Induction Chemotherapy In Elderly Patients Research Articles

Chemoradiotherapy versus radiotherapy alone following induction chemotherapy for elderly patients with stage III lung cancer.

PurposeIt is unclear whether adding concurrent chemotherapy (CT) to definitive radiotherapy (RT) following induction CT is a tolerable and cost effective treatment for non-small-cell lung cancer (NSCLC) patients aged 70 years or older with comorbidities. This study evaluated the actual clinical outcomes between concurrent chemoradiotherapy (CCRT) and RT alone following induction CT or not in patients (≥70 years) in a single institution’s clinical practice.Materials and MethodsA total of 82 patients with unresectable stage III NSCLC between 2004 and 2016 were retrospectively analyzed. Their treatment tolerance and clinical outcomes such as overall survival (OS), locoregional recurrence (LRR), treatment toxicities and distant metastasis (DM) were evaluated. Early mortality rates were also evaluated as 4-month mortality after RT.ResultsFifty-four patients received CCRT and 28 patients received RT alone. Induction CT before RT was performed for 68.5% and 50.0% in CCRT and RT alone groups. Treatment tolerance was significantly worse in CCRT (p = 0.046). The median survival was 21.1 and 18.1 months for CCRT and RT alone, which was not statistically significant. LRR and DM were also not different. Most early deaths after CCRT were attributed to non-cancer-related mortality. Acute esophagitis of grade ≥2 occurred more following CCRT (p = 0.017). In multivariate analysis, a Charlson Comorbidity Index (CCI) of ≥5 and a weight loss of ≥5% after RT were associated with poor OS. The factors adversely affecting 4-month survival were a CCI of ≥5 and CCRT.ConclusionThere were no significant differences in OS, LRR, and DM between CCRT and RT alone treatment in elderly patients. However, there was a poorer tolerance and higher incidence of acute esophagitis in the CCRT group. Specifically, when the patients had a CCI of ≥5, RT alone seems to be reasonable with a low probability of early death.

Early recovery of the platelet count after decitabine-based induction chemotherapy is a prognostic marker of superior response in elderly patients with newly diagnosed acute myeloid leukaemia

BackgroundDefinite prognostic clinical factors of benefit for decitabine-based induction chemotherapy in elderly patients newly diagnosed with acute myeloid leukaemia (AML) are not identified. This study was designed to explore the potential biomarker, especially regeneration of haematopoiesis, of treatment response and survival in elderly patients with newly diagnosed AML.MethodWe analysed the clinical data of 117 elderly AML patients who were treated with a decitabine dose of 15 mg/m2 for 5 days, granulocyte colony-stimulating factor of 300 μg/d for priming, plus cytarabine 10 mg/m2 q12h for 7 days and aclarubicin 10 mg/d for 4 days (D-CAG).ResultsAfter initial induction chemotherapy, the overall response rate and complete remission (CR) were 71.8% and 58.1%, respectively. Patients responding to the D-CAG regimen achieved higher platelet counts on day 14 after initial treatment (p < 0.001). Median counts were 59.5 × 109/L in the CR group, 37 × 109/L in the partial remission group and 28 × 109/L in the non-responsive group. We then classified patients into those who achieved platelet counts≥60 × 109/L or 100 × 109/L on day 14 after D-CAG vs. those who did not. Platelet counts≥60 × 109/L or 100 × 109/L on day 14 were significantly associated with superior CR, overall survival and disease-free survival (80.9% vs. 45.3% p < 0.001,16.5 vs. 9.1 months p = 0.009 and 16.3 vs. 7.4 months p = 0.024; 85.2% vs. 50% p = 0.001, 31 vs. 10.1 months p = 0.003 and 16.9 vs. 8.9 months p = 0.006). Multivariate analysis confirmed that poor cytogenetics (p = 0.010) and FLT3-ITD mutation (p = 0.007) were identified as independent factors of OS, but not platelet count (p = 0.091). However, platelet count≥100 × 109/L on day 14 was an independent prognostic factor of CR and DFS.ConclusionPlatelet count recovery on day 14 after D-CAG induction chemotherapy is associated with response.Trial registrationD-CAG regimen was registered on ChicTR with number 11001700.

GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML.

