Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome.
Narayan Rupa,Garcia Jacqueline S,Percival Mary-Elizabeth M,Berube Caroline,Coutre Steve,Gotlib Jason,Greenberg Peter,Liedtke Michaela,Hewitt Rhonda,Regan Kathleen,Williamson Charles,Doykan Camille,Cardone Michael H,McMillan Alex,Medeiros Bruno C
Leukemia & lymphoma
The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). This study describes a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. The median number of treatment cycles on study was two (range = 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders vs non-responders was 9.8 vs 4.0 months, respectively (HR = 0.36, p = 0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.
High-Intensity Induction Chemotherapy Is Feasible for Elderly Patients with Acute Myeloid Leukemia.
Shacham-Abulafia Adi,Itchaki Gilad,Yeshurun Moshe,Paul Mical,Peck Anat,Leader Avi,Shpilberg Ofer,Ram Ron,Raanani Pia
BACKGROUND:The prognosis of elderly patients with acute myeloid leukemia (AML) is poor, and the best treatment is controversial. Since the majority of AML patients are older than 60 years, identification of those who might benefit from intensive treatment is essential. METHODS:Data from electronic charts of consecutive AML patients treated in our center were analyzed. Eligibility criteria included newly diagnosed de novo or secondary AML, an age of 60 years or older, and intensive induction treatment. RESULTS:Sixty-two patients were included in the analysis. Forty-six patients (74%) achieved complete remission (CR) after 1-2 intensive induction courses. Twenty of them received consolidation with conventional chemotherapy, 20 proceeded to allogeneic hematopoietic cell transplantation (allo-HCT), and 6 were ineligible for further treatment. The projected overall survival (OS) at 2 and 3 years was 28 and 23%, respectively. A normal karyotype, CR achievement, and allo-HCT were associated with improved OS, while an Eastern Cooperative Oncology Group performance status of 0-1 was borderline associated. The median survival and disease-free survival at 2 years was 18.7 months and 49%, respectively, for patients who underwent allo-HCT in CR1, compared to 12.8 months and 25%, respectively, for those who did not. CONCLUSION:Based on our data, selected eligible elderly AML patients might benefit from intensive treatment.
Treatment with Low-Dose Cytarabine in Elderly Patients (Age 70 Years or Older) with Acute Myeloid Leukemia: A Single Institution Experience.
Heiblig Maël,Elhamri Mohamed,Tigaud Isabelle,Plesa Adriana,Barraco Fiorenza,Labussière Hélène,Ducastelle Sophie,Michallet Mauricette,Nicolini Franck,Plesa Claudiu,Wattel Eric,Salles Gilles,Thomas Xavier
Mediterranean journal of hematology and infectious diseases
OBJECTIVES:Low-dose cytarabine (LD-AraC) is still regarded as the standard of care in elderly patients with acute myeloid leukemia (AML) 'unfit' for intensive chemotherapy. In this study, we reported our experience with LD-AraC in patients ≥ 70 years old and compared the results to those of intensive chemotherapy, best supportive care (BSC), or hypomethylating agents in the same age population. METHODS:Between 2000 and 2014, 60 patients received LD-AraC at 20 mg once or twice daily by subcutaneous injection for 10 consecutive days every 4-6 weeks. RESULTS:Complete remission rate with LD-AraC was 7% versus 56% with intensive chemotherapy and 21% with hypomethylating agents. Median overall survival (OS) of patients treated with LD-AraC was 9.6 months with 3-year OS of 12%. Survival with LD-AraC was better than with BSC only (P = 0.001). Although not statistically significant, intensive chemotherapy and hypomethylating agents tended to be better than LD-AraC in terms of OS (median: 12.4 months and 16.1 months, respectively). There was no clear evidence that a beneficial effect of LD-AraC was restricted to any particular subtype of patients, except for cytogenetics. There was a trend for a better OS in LD-AraC treated patients in the setting of clinical trials as compared with those treated outside of a clinical trial. CONCLUSIONS:Despite a trend in favor of intensive chemotherapy and hypomethylating agents over LD-AraC, no real significant advantage could be demonstrated, while LD-AraC showed a significant advantage comparatively to BSC. All this tends to confirm that LD-AraC can still represent a baseline against which new promising agents may be compared either alone or in combination.
Myelodysplastic Syndromes and Acute Myeloid Leukemia in the Elderly.
Klepin Heidi D
Clinics in geriatric medicine
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic diseases that frequently affect older adults. Treatment is challenging. Management of older adults with MDS and AML needs to be individualized, accounting for both the heterogeneity of disease biology and patient characteristics, which can influence life expectancy and treatment tolerance. Clinical trials accounting for the heterogeneity of tumor biology and physiologic changes of aging are needed to define optimal standards of care. This article highlights key evidence related to the management of older adults with MDS and AML and highlights future directions for research.
Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia.
