Acute Myeloid Leukemia In Older Adults Research Articles

Variant Allele Frequency Status in Elderly Patients with Acute Myeloid Leukemia Can be Early Predictors of Responsiveness to Decitabine Treatment

As interest in elderly Acute Myeloid Leukemia (AML) patients increases, American society of hematology (ASH) 2020 guidelines for treating newly diagnosed AML in older adults suggested diverse treatment options. The guidelines suggest using monotherapy over combination of hypomethylation agent (HMAs) with other agents in newly diagnosed AML in older adults due to similar efficacy and the potential for more toxicity. HMAs alone is still used widely as an alternative treatment for patients who cannot use venetoclax due to the high cost and poor performance score. If there are early predictors of responsiveness to Decitabine mono therapy, it will be helpful to decide whether to combine Novel agents. This retrospective cohort study from a single institution aimed to evaluate the prognostic significance of Variant allele frequency (VAF) changes in elderly patients after 4 th cycle of decitabine. Total 123 patients with elderly AML were eligible. 57 patients performed follow-up bone marrow biopsy and 49 patients were available of follow up targeted NGS samples from biopsy after 4th cycle of decitabine. To clarify the immortal timed bias, landmark analyses were performed with patients (n=84) who remained at least the median time to perform follow-up bone marrow biopsy after 4th cycle of decitabine treatment. 24 patients (54.5%, 24 of 44) showed more than 50% decrease of VAF after 4 th cycle of decitabine (figure 1a). DMNT3A, TET2, IDH1, IDH2, and SETBP1 and SMC1A showed less than 50% of the decreases of VAF. Patients with DNA methylation genes showed significantly reduced VAF less than 50% (figure 1b). A significant difference of ∆VAF was observed depending on CR status (p=0.021). The survival outcome of patients who showed more than 50% decrease of initial VAF after 4th cycle of decitabine was significantly better than that that with less than 50% decrease of VAF(1-year OS VAF decrease ≥ 50% (n=23), 75.0%; VAF decrease < 50% (n=20), 38.5%; no mutation (n=12), 45.5%; not available of follow up targeted NGS sample (n=29), 16.6%; p < 0.001, figure 2a). Mutations in DNMT3A, TET2, and ASXL1 (DTA genes) were detected in samples from 19 patients at diagnosis. After the exclusion of DTA mutations, the survival outcome improved prognostic risk stratification power of NGS-based MRD assessment in AML. The survival outcome of patients who showed more than 50% decrease of initial VAF after 4th cycle of decitabine was significantly better than that that with less than 50% decrease of VAF(1-year OS VAF decrease ≥ 50% (n=24), 75.0%; VAF decrease < 50% (n=19), 35.1%; no mutation (n=12), 50.1%; not available of follow up targeted NGS sample (n=29), 16.6%; p<0.001, figure 2b). In conclusion, more than 50% decrease of VAF was important negative prognostic factors by improving overall response rate and OS. In case of patients with older adults who received decitabine treatment, if follow up BM biopsy after 4 th cycles of decitabine treatment showed more than 50% reduction of VAF, it may suggest to maintain decitabine treatment. However, if VAF is reduced by less than 50% in follow up BM biopsy, the residual disease burden is considered for the selection of combination treatment to improve survival outcome. [Display omitted] DisclosuresKim: Bristol-Meier Squibb: Research Funding; Paladin: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Age-Related Changes in the Interaction of Acute Myeloid Leukemia with the Bone Marrow Microenvironment Correlate with Response to Treatment and Survival: A Role for L-Selectin