2560 Background: The outcomes for elderly patients (pts) with acute myeloid leukemia (AML) remain poor, therefore newer and less toxic therapies are urgently needed. The binding of E-selectin (E-sel), an adhesion molecule expressed in the bone marrow, to the leukemic cell surface activates survival pathways and promotes chemotherapy resistance. GMI-1271, a novel E-sel antagonist, enhances chemotherapy responses and protects from common toxicities in preclinical models (Becker ASH 2013; Winkler ASH 2013 and 2014). We report interim Phase 2 data for GMI-1271 plus chemotherapy in elderly untreated pts with AML. Methods: Pts ≥ 60 yrs with untreated AML, ECOG 0-2, and adequate renal and hepatic function were eligible. Prior treatment of MDS was allowed. GMI-1271 (10 mg/kg) was given 24 hrs prior, during and 48 hrs post induction with infusional cytarabine and idarubicin (7+3). Safety, tolerability, and anti-leukemia activity were assessed. Two cycles of induction were allowed and responders could receive consolidation with GMI-1271 plus intermediate dose cytarabine. Dose-limiting toxicity (DLT), defined as myelosuppression in the absence of disease or related Grade 3 (Gr) non-hematologic toxicity beyond day 42, was assessed in the first 3 pts. Results: 24 pts have been enrolled to date and 17 are evaluable for response. The median age was 68 years (range, 60-79) with 58% male pts, 50% secondary AML (sAML) pts and 25% with high-risk cytogenetics (by SWOG). The first 3 pts had no DLT, allowing enrollment to proceed. Common Gr 3/4 AEs included febrile neutropenia (47%), pneumonia (20%), pulmonary edema (13%) and non-fatal respiratory failure (13%). 2 pts died of sepsis within 60 days. The remission rate (CR/CRi) was 12/17 (71%). CR/CRi rate was 75% for pts with de novodisease and 67% for pts with sAML. E-sel ligand was expressed at high levels on blasts in the majority of pts. Conclusions: The addition of GMI-1271 to anthracycline-based induction chemotherapy in untreated elderly pts with AML demonstrates a high remission rate with acceptable side effect profile and low induction mortality. This study compares favorably to previous studies (Lancet, ASCO 2016). A randomized trial is being planned. Clinical trial information: NCT02306291.

Comparison of Reduced-Intensity Idarubicin and Daunorubicin Plus Cytarabine as Induction Chemotherapy for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

The therapy in elderly patients with acute myeloid leukemia (AML) is a big challenge because of poor risk factors and inferior tolerance to intensive chemotherapy. This study aims to compare the efficacy between reduced-intensity idarubicin plus cytarabine and daunorubicin plus cytarabine (IA regimen and DA regimen, respectively) in elderly patients with newly diagnosed AML. We retrospectively investigated 74 patients with newly diagnosed non-M3 AML aged >60years, where 33 patients received IA regimen, 30 patients received DA regimen, while 11 patients received supportive treatment. We observed the complete remission (CR) rates, overall survival (OS) and side effects in different arms. The CR rate in IA arm (70.4%, 19/27) was significantly higher than that in DA arm (40%, 10/25) in de novo AML (p=0.028), and further significantly higher when white blood cell (WBC) count >10×109/L (p=0.042) and ECOG (Eastern Cooperative Oncology Group) score <2 (p=0.021). The overall survival of the entire population was poor with a median survival of 10months, 1- and 2-year survival rates were 40.5% (30/74) and 9.5% (7/74). The median survival of the patients with chemotherapy was 12months, which was significantly longer than patients treated supportively (4months) (p<0.001). There were no differences of median survival and duration of CR between two arms. Early mortality decreased in the past 5years in both groups. Meanwhile, low-dose idarubicin was well tolerated in elderly patients. Reduced-intensity chemotherapy offered an improvement in survival, and the reduced-intensity IA regimen could improve CR rate in elderly patients with de novo AML.

Efficacy and safety of CHG regimen (low-dose cytarabine, homoharringtonine with G-CSF priming) as induction chemotherapy for elderly patients with high-risk MDS or AML transformed from MDS