Aoki Jun,Kanamori Heiwa,Tanaka Masatsugu,Yamasaki Satoshi,Fukuda Takahiro,Ogawa Hiroyasu,Iwato Koji,Ohashi Kazuteru,Okumura Hirokazu,Onizuka Makoto,Maesako Yoshitomo,Teshima Takanori,Kobayashi Naoki,Morishima Yasuo,Hirokawa Makoto,Atsuta Yoshiko,Yano Shingo,Takami Akiyoshi
American journal of hematology
Previous studies have repeatedly reported that increasing age is a significant risk factor for worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among patients with acute myeloid leukemia (AML). However, more recent studies reported conflicting results regarding the association between age and outcomes in elderly patients. Therefore, we conducted a large-scale, nationwide retrospective study to examine the impact of age on outcomes of allo-HSCT with reduced intensity conditioning (RIC) for AML patients who were older than 50 years. Of the 757 patients, 89 patients (11.8%) were 50-54, 249 patients (32.9%) were 55-59, 301 patients (39.8%) were 60-64 and 118 patients (15.6%) were ≥65 years old. The 3-year overall survival (OS) (47.8, 45.2, 37.9, and 36.6% for patients aged 50-54, 55-59, 60-64, and ≥65 years, respectively, P = 0.24) and nonrelapse mortality (NRM) (24.0, 22.8, 29.2, and 27.6% for patients aged 50-54, 55-59, 60-64, and ≥65 years, respectively, P = 0.49) were not significantly different among the four age groups. Multivariate analysis revealed that increased age had no significant effect on OS or NRM after adjusting for covariates. These results suggested that advanced patient age is not a contraindication for RIC allo-HSCT in elderly AML patients.
Low Dose Cytosine Arabinoside and Azacitidine Combination in Elderly Patients with Acute Myeloid Leukemia and Refractory Anemia with Excess Blasts (MDS-RAEB2).
Atalay Figen,Ateşoğlu Elif Birtaş
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion
Only one-third of elderly (>60 years) AML and MDS-RAEB2 patients may receive intensive chemotherapy treatment alternatives that are limited in this patient group due to the potential of severe toxicity. Previous studies have shown that azacitidine and low dose cytarabine treatments may be a beneficial treatment option for these patients. In this study, we aimed to good results with low toxicity in elderly patients. We retrospectively analyzed the AML and MDS-RAEB2 patients who received azacitidine monotherapy and azacitidine and LDL-ara-c combination therapy for a comparison of their response to therapy, survival rates, and toxicity rates and for determining the factors that could affect their overall survival. A total of 27 patients who were diagnosed with de novo AML and MDS-RAEB2 and who received at least four cycles of chemotherapy were included in the study, and the data were evaluated retrospectively. When monotherapy and combination therapy groups were compared, the pretreatment bone marrow blast count was observed to be greater in the combination therapy group. A statistically significant difference was not detected between the groups regarding the response to therapy ratios (p = 0.161) (42.9 and 57.1 %, respectively). No difference was detected between the groups regarding therapy-related toxicity. Infections were the most common complication. Progression-free survival was 30.3 % for the azacitidine monotherapy group and 66.7 % for the combination (azacitidine + LD-ara-c) group. The factors influencing the overall survival rate were determined based on the response to the first-line therapies, more than a grade 2 infection, fever, and relapse in a multi-variance analysis. The combination therapy may be a well-tolerated treatment option for the elderly, vulnerable AML patients whose blast count is high in response to therapy rates, overall survival rates, and toxicities are not different, although the pre-treatment bone marrow blast count was greater in the combination therapy groups compared with the monotherapy group.
Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis.
Rashidi Armin,Ebadi Maryam,Colditz Graham A,DiPersio John F
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
A large number of elderly patients with acute myeloid leukemia (AML) are not offered treatments with curative intent, such as allogeneic stem cell transplantation (SCT), because of fears of toxicity and perceived futility of intensive treatment. Therefore, the outcomes of SCT in elderly AML patients remain poorly defined. We performed a meta-analysis of all previous articles up until September 22, 2015 of SCT in AML patients >60 years. The primary endpoints were relapse-free survival (RFS) and overall survival (OS) at 6 months and at 1, 2, and 3 years. A total of 13 studies (749 patients) were included. The pooled estimates and 95% confidence intervals (CI) for RFS at 6 months, 1 year, 2 years, and 3 years were 62% (95% CI, 54% to 69%), 47% (95% CI, 42% to 53%), 44% (95% CI, 33% to 55%), and 35% (95% CI, 26% to 45%), respectively. The corresponding numbers for OS were 73% (95% CI, 66% to 79%), 58% (95% CI, 50% to 65%), 45% (95% CI, 35% to 54%), and 38% (95% CI, 29% to 48%), respectively. We found no evidence of publication bias in our primary endpoints, with the exception of relapse, where there appeared to be a relative lack of small studies with high relapse rates. Sensitivity analysis did not identify an overtly influential study for our primary endpoints, with 1 exception in 2-year RFS analysis. The present analysis argues against significant publication bias and demonstrates consistency among reports despite differences in patient-, disease-, center-, and transplantation-related characteristics. Our results suggest that reduced-intensity SCT is a viable treatment option for elderly AML patients with a 3-year RFS of 35% for those over the age of 60. These results argue against using age per se as the sole criterion against SCT and would help remove some of the barriers that often preclude curative intent treatment. Correct identification of patients who would benefit from SCT can improve outcomes in this frequently undertreated population.
Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients.
Curti Antonio,Ruggeri Loredana,Parisi Sarah,Bontadini Andrea,Dan Elisa,Motta Maria Rosa,Rizzi Simonetta,Trabanelli Sara,Ocadlikova Darina,Lecciso Mariangela,Giudice Valeria,Fruet Fiorenza,Urbani Elena,Papayannidis Cristina,Martinelli Giovanni,Bandini Giuseppe,Bonifazi Francesca,Lewis Russell E,Cavo Michele,Velardi Andrea,Lemoli Roberto M
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE:In acute myeloid leukemia (AML), alloreactive natural killer (NK) cells are crucial mediators of immune responses after haploidentical stem cell transplantation. Allogeneic NK cell infusions have been adoptively transferred with promising clinical results. We aimed at determining whether the composition of NK graft in terms of frequency of alloreactive NK cells influence the clinical response in a group of elderly AML patients undergoing NK immunotherapy. EXPERIMENTAL DESIGN:Seventeen AML patients, in first complete remission (CR; median age 64 years, range 53-73) received NK cells from haploidentical KIR-ligand-mismatched donors after fludarabine/cyclophosphamide chemotherapy, followed by IL2. To correlate donor NK cell activity with clinical response, donor NK cells were assessed before and after infusion. RESULTS:Toxicity was moderate, although 1 patient died due to bacterial pneumonia and was censored for clinical follow-up. With a median follow-up of 22.5 months (range, 6-68 months), 9 of 16 evaluable patients (0.56) are alive disease-free, whereas 7 of 16 (0.44) relapsed with a median time to relapse of 9 months (range, 3-51 months). All patients treated with molecular disease achieved molecular CR. A significantly higher number of donor alloreactive NK cell clones was observed in responders over nonresponders. The infusion of higher number of alloreactive NK cells was associated with prolonged disease-free survival (0.81 vs. 0.14, respectively;P= 0.03). CONCLUSIONS:Infusion of purified NK cells is feasible in elderly AML patients as post-CR consolidation strategy. The clinical efficacy of adoptively transferred haploidentical NK cells may be improved by infusing high numbers of alloreactive NK cells.
Metronomic therapy with oral 6-mercaptopurine in elderly acute myeloid leukemia: A prospective pilot study.
Kapoor Akhil,Beniwal Surender Kumar,Kalwar Ashok,Singhal Mukesh Kumar,Nirban Raj Kumar,Kumar Harvindra Singh
South Asian journal of cancer
INTRODUCTION:Acute myeloid leukemia (AML) in elderly patients differs biologically from that in younger patients and is known to have unfavorable chromosomal rearrangements, higher resistance, and lower tolerance to chemotherapy. In such circumstances, instead of giving full-blown chemotherapy, palliative metronomic chemotherapy (MCT) could be a treatment option. PATIENTS AND METHODS:We performed a prospective pilot study of old AML patients (age >60 years) not amenable to curative treatment. Thirty-two patients were enrolled into the study and were treated with daily oral 6-mercaptopurine 75 mg/m(2). The following inclusion criteria were used: age >60 years, nonpromyelocytic AML, the absence of uncontrolled comorbidities, and patient not amenable to curative treatment. Overall survival (OS) was calculated using Kaplan-Meier method and Cox regression analysis were used to calculate the hazards ratio of significant factors. RESULTS:The median age of the patients was 69 years (range: 61-86 years) with male: female ratio of 2.5:1. About 59.4% of patients had Eastern Cooperative Oncology Group performance status of 2 while rest had the status of 3. The median OS was 6 months (95% confidence interval [CI]: 4.4-7.6). Males had median OS of 7 months (95% CI: 5.4-8.6) versus females with OS of 3 months (95% CI: 1.5-4.4; P = 0.008). There was no survival difference on the basis of baseline hemoglobin or French-American-British class. There were no Grade 4 toxicities and no episode of febrile neutropenia. CONCLUSIONS:MCT with oral 6-mercaptopurine is an attractive treatment option in elderly AML patients who are not amenable to curative therapy with minimal toxicities.
Elderly patients > 65 years of age with acute myeloid leukemia and normal karyotype benefit from intensive therapeutic programs.
Bernardi Massimo,Carrabba Matteo,Messina Carlo,Milani Raffaella,Sala Elisa,Pavesi Francesca,Gentner Bernhard,Peccatori Jacopo,Assanelli Andrea,Marktel Sarah,Corti Consuelo,Forcina Alessandra,Vago Luca,Ciceri Fabio
American journal of hematology
Decitabine-based chemotherapy followed by haploidentical lymphocyte infusion improves the effectiveness in elderly patients with acute myeloid leukemia.