Introduction: Acute myeloid leukemia (AML) arises in the bone marrow microenvironment (BME), where cell-cell and cell-matrix adhesion promote AML survival. There is increased incidence of AML in older adults and age-related changes in the BME such as the senescence associated secretory phenotype (SASP) may promote myeloid disorders and cancer. Our objective is to further elucidate the influence of the BME on AML pathobiology.Methods: Using flow cytometry, we prospectively characterized 17 cell adhesion receptors expressed on AML blasts derived from 106 patient blood and bone marrow samples on an IRB approved protocol. For 55 patients, we correlated expression of these individual adhesion receptors with age, cytogenetics, complete remission (CR), relapse free survival (RFS) and overall survival (OS). We correlated expression of adhesion receptors with basal levels of DNA damage in AML blasts, as measured by phosphorylation of histone H2AX (γ-H2AX) by flow cytometry. mRNA microarray gene expression profiling (GEP) on 30 patients, we examined for age-associated differences in the gene expression of cell-cell and cell-matrix adhesion proteins. For 6 patients, we evaluated for changes in GEP that occur in AML blasts with adhesion to plates coated with alternative spliced fibronectin peptide CH296, RetronectinTM (RN) vs. bovine serum albumin (BSA) control.Results: We found a significant positive correlation between L-selectin cell surface expressed protein levels with advancing age (Spearman r = 0.35, p = 0.009) (Figure 1). The response to treatment (CR/CRi) rate, but not RFS, increased with greater surface expression of the following adhesion proteins: CD11a (αL), CD29 (β1), CD44, CD49a (α1) and CD49e (α5). OS improved with greater cell surface expressed protein levels of CD11a (αL) and CD29 (β1).There was a significant negative correlation in L-selectin mRNA levels with basal DNA damage in AML blasts, as measured by γ-H2AX (Spearman r = -0.6, p = 0.005). To further investigate the relationship between L-selection expression and DNA damage in AML, we cultured AML blasts on an L-selectin ligand, P-selectin glycoprotein-1 (PSGL-1) vs. BSA control. We observed increased blast survival and reduced apoptosis when adherent on PSGL-1 compared to BSA after treatment with cytarabine arabinoside (Ara-C) in 4/15 (27%) of samples tested (Figure 2).Ingenuity Pathway Analysis (IPA) results on the gene expression data showed age-associated changes in the expression of L-selectin and cell-matrix proteins involved in the SASP, such as tissue inhibitor of metalloproteinases (TIMP). Adhesion of AML blasts to RN vs. BSA control resulted in up-regulation of genes involved in protein ubiquitination and the PI3K/AKT, nuclear factor-kappa beta (NF-kβ) and IL-8 signaling pathways.Conclusions: Age-related changes in the expression of L-selectin, cell-cell and cell-matrix proteins in AML blasts appear to influence DNA damage signaling/response (DDR), promote Ara-C resistance, and influence patient response to treatment and survival. Adhesion of AML blasts to the BME results in up-regulation of cell survival pathways that confer resistance to apoptosis and maintenance of the SASP. Our results support disruption of L-selectin and other BME-mediated interactions as potential targets to enhance cytotoxicity to chemotherapy and improve age-specific outcomes in AML. [Display omitted] [Display omitted] DisclosuresBecker:Invivoscribe: Honoraria; CVS Caremark: Other: Accordant Health Services Medical Advisory Board; Millennium: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding; Pfizer: Other: Scientific Steering Committee for a post marketing study; JW Pharmaceutical: Research Funding.

TP53 mutations in older adults with acute myeloid leukemia

The net benefits of induction therapy for older adults with acute myeloid leukemia (AML) remain controversial. Because AML in older adults is a heterogeneous disease, it is important to identify those who are unlikely to benefit from induction therapy based on information available at the initial assessment. We used next-generation sequencing to analyze TP53 mutation status in AML patients aged 60 years or older, and evaluated its effects on outcomes. TP53 mutations were detected in 12 of 77 patients (16 %), and there was a significant association between TP53 mutations and monosomal karyotype. Patients with TP53 mutations had significantly worse survival than those without (P = 0.009), and multivariate analysis identified TP53 mutation status as the most significant prognostic factor for survival. Neverthelsess, TP53-mutated patients had a 42 % chance of complete remission and a median survival of 8.0 months, which compares favorably with those who did not undergo induction therapy, even in the short term. These results suggest that screening for TP53 mutations at diagnosis is useful for identifying older adults with AML who are least likely to respond to chemotherapy, although the presence of this mutation alone does not seem to justify rejecting induction therapy.