To evaluate the efficacy and toxicity of CHG regimen (low-dose cytarabine, homoharringtonine with G-CSF priming) as an induction chemotherapy for elderly patients with high-risk MDS or acute myeloid leukemia transformed from MDS (MDS-AML). Thirty-three untreated patients (21 high-risk MDS and 12 MDS-AML) were enrolled in this study. Each patient was administered with the CHG regimen comprised of low-dose cytarabine (25mg/day, days 1-14) and homoharringtonine (1mg/day, days 1-14) by intravenous continuous infusion in combination with G-CSF (300μg/day) by subcutaneous injection from day 0 until neutrophil count recovery to 2.0×10(9)/L. The overall response rate (OR) was 66.7% after one course of the CHG regimen with 19 patients reaching CR (57.6%) and 3 patients reaching partial remission (PR) (9.1%). The median overall survival (OS) was 15.0months. Patients with normal serum lactate dehydrogenase (LDH) appeared longer median OS when compared to patients with high LDH level (18months vs. 5months, P=0.011). Grade 3/4 thrombocytopenia occurred in 28% of patients, neutropenia in 34%. No treatment-related deaths occurred during the induction therapy. These data suggest that the CHG priming regimen is effective and safe as a novel induction therapy for elderly patients with high-risk MDS and MDS-AML. The results need to be conformed in further study involving a larger cohort of patients.

Cost Burden Analysis of Ineffective Induction Chemotherapy in Elderly Patients with AML.

Abstract 4531 IntroductionAccording to the Surveillance, Epidemiology, and End Results (SEER) database 12,810 patients will be diagnosed with acute myeloid leukemia (AML) in 2009 with an incidence rate of 3.5 per 100,000 persons in the United States. The SEER data estimates that 55% of those diagnosed are 65 years or older. Standard first line therapy for the treatment of AML consists of at least one round of chemotherapy commonly referred to as induction. A significant portion of those patients who receive standard induction chemotherapy will have leukemia that fails to show a complete response as defined by less than 5% leukemia blasts in the bone marrow with normal tri-lineage hematopoiesis and peripheral blood count recovery (Mueller S, et al. BMC Cancer 2006, 6:143). Age, patient performance status, the presence of secondary AML, cytogenetics, and molecular markers are prognostic for particular cohorts of patients, however, there is currently no means to predict whether an individual's leukemia will or will not undergo a complete response (CR) after the administration of standard AML induction chemotherapy. MethodsA budget impact model was designed to assess the incremental societal cost and incremental cost to a typical national health plan of treating patients who will fail induction therapy. The analysis only evaluated elderly patients over the age of sixty five. Data were gathered from the peer reviewed literature. All costs have been updated to 2009 dollars using the medical care component of the consumer price index. The patient population was determined to be 6,981 patients in 2009 with 30% receiving induction therapy (Menzin J, et al. Arch Intern Med. 2002; 162:1597-1603) and only 38% demonstrating a CR (Appelbaum FR, et al. Blood 2006 107:3481-5) resulting in 1,303 patients failing during induction therapy. The costs were taken from Menzin et al., which used Medicare claims data to determine the associated costs of AML patients during the first two years post diagnosis. In the model Medicare payments are used as a proxy for direct costs to society and a national health plan. These reimbursements are able to capture the costs of the initial hospital visit, lab/diagnostic/radiology, supportive care, drugs, and adverse events through the observation of payments across all appropriate settings of care (inpatient hospitalization, skilled nursing facility, outpatient hospital/clinical, physician's office, home health, and hospice). A patient undergoing chemotherapy incurred costs of $120,468 over two years, while a patient avoiding chemotherapy only incurred costs of $40,720. ResultsThe incremental cost of a patient receiving induction therapy was calculated to be $79,748. For a national health care plan with an assumed average of one million members results in a cost of $283,856 to treat patients whose leukemia would not respond to induction chemotherapy. The overall societal impact of treating this patient population with ineffective therapy is $104 million. ConclusionsPatients who are subjected to ineffective chemotherapy face the cytotoxic effects of the treatment, none of the benefits of treatment response, and impose a significant cost burden to themselves and the healthcare payment system. Diagnostics currently in development that can identify patients at the time of diagnosis with disease unresponsive to therapy may have the ability to alleviate unnecessary costs, while steering patients to better tailored and more effective therapies. Disclosures:Cleary Cohen:Nodality, Inc: Employment. Middlebrook:Nodality Inc: Employment.

Feasibility Study of Temozolomide Maintenance Therapy in Elderly Patients with AML Following Induction Therapy with High Dose Mitoxantrone and High Dose Ara-C.