Jing Yu,Jin Xiangshu,Wang Lixin,Dou Liping,Wang Quanshun,Yao Yushi,Lian Shimei,Zhou Jihao,Zhu Haiyan,Yao Zilong,Gao Lijun,Wang Lili,Li Yonghui,Bai Xuefeng,Fang Meiyun,Yu Li
In this study, we first initiated a multicenter, single-arm, phase-II clinical trial using decitabine (DAC) (20mg/m for five days) based chemotherapy, followed by haploidentical lymphocyte infusion (HLI) that was applied as induction therapy for elderly patients with AML. Furthermore, the role of HLI infusion was explored in a mouse model. The clinical trial included 29 elderly patients (median age: 64, range 57-77) with AML. Sixteen cases achieved complete remission (CR) and 9 cases achieved partial remission (PR) after the first treatment cycle. Of the patients with PR, 5 subjects achieved remission after the second induction, which brings the overall CR rate to 72.4%. The 2-year overall survival (OS) and disease-free survival (DFS) was 59.6% and 36.9% respectively. The treatment regimen was well tolerated with only one patient died of severe pneumonia one month after the first treatment. In the mouse experiment, we found that DAC/HLI significantly enhanced the survival of leukemic mice. These results suggested that DAC-based chemotherapy combined with HLI is an alternative first line induction therapy for elderly patients with AML. This trial is registered at ClinicalTrials.gov (NCT01690507).
A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia.
Schliemann Christoph,Gerss Joachim,Wiebe Stefanie,Mikesch Jan-Henrik,Knoblauch Nicola,Sauer Tim,Angenendt Linus,Kewitz Tobias,Urban Marc,Butterfass-Bahloul Trude,Edemir Sabine,Vehring Kerstin,Müller-Tidow Carsten,Berdel Wolfgang E,Krug Utz
Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28-day cycles. Dose-limiting toxicity (DLT) was defined as non-hematological severe adverse reaction CTC grade ≥ 4 with possible or definite relationship to nintedanib. Between April 2012 and October 2013, 13 patients (median age 73 [range: 62-86] years) were enrolled. One patient did not receive study medication and was replaced. Nine (69%) patients had relapsed or refractory disease and 6 (46%) patients had unfavorable cytogenetics. The most frequently reported treatment-related adverse events (AE) were gastrointestinal events. Twelve SAEs irrespective of relatedness were reported. Two SUSARs were observed, one fatal hypercalcemia and one fatal gastrointestinal infection. Two patients (17%) with relapsed AML achieved a complete remission (one CR, one CRi) and bone marrow blast reductions without fulfilling PR criteria were observed in 3 patients (25%). One-year overall survival was 33%. Nintedanib combined with LDAC shows an adequate safety profile and survival data are promising in a difficult-to-treat patient population. Continuation of this trial with a phase II recommended dose of 2 x 200 mg nintedanib in a randomized, placebo-controlled phase II study is planned. The trial is registered to EudraCT as 2011-001086-41. TRIAL REGISTRATION:ClinicalTrials.gov NCT01488344.
The Role of Azacitidine in the Treatment of Elderly Patients with Acute Myeloid Leukemia: Results of a Retrospective Multicenter Study.
Tombak Anıl,Uçar Mehmet Ali,Akdeniz Aydan,Tiftik Eyüp Naci,Gören Şahin Deniz,Akay Olga Meltem,Yıldırım Murat,Nevruz Oral,Kis Cem,Gürkan Emel,Solmaz Şerife Medeni,Özcan Mehmet Ali,Yıldırım Rahşan,Berber İlhami,Erkurt Mehmet Ali,Fıratlı Tuğlular Tülin,Tarkun Pınar,Yavaşoğlu İrfan,Doğu Mehmet Hilmi,Sarı İsmail,Merter Mustafa,Özcan Muhit,Yıldızhan Esra,Kaynar Leylagül,Mehtap Özgür,Uysal Ayşe,Şahin Fahri,Salim Ozan,Sungur Mehmet Ali
Turkish journal of haematology : official journal of Turkish Society of Haematology
OBJECTIVE:In this study, we aimed to investigate the efficacy and safety of azacitidine (AZA) in elderly patients with acute myeloid leukemia (AML), including patients with >30% bone marrow (BM) blasts. MATERIALS AND METHODS:In this retrospective multicenter study, 130 patients of ≥60 years old who were ineligible for intensive chemotherapy or had progressed despite conventional treatment were included. RESULTS:The median age was 73 years and 61.5% of patients had >30% BM blasts. Patients received AZA for a median of four cycles (range: 1-21). Initial overall response [including complete remission (CR)/CR with incomplete recovery/partial remission] was 36.2%. Hematologic improvement (HI) of any kind was documented in 37.7% of all patients. HI was also documented in 27.1% of patients who were unresponsive to treatment. Median overall survival (OS) was 18 months for responders and 12 months for nonresponders (p=0.005). In the unresponsive patient group, any HI improved OS compared to patients without any HI (median OS was 14 months versus 10 months, p=0.068). Eastern Cooperative Oncology Group performance status of <2, increasing number of AZA cycles (≥5 courses), and any HI predicted better OS. Age, AML type, and BM blast percentage had no impact. CONCLUSION:We conclude that AZA is effective and well tolerated in elderly comorbid AML patients, irrespective of BM blast count, and HI should be considered a sufficient response to continue treatment with AZA.
Addition of Androgens Improves Survival in Elderly Patients With Acute Myeloid Leukemia: A GOELAMS Study.