Management of Newly Diagnosed Acute Myeloid Leukemia in the Elderly: Current Strategies and Future Directions.

The incidence of acute myeloid leukemia (AML) increases with age, and the majority of cases occur in adults aged >55years. The prognosis of AML in older adults is generally poor; however, AML is a heterogeneous disease regardless of age, and prognosis depends on cytogenetic changes, genetic mutations, and patient characteristics. Several lines of evidence support offering treatment to the vast majority of older patients, and the survival benefit associated with this approach generally outweighs the risk of toxicity. Response and long-term survival using intensive induction regimens are significantly lower in older patients, although a small proportion of patients can achieve durable remissions. Selection of patients for intensive induction therapy requires comprehensive assessment of disease characteristics, performance status, and comorbidities. In unfit patients, options for treatment include hypomethylating agents, low-dose ara-C, or consideration of a clinical trial if available. The incorporation of novel therapies into treatment, such as FLT3 inhibitors and antibody-drug conjugates, offers significant promise in older patients, although, thus far, increased responses using novel agents have often not translated to improved survival outcomes. The development of reduced-intensity conditioning regimens and improvements in supportive care has increased the use of allogeneic stem cell transplant (ASCT) in older patients. Selection of patients for ASCT requires an estimation of the trade-off between toxicity and risk of relapse.

The FLAG Chemotherapy Regimen Is an Alternative to Anthracycline Based Therapy for the Treatment of Acute Myeloid Leukemia for Patients with Multiple Co-Morbidities or Preexisting Cardiac Disease