With intensive chemotherapy, approximately 50% of elderly patients with AML achieve a complete remission, however essentially all will relapse within 2 years. To date, there is no standard effective postremission therapy for these patients, and most elderly patients tolerate multiple courses of intensive chemotherapy poorly. We previously demonstrated that temozolomide has significant antileukemic activity in patients with relapsed/refractory acute leukemia (Seiter K, et al JCO 2002). In that study 9/20 patients treated had a significant reduction in bone marrow blasts, and 4 patients had a formal complete response. Currently we are evaluating the feasibility and efficacy of temozolomide maintenance therapy administered after one cycle of intensive induction chemotherapy in elderly patients with newly-diagnosed AML. Induction consists of ara-C, 3 gm/m2 daily for 5 days, and mitoxantrone, 80 mg/m2 times one on day 2. Patients achieving complete remission then receive temozolomide 200 mg/m2/d for 7 days every 5 weeks until progression. To date, 34 pts have been treated: median age 69.5 (range 61–84); M/F: 21/13; prior AHD: 47%; cytogenetics: good: 1, intermediate: 24, poor: 7, insufficient: 2. Response to high-dose ara-C/high-dose mitoxantrone induction: CR: 56%, failure: 32%, toxic death: 12%. Two pts expired in remission unrelated to temozolomide: pneumonia, 1 pt, C. difficile colitis: 1 pt. Of 19 patients in CR, 16 received temozolomide maintenance. The median number of temozolomide cycles was 2 (range 1–14). 3 pts stopped temozolomide after 1 cycle (1 refused further therapy, 1 had stem cell transplant, 1 died from C. difficile colitis). Treatment was well tolerated and was administered in the outpatient setting. The median duration of remission is 6.8 months (95% CI: 4.5–9.1 months), and median survival is 5.5 months (95% CI: 3.7–7.3 months) for all patients and 10.1 months (95% CI: 4.9–15.2 months) for patients achieving CR. Temozolomide maintenance is feasible in patients with AML in CR. Further accrual is continuing to assess if remission duration and survival will be improved compared to historical controls.

Feasibility Study of Temozolomide Maintenance Therapy in Elderly Patients with AML Following Induction Therapy with High Dose Mitoxantrone and High Dose Ara-C.

With intensive chemotherapy, approximately 50% of elderly patients with AML achieve a complete remission, however essentially all will relapse within 2 years. To date, there is no standard effective postremission therapy for these patients, and most elderly patients tolerate multiple courses of intensive chemotherapy poorly. We previously demonstrated that temozolomide has significant antileukemic activity in patients with relapsed/refractory acute leukemia (Seiter K, et al JCO 2002). In that study 9/20 patients treated had a significant reduction in bone marrow blasts, and 4 patients had a formal complete response. Currently we are evaluating the feasibility and efficacy of temozolomide maintenance therapy administered after one cycle of intensive induction chemotherapy in elderly patients with newly-diagnosed AML. Induction consists of ara-C, 3 gm/m2 daily for 5 days, and mitoxantrone, 80 mg/m2 times one on day 2. Patients achieving complete remission then receive temozolomide 200 mg/m2/d for 7 days every 5 weeks until progression. To date, 30 pts have been treated: median age 69 (range 60–84); M/F: 17/13; prior AHD: 23%; cytogenetics: good: 1, intermediate: 21, poor: 6, insufficient: 2. Response to high-dose ara-C/high-dose mitoxantrone induction: CR: 59%, progression: 24%, aplastic death: 17%. Two pts expired in remission unrelated to temozolomide: pneumonia, 1 pt, c. difficile: 1 pt. Of 17 patients in CR, 15 received temozolomide maintenance. The median number of temozolomide cycles was 2 (range 1–11). 3 pts stopped temozolomide after 1 cycle (1 refused further therapy, 1 had stem cell transplant, 1 died c. diff). Treatment was well tolerated and was administered in the outpatient setting. The median duration of remission is 5.5 months (95% CI: 3.0–9.8 months), and median survival is 7.6 months (95% CI: 5.7–13.3 months) for all patients and 10.2 months (95% CI: 5.6–15.2 months) for patients achieving CR. Temozolomide maintenance is feasible in patients with AML in CR. Further accrual is continuing to assess if remission duration and survival will be improved compared to historical controls.

Gemtuzumab Ozogamicin (MylotargR) as Primary Induction Therapy for Elderly Patients with Acute Myeloid Leukemia: A Phase II Trial.