Pigneux Arnaud,Béné Marie C,Guardiola Philippe,Recher Christian,Hamel Jean-Francois,Sauvezie Mathieu,Harousseau Jean-Luc,Tournilhac Olivier,Witz Francis,Berthou Christian,Escoffre-Barbe Martine,Guyotat Denis,Fegueux Nathalie,Himberlin Chantal,Hunault Mathilde,Delain Martine,Lioure Bruno,Jourdan Eric,Bauduer Frederic,Dreyfus Francois,Cahn Jean-Yves,Sotto Jean-Jacques,Ifrah Norbert
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m on days 1 to 5, cytarabine 100 mg/m on days 1 to 7, and lomustine 200 mg/m on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m on day 1, cytarabine 100 mg/m on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 10/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.
[Allogeneic stem cell transplantation in elderly patients with acute myeloid leukemia].
[Rinsho ketsueki] The Japanese journal of clinical hematology
Acute myeloid leukemia is a disease that mainly affects older populations, with a median age at diagnosis of 67 years, and outcomes for these patients are poor. Reduced-intensity regimen improves survival after allogeneic hematopoietic cell transplantation (HCT), but this has not been well studied. To reduce non-relapse mortality (NRM) among the elderly, geriatric assessment, HCT-Comorbidity index, and disease risk must be studied before HCT.
Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia.
DiNardo Courtney D,Pratz Keith,Pullarkat Vinod,Jonas Brian A,Arellano Martha,Becker Pamela S,Frankfurt Olga,Konopleva Marina,Wei Andrew H,Kantarjian Hagop M,Xu Tu,Hong Wan-Jen,Chyla Brenda,Potluri Jalaja,Pollyea Daniel A,Letai Anthony
Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m, days 1-5, intravenously [IV]) or azacitidine (75 mg/m, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).
Elderly do benefit from induction chemotherapy: High dose mitoxantrone-based ("5 + 1") induction chemotherapy regimen in newly diagnosed acute myeloid leukemia.
Saini Neeraj Y,Cerny Jan,Furtado Vanessa F,Desmond Angela,Zhou Zheng,Raffel Glen,Puthawala Imran,Bednarik Jayde,Shanahan Lindsey,Miron Patricia M,Woda Bruce,Ramanathan Muthalagu,Nath Rajneesh
American journal of hematology
An intensive "5 + 1" regimen, which included bolus high dose cytarabine (HiDAC) at 3 g/m once daily over 3 hours on days 1-5 and high dose mitoxantrone (HDM) 80 mg/m on day 2, was evaluated in 101 consecutively treated newly diagnosed acute myeloid leukemia (AML) patients at a single center since 2009. The median age was 65 (range 18-90) years. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%), respectively. The overall response (complete remission [CR] + CRi) was 76.2% (77/101). The median overall survival (OS) stratified by age group <60, 60-69 and ≥70 years were 56, 31 and 9 months respectively (log-rank, P = 0.02). 51.7% (45/84) of patients with intermediate/adverse risk category proceeded to allogeneic stem cell transplants. Among these 84 patients, the percentage of patients able to proceed to transplant in age groups <60, 60-69, and ≥ 70 years were 75% (18/24), 60.7% (17/28), and 31.2% (10/32), respectively. In conclusion, HDM-based chemotherapy regimen produces high CR rates, is well tolerated and more patients can undergo curative postremission therapy including stem cell transplant.
Treatment patterns and comparative analysis of non-intensive regimens in elderly acute myeloid leukemia patients-a real-world experience from India.
Kanakasetty Govind B,R Chethan,K C Lakshmaiah,Dasappa Lokanatha,Jacob Linu Abraham,M C Suresh Babu,K N Lokesh,Haleshappa Rudresha Antapura,L K Rajeev,Saldanha Smitha Carol,Deepak Koppaka,Rajesh Patidar,Asati Vikas
Annals of hematology
Elderly patients with acute myeloid leukemia have a poor prognosis. Data from developing countries is sparse in the literature. In this retrospective study, 402 patients aged ≥ 60 years, diagnosed between Jan 2013 and Dec 2017, were analyzed for treatment patterns and survival. Median age of the whole cohort was 68 years (range 61-84). A total of 213 patients (53.3%) refused care; 188 patients (46.7%) received either BSC, LDAC, or HMA. Survival (in months) was 3.9, 6.4, and 1.2 with LDAC, HMA, and BSC, respectively. One-year survival was 17.2% and 6% with HMA and LDAC, respectively (P = 0.02). Overall response rate (ORR) did not differ between HMA and LDAC group (p = 0.12). HMA cohort had higher complete responses (20.6% vs 7.4%, p = 0.02), stable disease (32.7% vs 13.5%, p = 0.02), and transfusion independence (TI) (46.5% vs 22.2%, p = 0.01). Survival did not differ between the groups if the patients achieved ORR (12.3 vs 9.8 p = 0.2) or TI (11.6 vs 6.4 p = 0.2). Stable disease with HMA led to longer survival (8.1 vs 5.3 p = 0.01). HMAs were more effective than LDAC irrespective of cytogenetic risk category and blasts, of note HMAs improved survival of poor risk patients (5.6 vs 2.9 p = 0.004). HMA treatment (HR = 0.48; 95% 0.29-0.79, p = 0.004) and transfusion independence (HR = 0.2; 95% 0.1-0.3, p = 0.0001) predicted survival in multivariate analysis. Neutropenia and febrile neutropenia were frequent in HMA. Thrombocytopenia was the common adverse event with LDAC. Novel and cost-effective drugs are essential to improve the prognosis of these patients.