BACKGROUND: Anthracycline based treatment for acute myeloid leukemia (AML) can be associated with significant morbidity and mortality amongst older patients or those with significant co-morbidities. Furthermore, for patients with previous anthracycline exposure or preexisting cardiac disease anthracyclines pose an increased risk of cardiotoxicity. For such patients intensive treatment options are limited.The FLAG (fludarabine, cytarabine and filgrastim) regimen is a non-anthracycline based chemotherapy useful for relapsed/refractory AML and as initial therapy for “fit” eligible patients. We present our experience using FLAG as first line therapy in a cohort of newly diagnosed AML patients with advanced age, significant co-morbidities or preexisting cardiac disease.METHODS: A single institution retrospective chart review was undertaken of patients treated with FLAG as frontline therapy from 2004 – 2013 with follow-up until June 2014. All patients were considered ineligible for standard '3+7’ treatment by the attending physician.RESULTS: Over the study period 56 patients received FLAG. Due to patient refusal or induction complications bone marrow assessments to ascertain remission status were not performed in 10 patients – to minimize bias these patients were evaluated for toxicity and overall survival (OS) but excluded from complete remission (CR) and relapse free survival (RFS) analysis.Of the 56 patients, 68% were males. The median age was 69 (21 – 80) with 79% aged ≥ 60 and 43% aged ≥ 70. Fifty-five percent (31) of the patients had primary AML and cytogenetics were favorable in 5% (3), intermediate in 66% (37), poor-risk in 21% (12) and failed in 7% (4). Forty-six percent (26) were treated with FLAG due to preexisting cardiac disease and others due to advanced age (20%), poor performance status (16%), co-morbidities (16%) or previous anthracycline exposure (2%). The ages of patients treated with FLAG due to cardiac disease or other reasons was similar (63.5 years vs. 66.9 years, p=0.27). Amongst patients with cardiac disease a pre-chemotherapy cardiac evaluation revealed wall motion abnormalities in 39% and an ejection fraction (EF) ranging from 33% - 81% with a borderline (≤ 50-51%) EF in 46%.Febrile neutropenia was observed in 82% (46) of patients, 27% (15) required intensive care support and the induction mortality was 16% (9). Amongst patients evaluated for a CR (46/56), 48% (22/46) obtained a CR. Although a CR was seen in 100% (3/3), 46% (15/33) and 37% (3/8) of patients with favorable, intermediate and poor-risk cytogenetics respectively there was no statistically significant difference (p=0.22) between groups. A CR was obtained in two additional patients following a second course of FLAG for an overall CR rate of 52% (24/46). Of these 24 patients, 8 (33.3%) received no additional treatment while 16 (66.7%) received consolidative chemotherapy. Of 10 eligible patients, 4 proceeded to an allogeneic stem cell transplant (allo-SCT) including two with preexisting cardiac disease.Of patients not transplanted 50% (10/20) eventually relapsed. There was no difference in relapse rates for those receiving FLAG for age/co-morbidities vs. cardiac disease (60% vs. 40%, p= 0.66) or for patients age <60 vs. ≥ 60 (50% vs. 50%, p=1.0). The median RFS was 441 days with no difference between patients treated with FLAG for cardiac reasons vs. other reasons (p=0.33) or for patient’s age < 60 vs. ≥ 60 (p=0.66).The median OS for the 56 patients was 278 days with 1 and 2 year survivals of 44% and 22% respectively. The median OS for patient’s age < 60 was higher than those age ≥ 60 (1102 days vs. 218 days, p=0.009) but there was no difference in the OS between patients treated with FLAG for cardiac disease and those treated for other reasons (305 days vs. 254 days, p=0.202). The median survival of patients with favorable, intermediate and unfavorable risk cytogenetics was 523 days, 311 days and 87 days respectively but this was not statistically significant (p=0.25) likely due to limited patient numbers.Conclusions: The FLAG regimen is a non-anthracycline based regimen that may serve as an alternative to the standard '3+7’ induction for AML in older adults or those with significant co-morbidities including preexisting cardiac disease. It is associated with comparable remission rates and overall survival in older patients. In addition, it may allow some patients with preexisting cardiac disease to proceed to allo-SCT. DisclosuresNo relevant conflicts of interest to declare.

Acute myeloid leukemia in older adults

Acute myeloid leukemia (AML) is predominantly a disease of older adults, with a median age at diagnosis of over 65 years. AML in older adults differs biologically and clinically from that in younger ones, and is characterized by stronger intrinsic resistance and lower tolerance to chemotherapy. The effects of age on both patient- and disease-related factors result in a higher incidence of early death during chemotherapy, a lower rate of complete remission, and a reduced chance of long-term survival. Treatment options for older adults with AML include intensive chemotherapy, less-intensive chemotherapy, best supportive care, or enrolment in clinical trials. Given the heterogeneous nature of AML in older adults, therapeutic decisions need to be individualized after systematic assessment of disease biology and patient characteristics. Regardless of treatment, however, outcomes for older AML patients remain in general unsatisfactory. In contrast with the progress made for younger adults, the treatment of AML in older adults has not improved significantly in recent decades. Development of less toxic and more targeted agents may well provide treatment alternatives for a majority of these patients. The overall dismal outcome with currently available treatment approaches has encouraged older AML patients to participate in prospective clinical trials.

Prognostic Factors and Outcomes of Patients with Acute Myeloid Leukemia (AML) Receiving Non Intensive Chemotherapy (NIC) or Best Supportive Care (BSC).