The prognosis of older adults with acute myeloid leukemia (AML) remains poor. Cytotoxic chemotherapy has been associated with low complete remission rates (30–50%), short relapse free survival and excessive toxicity in elderly patients with AML. There is a need for development of more effective and tolerable therapies for this population. Gemtuzumab ozogamicin (GO) is a humanized murine anti-CD33 monoclonal antibody, covalently linked to the antitumor antibiotic, calicheamicin. GO has been shown to be effective in patients with relapsed CD33+ AML, with an overall response rate of 26% in patients older than 60 years. From May 2001 to December 2003, 16 patients > 60 years of age with newly diagnosed CD33+ AML were treated with single-agent GO as induction chemotherapy. A two-stage design was employed; if fewer than 5 of the first 16 patients achieved CR, the study would be terminated. Treatment regimen: GO 9mg/m2 was given on day #1. Hydroxyurea could be used to control hyperleukocytosis prior to the first dose of GO. A bone marrow biopsy was performed on day #8. If a response to GO was seen, then patients continued on study and received GO 6mg/m2 IV on day #10. If progressive disease or no response was noted by day #8, patients were removed from the study. Post-remission therapy was at the discretion of the physician. Supportive care included GM-CSF and interleukin-11 beginning day #11, allopurinol, acyclovir, norfloxacin, IV hydration, and antiemetics. Patients received dexamethasone 8mg 12-18 hours prior to each dose of GO, as well as 30 minutes prior along with acetaminophen and diphenhydramine to help prevent infusion reactions. Patient characteristics: median age 69 (60–84); 9 patients with secondary AML; 8 patients with poor risk karyotypes and 8 with intermediate risk; performance status of 2 or less. Results: 4/16 patients achieved a CR (25%), 2 patients had no response, 9 progressed on therapy, and one patient died from sepsis and ARDS prior to a response evaluation. Therefore, the study was terminated after accrual of 16 patients. Two responders have relapsed, within 0.6 month and 9.7 months of CR. These two patients were ages 76 and 78, both with high risk karyotypes, and with de novo and secondary AML, respectively. The remaining two responders remain in CR for 27 months. These 2 patients were ages 65 and 79 at the time of treatment, both with de novo AML-M2 and normal karyotypes. Treatment-related toxicities included grade III-IV neutropenia (average duration 30 days) and thrombocytopenia (average duration 36 days), grade I-III infusion reaction in 5 patients, and grade III GI hemorrhage in 4 patients. Grade III-IV neutropenic fever occurred in 10 patients, of which there was only 1 patient with a life-threatening infection (VRE sepsis). There were 2 patients with grade III-IV elevation of hepatic transaminases, but hepatic veno-occlusive disease was not observed. 3/16 patients were able to receive the therapy as an outpatient. Conclusion: When used as induction chemotherapy for elderly patients with CD33+ AML, single agent GO produces response rates inferior to standard anthracycline-based induction regimens, with a comparable safety profile. However, two patients have had prolonged responses with single-agent GO, suggesting a possible role for this agent in a subset of elderly AML patients, yet to be defined.

Economic Analysis of Granulocyte Colony Stimulating Factor as Adjunct Therapy for Older Patients with Acute Myelogenous Leukemia (AML): Estimates from a Southwest Oncology Group Clinical Trial

Considerable morbidity, mortality, and economic costs result during remission induction therapy for elderly patients with acute myeloid leukemia (AML). In this study, the economic costs of adjunct granulocyte colony stimulating factor (G-CSF) are estimated for AML patients >55 years of age who received induction chemotherapy on a recently completed Southwest Oncology Group study (SWOG). Clinical data were based on Phase III trial information from 207 AML patients who were randomized to receive either placebo or G-CSF post-induction therapy. Analyses were conducted using a decision analytic model with the primary source of clinical event probabilities based on in-hospital care with or without an active infection requiring intravenous antibiotics. Estimates of average daily costs of care with and without an infection were imputed from a previously reported economic model of a similar population. When compared to AML patients who received placebo, patients who received G-CSF had significantly fewer days on intravenous antibiotics (median 22 vs. 26, p = 0.05), whereas overall duration of hospitalization did not differ (median 29 days). The median cost per day with an active infection that required intravenous antibiotics was estimated to be $1742, whereas the median cost per day without an active infection was estimated to be $1467. Overall, costs were $49,693 for the placebo group and $50,593 for the G-CSF patients. G-CSF during induction chemotherapy for elderly patients with AML had some clinical benefits, but it did not reduce the duration of hospitalization, prolong survival, or reduce the overall cost of supportive care. Whether the benefits of G-CSF therapy justify its use in individual patients with acute leukemia for the present remains a matter of clinical judgment.