Acute myeloid leukemia in the elderly: what constitutes treatment value?
Nabhan Chadi,Kamat Siddhesh,Karl Kish Jonathan
Leukemia & lymphoma
Treatment options for patients with acute myeloid leukemia (AML), who are unfit for induction chemotherapy are unsatisfactory. Overall survival (OS) superiority has not been demonstrated in randomized controlled trials (RCT) in this population, challenging the value of available therapies. We sought to assess the relative value of approved therapies using value-assessment tools. Clinical, safety, quality-of-life (QOL), supportive care, and resource utilization outcomes data were abstracted from RCTs and examined using value-assessment frameworks. Three RCTs, one each of azacitidine, decitabine, and low-dose cytarabine were identified. OS was not statistically significant and secondary outcomes including response rates, rates of transfusion independence, the frequency of hospitalizations and changes in QOL were reported differently across trials. Value-assessment tools considered OS as the primary efficacy endpoint without consideration to response rates. The NCCN Evidence Blocks were most successful in considering secondary endpoints. With the move toward value-based care, understanding how these value tools apply to AML patients is critical.
Acute Myeloid Leukemia: Update on Upfront Therapy in Elderly Patients.
Keiffer Gina,Palmisiano Neil
Current oncology reports
PURPOSE OF REVIEW:Acute myeloid leukemia (AML) disproportionately impacts elderly patients. Treating elderly patients with AML has been a challenge due to the increased prevalence of medical comorbidities and decreased performance status in this population, as well as the different biology of AML in elderly patients. RECENT FINDINGS:The care of elderly patients with AML has advanced significantly over the past few years. Our greater understanding of the biology of AML in elderly patients has led to the development of novel, lower-intensity treatment options. We present here a review of the most recent literature regarding therapeutic options available to older patients, as well as tools to help identify the right treatment for the right patient. As targeted and lower-intensity treatment options become available, developing an approach to "right size" therapy for individual elderly patients is paramount.
Low-dose decitabine priming with intermediate-dose cytarabine followed by umbilical cord blood infusion as consolidation therapy for elderly patients with acute myeloid leukemia: a phase II single-arm study.
Li Xiaoyang,Dong Yuexin,Li Ya,Ren Ruibao,Wu Wen,Zhu Hongming,Zhang Yunxiang,Hu Jiong,Li Junmin
BACKGROUND:Treatment of acute myeloid leukemia (AML) in elderly patients remains a great challenge. In this prospective single arm study (ChiCTR-OPC-15006492), we evaluated the efficacy and safety of a novel consolidation therapy with low-dose decitabine (LD-DAC) priming with intermediate-dose cytarabine (ID-Ara-C) followed by umbilical cord blood (UCB) infusion in elderly patients with AML. METHODS:A total of 25 patients with a median age of 64-years-old (60-74-years-old) who achieved complete remission (CR) after induction chemotherapy were enrolled in the study. RESULTS:The 2-year actual overall survival (OS) rate and leukemia-free survival (LFS) was 68.0 and 60.0%, respectively. The hematological and non-hematological toxicity were mild to moderate, and only one patient died in remission due to infection with possible acute graft versus host disease (aGVHD). Compared to a concurrent cohort of patients receiving conventional consolidation therapy, the study group tended to have an improved OS and LFS (p = 0.046 and 0.057, respectively), while the toxicity was comparable between the two groups. CONCLUSIONS:This study suggested the novel combination of LD-DAC, ID-Ara-C, and UCB infusion might be an optimal consolidation therapy for elderly patients with AML, and a prospective phase III randomized study is warranted to confirm this observation. TRIAL REGISTRATION:This single-arm phase II clinical trial in elderly AML patients was registered prospectively at www.chictr.org.cn (identifier: ChiCTR-OPC-15006492 ) on June 2, 2015.
[Research Advances on Combination Strategies of Demethylating Agents for Elderly Acute Myeloid Leukemia--Review].
Sun Wen-Xuan,Jiang Bin
Zhongguo shi yan xue ye xue za zhi
Abstract Demethylating agents (HMAs) hold an important status in therapy for elderly acute myeloid leukemia, who are not eligible for intensive chemotherapy (ICT). Beyond the edge of monotherapy, domestic and foreign scholars have carried out a lot of studies on combination strategies, such as HMAs with low-intensity therapy (G-CSF, low-dose cytarabine and aclarubicin, CAG), with targeted therapy (BCL-2 inhibitor), with immunotherapy (immune checkpoint inhibitors, ICI), and with other epigenetic therapys (isocitrate dehydrogenase or histonedeacetylase inhibitor）. Some of these researches have obtained positive results and discussed the mechanisms of combination strategies besides. In this review, the combination of HMAs with other drugs are summraized briefly.
Treatment of Elderly Patients With Acute Myeloid Leukemia.