Background: AML in older adults poses therapeutic challenges, as many patients are not candidates for intensive chemotherapy (IC), and it is not clear that IC provides a survival benefit compared to NIC/BSC. While risk factors and outcomes of patients treated with IC are well-defined, few data support similar prognostication in patients treated with NIC or BSC.Methods: We conducted a retrospective review of all patients with AML receiving NIC or BSC at the Cleveland Clinic between January 1997 and December 2005. NIC consisted of treatment with hydroxyurea, low-dose cytarabine, or azacitidine. The choice and decision of therapy was dictated by patient and physician preferences. Data on known prognostic factors (age, white blood cell count (WBC) at diagnosis, cytogenetic risk groups (as defined by CALGB 8461) and AML etiology (de novo vs. secondary AML)) were collected and controlled for in multivariable analyses, and survival determined using the log-rank test, measured from the time of diagnosis. Race and residential zipcodes were obtained from information disclosed by patients in their electronic medical records. Average annual household income in a zipcode was obtained using a web-based database, www.melissadata.com.Results: Fifty-three patients were identified. The median age was 74 years (range 33–92), and 26 patients (49%) were female. Eight patients (15%) were African American (AA), while 44 patients were Caucasian (C) and 1 patient was neither AA nor C. The median WBC at presentation was 6.0 ×103/μL. Cytogenetics were favorable in 1 patient (2%), intermediate in 10 (19%), unfavorable in 19 (36%), and unknown in 23 (43%). Most patients (60%) had secondary AML. The median average annual income was $39,332 (range 23,375–82,806). The median survival was 54 days (95% CI 33–80 days) for all patients, and the 1 year survival was 7%. Known prognostic factors for AML (WBC at presentation, de novo vs. secondary AML, cytogenetics, and age at diagnosis) were not predictors of overall survival in multivariable analyses in patients not receiving intensive chemotherapy, though higher WBC count was predictive in univariable analyses. Race was a predictor for outcomes, with AA patients experiencing a worse median survival than their C counterparts (22 days versus 64 days, log rank p=0.03, figure 1) despite similar baseline characteristics. SES, however, had no impact on outcome.Conclusions: AML patients receiving NIC or BSC have a median survival of almost 8 weeks, with AA patients experiencing worse outcomes. A small but significant percentage of patients remain alive at one year. Prognostic variables useful in treatment decision-making in patients receiving IC are less valuable for NIC/BSC patients. This information can be used for patient counseling and to help guide treatment decisions. [Display omitted]

Quality of life (QOL) of older adults with acute myeloid leukemia (AML): Effects of treatment and time

6566 Background: AML in older adults has a poor prognosis. Although intensive chemotherapy may be associated with a modest improvement in survival, this needs to be balanced against possible worsening of QOL. However, published research in this area is limited. Methods: English-speaking patients aged 60 or older presenting with newly diagnosed AML to our referral centre were enrolled. Patients were excluded if life expectancy was &lt;1 month. QOL was measured at baseline and at 1, 4, and 6 months. Questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 (global health and 5 QOL domains) and the Functional Assessment of Cancer Therapy Fatigue subscale. Patients were stratified into intensive (IT) and non-intensive treatment (NIT) groups. Baseline scores between groups were compared using Student’s T-test. Repeated measures modeling was used to compare the groups over time. Results: From June 2003 to December 2005, 63 patients (mean age 72, 46 IT, 17 NIT) were enrolled. At baseline, physical function and social function were the most affected domains and most patients had moderate fatigue. IT patients had better physical function and slightly less fatigue at baseline than NIT patients but were similar in 4 QOL domains and global health scores. By 6 months, 44% of IT and 60% of NIT patients had died. Over time, global health, role function, and emotional function improved but physical function, social function, and cognitive function did not change. Improvements in QOL domains were similar for IT and NIT patients for all measures. Fatigue scores remained unchanged over time. Conclusion: Intensive chemotherapy is not associated with worse QOL than NIT in older patients with AML, although our small sample size and attrition bias may overestimate QOL among survivors. Concerns about worse QOL with IT appear to be unfounded and this should not deter clinicians from considering IT for older adults with AML. No significant financial relationships to disclose.

