern Cooperative Oncology Group ◽  
Poor Performance ◽  
Risk Groups ◽  
Complete Response ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

Patients ≥ 70 years of age with acute myeloid leukemia (AML) have a poor prognosis. Recent studies suggested that intensive AML-type therapy is tolerated and may benefit most. We analyzed 446 patients ≥ 70 years of age with AML (≥ 20% blasts) treated with cytarabine-based intensive chemotherapy between 1990 and 2008 to identify risk groups for high induction (8-week) mortality. Excluding patients with favorable karyotypes, the overall complete response rate was 45%, 4-week mortality was 26%, and 8-week mortality was 36%. The median survival was 4.6 months, and the 1-year survival rate was 28%. Survival was similar among patients treated before 2000 and since 2000. A multivariate analysis of prognostic factors for 8-week mortality identified the following to be independently adverse: age ≥ 80 years, complex karyotypes, (≥ 3 abnormalities), poor performance (2-4 Eastern Cooperative Oncology Group), and elevated creatinine > 1.3 mg/dL. Patients with none (28%), 1 (40%), 2 (23%), or ≥ 3 factors (9%) had estimated 8-week mortality rates of 16%, 31%, 55%, and 71% respectively. The 8-week mortality model also predicted for differences in complete response and survival rates. In summary, the prognosis of most patients (72%) ≥ 70 years of age with AML is poor with intensive chemotherapy (8-week mortality ≥ 30%; median survival < 6 months).

scholarly journals Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome:

Cancer ◽  
2006 ◽  
Vol 106 (5) ◽  
pp. 1090-1098 ◽  
Author(s):  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Jorge Cortes ◽  
Francis Giles ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

scholarly journals Geriatric perspective: how to assess fitness for chemotherapy in acute myeloid leukemia

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 8-13 ◽  
Author(s):  
Heidi D. Klepin
Keyword(s):  
Older Adults ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Functional Decline ◽  
Improve Risk Stratification ◽  
Therapeutic Decisions ◽  
Comorbidity Burden ◽  
Acute Myeloid

Abstract Characterizing “fitness” in the context of therapeutic decisions for older adults with acute myeloid leukemia (AML) is challenging. Available evidence is strongest in identifying those older adults who are frail at the time of diagnosis by characterizing performance status and comorbidity burden. However, many older adults with adequate performance status and absence of major comorbidity are “vulnerable” and may experience clinical and functional decline when stressed with intensive therapies. More refined assessments are needed to differentiate between fit and vulnerable older adults regardless of chronologic age. Geriatric assessment has been shown to add information to routine oncology assessment and improve risk stratification for older adults with AML. This review highlights available evidence for assessment of “fitness” among older adults diagnosed with AML and discusses future treatment and research implications.

scholarly journals Multiple Myeloma (MM) in the Very Old: Disease Characteristics, Treatment Patterns and Outcomes in the Real World

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-22
Author(s):  
Smith Giri ◽  
Susan Bal ◽  
Kelly N. Godby ◽  
Grant R Williams ◽  
Luciano J. Costa ◽  
...  
Keyword(s):  
Older Adults ◽  
High Risk ◽  
Research Funding ◽  
Performance Status ◽  
Surrogate Marker ◽  
Progression Free Survival ◽  
First Line ◽  
Ecog Performance Status ◽  
Systems Research ◽  
Ecog Ps

Introduction: Older adults with MM continue to remain under-represented in clinical trials, leading to paucity of information regarding the clinical characteristics and treatment outcomes, particularly among those 80y or older at the time of diagnosis. The International Myeloma Working Group (IMWG) classifies any patient &gt;80y as frail, irrespective of their fitness status. The value of geriatric assessment and frailty evaluation in this subgroup remain unclear. Methods: We used the Flatiron Health electronic record-derived de-identified database to source patients with incident MM diagnosed between January 1, 2011 and February 1, 2020. We compared clinical and demographic characteristics of patients ≥80y at the time of diagnosis with patients who were &lt;80y of age. We abstracted baseline labs and cytogenetic data documented within 90 days from the start of first-line therapy. For those ≥80y, we captured the receipt of first line anti-myeloma therapy and examined early mortality (death within 6 months of diagnosis), derived progression-free survival (dPFS) and overall survival (OS) using Kaplan-Meier methods and Cox multivariate regression, with date of diagnosis as the index date. Finally, we compared dPFS and OS among potentially fit ≥80yo MM vs those between 75-79y, using ECOG performance status (PS) of zero as a surrogate marker of fitness status. Results: Of 8298 MM patients in this cohort, 1144 (13.5%) patients were ≥80y at diagnosis (median 81y, range 80-85y). Compared with the younger cohort, those ≥80y were more likely to be white, and have anemia, renal insufficiency, higher β2-microglobulin and higher stage at diagnosis. However, there was a lower prevalence of documented high-risk cytogenetic abnormalities, particularly high risk translocations (t4;14 and t14;16) even after adjusting for race/ethnicity (Mantel Haenszel OR=0.67; p 0.001). Common first line therapies included proteasome inhibitor (PI) + Immunomodulatory agent (Imid) based triplet (23%), Imid doublet (21%) and PI doublet (27%) (Table). Patients ≥80y received a median of 1 (IQR 1-2) lines of therapy, as opposed to those &lt;80 (median 2, IQR 1-3). Overall, the outcome was significantly inferior among the ≥80y patients be those &lt;80y (median dPFS 16 vs. 39 months, p&lt;0.01; median OS: 26 vs 37 months, p&lt;0.01; and 6-month mortality rate: 20.1% vs 6.2%, p&lt;0.01). However, patients ≥80y and ECOG PS of 0 had similar 3y-dPFS (36.8 vs 33.1%; p=0.66) and 3y-OS (61.8 vs 65.2%; p=0.50) when compared to those between 75-79y with similar PS (ECOG PS of 0) (Figure). Conclusion: Patients 80y or above with newly diagnosed MM have distinct clinical and treatment characteristics as compared to their younger counterparts. Similar survival outcomes between older adults with good performance status vs their younger fit counterparts suggest the need for conducting a comprehensive frailty evaluation and individualized decision-making even in this cohort. Disclosures Giri: Carevive Systems: Honoraria; Pack Health: Research Funding; Carevive Systems: Research Funding. Costa:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Genentech: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Sanofi: Consultancy, Honoraria.

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