Thomas Xavier,Le Jeune Caroline
Current treatment options in oncology
OPINION STATEMENT:There is no standard of care for older patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy. AML in older patients remains an area of significant unmet need necessitating novel therapeutic strategies. In older patients with normal cytogenetics, molecular variables can be helpful in refining risk. This molecular revolution has promoted a shift in the treatment paradigm of AML. Open new questions concern the necessity of an individualized therapy that may take into account not only an increase in survival but also the maintenance or improvement in terms of quality of life, the management of symptoms, and a maximization of time outside of hospital care. Molecular abnormalities provide the genomic footprint for the development of targeted therapies. Clinical trials testing the activity of these new agents are ongoing and may reshape treatment strategies for these patients. One promising strategy is to combine low-intensity treatments with novel agents.
Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy.
Goldsmith S R,Lovell A R,Schroeder M A
Drugs of today (Barcelona, Spain : 1998)
On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.
Comparison of Reduced-Intensity Idarubicin and Daunorubicin Plus Cytarabine as Induction Chemotherapy for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia.
Liu Hui,Fu Rong,Li Lijuan,Wang Guojin,Song Jia,Ruan Erbao,Wang Huaquan,Wu Yuhong,Wang Xiaoming,Ding Kai,Shao Zonghong
Clinical drug investigation
BACKGROUND AND OBJECTIVES: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. METHODS:We retrospectively investigated 74 patients with newly diagnosed non-M3 AML aged >60 years, 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. RESULTS: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 × 10/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 10 months, 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 12 months, which was significantly longer than patients treated supportively (4 months) (p < 0.001). There were no differences of median survival and duration of CR between two arms. Early mortality decreased in the past 5 years in both groups. Meanwhile, low-dose idarubicin was well tolerated in elderly patients. CONCLUSIONS: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.
Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure-response analysis.
Agarwal Suresh,Gopalakrishnan Sathej,Mensing Sven,Potluri Jalaja,Hayslip John,Kirschbrown Whitney,Friedel Anna,Menon Rajeev,Salem Ahmed Hamed
The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.
Second line azacitidine for elderly or infirmed patients with acute myeloid leukemia (AML) not eligible for allogeneic hematopoietic cell transplantation-a retrospective national multicenter study.
Ram Ron,Gatt Moshe,Merkel Drorit,Helman Ilana,Inbar Tsofia,Nagler Arnon,Avivi Irit,Ofran Yishai
Annals of hematology
Elderly and infirm patients with acute myeloid leukemia (AML) with either induction refractory or relapse disease may benefit from treatment with azacitidine. We retrospectively reviewed the data from five tertiary centers in Israel, treated between 2009 and 2015. Thirty-four patients (median age 74 years) were identified. Sixty-two percent of the patients had relapsed disease and 38% had refractory disease. Median time of follow-up was 12.1 months. Out of a total of 327 courses, incidence of infectious episodes was 6%. Eighteen percent experienced major bleeding. Thirty-two percent of the patients achieved morphologic complete remission, and 26% had stabilization of disease during at least three courses. At 12 and 18 months after the first course of azacitidine, 33 and 10% of the patients were progression-free, respectively. Incidences of overall survival at 12 and 24 months were 54.5 and 16%, respectively. Age <75 years was associated with better overall survival. Normal leukocyte count at the first dose of azacitidine and standard doses of azacitidine were both associated with a better progression-free and overall survival. We conclude that azacitidine is feasible in patients who have failed induction chemotherapy and may be associated with prolongation of survival. A prospective trial to validate these results is warranted.
Decitabine before Low-Dose Cytarabine-Based Chemotherapy Combined with Human Leukocyte Antigen-Mismatched Stem Cell Microtransplantation Improved Outcomes in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia.
Zhu Yu,Zhao Huihui,Zhang Xiaoyan,Wu Yujie,Xie Yue,Li Yanru,Lian Yun,Huang Jiayu,Li Jianyong,Chen Yaoyu,Qian Sixuan
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
The optimal treatment for elderly patients with acute myeloid leukemia (AML) remains a great challenge. Establishing a more feasible, acceptable, accessible and safe treatment strategy for elderly patients is urgently needed. We conducted a prospective study of 23 elderly patients (median age, 68 years; range, 60 to 87 years) with newly diagnosed AML to evaluate the efficacy and toxicity of decitabine plus granulocyte colony-stimulating factor priming, low-dose aclarubicin, and cytarabine (DCAG) chemotherapy combined with HLA-mismatched stem cell microtransplantation (SC-MST) without graft-versus-host disease (GVHD) prophylaxis. After the first cycle, the overall response and the complete remission (CR) rates were 86.4% and 81.8%, respectively. CR was achieved in 90.9% of the normal karyotype group and in 80.0% of patients with unfavorable karyotypes at baseline. The median overall survival (OS) and disease-free survival rates were 17 and 13 months, respectively, with a 2-year OS of 34.8%. The median OS of the patients who received ≥3 cycles of SC-MST was significantly longer than those who received only 1 or 2 cycles of treatment. The regimen was well tolerated with a 4-week mortality of 4.3%, and no GVHD was observed. The most common adverse events were hematologic toxicities. Our data suggest that the innovative combination of DCAG with SC-MST may optimize the clinical strategy for elderly patients with newly diagnosed AML.