A longitudinal assessment of the quality of life (QOL) of older adults with newly diagnosed acute myeloid leukemia (AML): A pilot study

8277 Background: Older patients with AML often have a poor prognosis and often do not tolerate intensive chemotherapy. When weighing alternate management strategies, impact upon QOL is an important consideration. However, there is limited published research in this area. Methods: Patients aged 60 or older with newly diagnosed AML were enrolled at diagnosis regardless of treatment intent. Patients were excluded if life expectancy was less than one month or they did not speak English. QOL was measured at baseline and at 1, 4, and 6 months. Questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 (global health, 5 QOL domains, 3 symptom domains) and the Functional Assessment of Cancer Therapy Anemia and Fatigue subscale. Demographic and clinical information was also recorded. Patients were stratified by intensive versus non-intensive treatment. Results: From June to December 2003, 14 patients (mean age 73) were enrolled. At baseline, global health, role function, and social function were the most affected domains. Fatigue was the predominant symptom. Among patients treated intensively, global health, role function, emotional function, cognitive function, and social function improved from baseline to 1-month and 4-month follow-up. Physical function and fatigue scores worsened at 1 month but improved by 4-months follow-up. Non-intensively managed patients had smaller improvements in global health, role function, cognitive function, and social function. Physical function and emotional function remained stable. Fatigue scores showed a similar pattern to intensively managed patients. Pain scores were higher in non-intensively managed patients. Conclusions: QOL in older patients appears to be significantly affected by AML. Intensive chemotherapy is associated with greater improvement or less decline in most domains of QOL and better control of pain but not fatigue. Further patient enrollment and follow-up may lead to an improved understanding of QOL in AML in older adults and may facilitate better symptom management and treatment decision-making. No significant financial relationships to disclose.

A longitudinal assessment of the quality of life (QOL) of older adults with newly diagnosed acute myeloid leukemia (AML): A pilot study

8277 Background: Older patients with AML often have a poor prognosis and often do not tolerate intensive chemotherapy. When weighing alternate management strategies, impact upon QOL is an important consideration. However, there is limited published research in this area. Methods: Patients aged 60 or older with newly diagnosed AML were enrolled at diagnosis regardless of treatment intent. Patients were excluded if life expectancy was less than one month or they did not speak English. QOL was measured at baseline and at 1, 4, and 6 months. Questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 (global health, 5 QOL domains, 3 symptom domains) and the Functional Assessment of Cancer Therapy Anemia and Fatigue subscale. Demographic and clinical information was also recorded. Patients were stratified by intensive versus non-intensive treatment. Results: From June to December 2003, 14 patients (mean age 73) were enrolled. At baseline, global health, role function, and social function were the most affected domains. Fatigue was the predominant symptom. Among patients treated intensively, global health, role function, emotional function, cognitive function, and social function improved from baseline to 1-month and 4-month follow-up. Physical function and fatigue scores worsened at 1 month but improved by 4-months follow-up. Non-intensively managed patients had smaller improvements in global health, role function, cognitive function, and social function. Physical function and emotional function remained stable. Fatigue scores showed a similar pattern to intensively managed patients. Pain scores were higher in non-intensively managed patients. Conclusions: QOL in older patients appears to be significantly affected by AML. Intensive chemotherapy is associated with greater improvement or less decline in most domains of QOL and better control of pain but not fatigue. Further patient enrollment and follow-up may lead to an improved understanding of QOL in AML in older adults and may facilitate better symptom management and treatment decision-making. No significant financial relationships to disclose.

Low expression of the myeloid differentiation antigen CD65s, a feature of poorly differentiated AML in older adults: study of 711 patients enrolled in ECOG trials.

CD65s appears when the progenitor antigen CD34 disappears, suggesting that this sialylated carbohydrate antigen marks a turning point in normal myeloid differentiation. We characterized acute myeloid leukemia (AML) with low CD65s expression (CD65s(low) AML) in 711 patients entered on seven Eastern Cooperative Oncology Group AML treatment trials (1986-1999). Of those, 198 (28%) qualified as having CD65s(low) AML. Morphologically, CD65s(low) AML was more common in FAB subgroups with minimal differentiation, M0/M1 (P=<0.0001). Early precursor antigens CD34, CD117 and terminal transferase were more frequent in CD65s(low) than CD65s(high) AML (P=<0.0001). Myeloperoxidase was present in fewer CD65s(low) myeloblasts, and the more mature myeloid antigens, CD15 and CD11b, were rarely detected (P=<0.0001). Yet, the two diagnoses did not differ in the distribution of cytogenetic prognostic groups or the occurrence of the multidrug-resistance mediator, P-glycoprotein. CD65s(low) AML patients were significantly older than CD65s(high) cases (P<0.0001). Furthermore, the incidence of CD65s(low) cases increased with age, from 20% in patients under the age of 50 years to 67% in patients older than 80 years (P<0.0001). Overall, complete remission (CR) rate and overall survival were comparable in CD65s(low) and CD65s(high) AML. However, among patients >55 years of age, CD65s(low) AML had a decreased CR rate of 33 vs 44% in CD65s(high) AML (P=0.055). Thus, CD65s(low) AML represents immunophenotypically undifferentiated disease and occurs predominantly in older adults. Although not statistically significant, the observed association between low CD65s expression and decreased CR rate only in patients over the age of 55 is intriguing.

Managing therapy in older adult patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is predominantly a disease of older adults, with more than 50% of cases occurring in adults over 60 years of age. Treatment of AML in older adults is complicated not only by comorbidities that are common in this patient population, but also by the prevalence, in this age group, of forms of AML with a poor prognosis. The problems encountered and the strategies that have been used to improve the outlook in older adults with AML are presented. The two main strategies for improving outcomes in older adults with AML are to develop effective chemotherapeutic regimens with improved tolerability, and to reduce drug resistance. In studies to identify optimal chemotherapeutic regimens in older adults, a satisfactory balance between efficacy and toxicity has not yet been achieved. Also, the use of growth factors to promote hematopoietic recovery has yet to yield consistent reductions in treatment-related morbidity or mortality. Drug resistance can be modified by inhibiting drug efflux mechanisms or by increasing sensitivity to cytotoxic agents, but these strategies have not yet been shown to significantly affect outcomes. Novel approaches including antibody-targeted and molecular-targeted chemotherapy may have the potential to improve the prognosis for older adults with AML.

The Treatment of Older Adult Patients with Acute Myeloid Leukemia by Triple Infusion Chemotherapy

Adult patients (> or = 56 years old) with acute myeloid leukemia (AML) received induction therapy consisting of daunorubicin (60 mg/m2), etoposide (80 mg/m2), and cytarabine (200 mg/m2) daily for 5 days by continuous i.v. infusion (120 hours). The initial protocol was modified so that patients who were not hypoplastic after the first cycle of chemotherapy received a second cycle of treatment, utilizing 30 mg/m2 of daunorubicin/24 hours for 5 days plus etoposide and cytarabine as used in the first cycle. Two courses of consolidation with etoposide and cytarabine at the same dose and schedule were given. Patients were then maintained on cytarabine monthly. Twelve of 29 previously untreated patients (41%) achieved complete remission (CR). Excluding patients with secondary AML, 48% of all patients (11/23) achieved CR, including 56% > or = 70 years old. The median duration of CR was 41 weeks and median survival of CR patients was 54 weeks. Six of 13 patients (46%) with relapsed AML achieved CR. Toxicity in these older adult patients has been mild. Two patients (8%) had severe mucositis and one had severe (bloody) diarrhea. Most patients developed a mild transient asymptomatic rash. Triple infusion chemotherapy (TIC) may be as effective as other chemotherapy regimens for AML in older adults and has acceptable toxicity.