Real-world outcomes of unselected elderly acute myeloid leukemia patients referred to a leukemia/hematopoietic cell transplant program.
Solomon Scott R,Solh Melhem,Jackson Katelin C,Zhang Xu,Kent Holland H,Bashey Asad,Morris Lawrence E
Bone marrow transplantation
Due to perceived intolerance, many elderly AML patients do not receive therapy, and few are considered for hematopoietic cell transplantation (HCT). To better understand "real-world" outcomes, 323 consecutive AML patients ≥ 60 years referred from 2009 to 2017 were evaluated (median age 70 [60-88] years); favorable (fav) in 48 (15%), intermediate (int) in 112 (35%) and poor risk in 161 (50%). Remission induction therapy, either intensive chemotherapy (IC, n = 205) or hypomethylating agents (HMA, n = 57), was given to all but 61 (19%) patients. With median f/u of 34 months, 2-year overall survival (OS) for the whole cohort was 31%; 40 and 33% for IC- and HMA-treated vs. 0% for untreated patients. Early mortality was 14%. Remission (CR/CRi) was achieved in 60% of patients, with approximately half of these surviving 2 years. In transplant-eligible patients (60-75-year-old, int/poor risk, achieving remission), 54 (46%) of 118 received HCT. Transplanted patients had improved 2- and 3-year post-remission survival of 59% and 40% compared to 26% and 18% in similar patients not receiving HCT (HR = 0.59, 95% CI 0.37-0.93, p = 0.023). These results suggest that survival of elderly AML patients may be improved through a coordinated approach of remission induction therapy for most patients followed by HCT when feasible.
[New Drugs in the Treatment of Acute Myeloid Leukemia in the Elderly].
Šustková Z,Čulen M,Semerád L,Ježíšková I,Dvořáková D,Ráčil Z,Mayer J
Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti
BACKGROUND:At the time of diagnosis, most patients with acute myeloid leukemia are older than 65 years of age. Treatment of this group of patients is challenging because they become less tolerant to aggressive chemotherapy with increasing age. Less than one-third of elderly patients are considered eligible for intensive treatment; nevertheless, the survival analysis for this population remains poor. Due to numerous comorbidities and an overall deteriorating condition, most elderly patients with acute myeloid leukemia receive only palliative or best supportive care, which are associated with a high mortality rate. New therapeutic approaches are expected to improve the overall survival and quality of life of this group of patients. These promising treatments include cell kinase inhibitors, cytotoxic agents, monoclonal antibodies, and epigenetic therapy including hypomethylating agents and inhibitors of isocitrate dehydrogenase and histone deacetylase. In monotherapy, these new drugs show lower levels of toxicity than those commonly used in chemotherapy; however, they do not lead to a better long-lasting treatment response. To enhance therapeutic efficacy, combinations of the above-mentioned treatments are often used, and, during clinical trials, combinations with standard cytostatics are also common. The promising results of these studies show that even low-toxicity therapies can lead to a better overall treatment response and to longer overall survival. AIM:This article provides a brief overview of new drugs that are evaluated for their mechanism of effect, efficacy and toxicity in therapy of patients suffering from acute myeloid leukemia.Key words: acute myeloid leukemia - elderly - FLT3 inhibitors - epigenetic therapy - monoclonal antibodies The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 4. 11. 2016Accepted: 13. 12. 2016.
Patterns of Care and Survival for Elderly Acute Myeloid Leukemia-Challenges and Opportunities.
Mangaonkar Abhishek A,Patnaik Mrinal M
Current hematologic malignancy reports
PURPOSE OF REVIEW:Acute myeloid leukemia (AML) is a disease of the elderly, with a median age of diagnosis in the sixth decade of life. Mortality has declined over the last few years, but this impact is apparent only in the young, fit AML population. Outcomes for the elderly remain poor, with less than 20% 5-year overall survival rates. Hence, there is an unmet need to identify treatment strategies to maximize benefit in this age group. RECENT FINDINGS:Elderly AML is a difficult entity to treat due to both disease and patient-related factors. Treatment of this group has a lot of inter-physician and inter-institutional variability. Several objective criteria to assess biological age, impact of co-morbidities, and fitness have been published, which could be utilized to make management decisions. For old and unfit AML patients, a variety of novel therapeutic agents are currently being investigated. Objective analysis of biological age should include assessment of fitness, frailty, and co-morbidities in elderly AML. Future areas of research include development of an objective risk-based approach and its validation in clinical trials, development of novel therapeutic agents, and improvement in supportive care measures.
Arsenic-Containing Qinghuang Powder () is an Alternative Treatment for Elderly Acute Myeloid Leukemia Patients Refusing Low-Intensity Chemotherapy.
Fan Teng,Quan Ri-Cheng,Liu Wei-Yi,Xiao Hai-Yan,Tang Xu-Dong,Liu Chi,Li Liu,Lv Yan,Wang Hong-Zhi,Xu Yong-Gang,Guo Xiao-Qing,Hu Xiao-Mei
Chinese journal of integrative medicine
OBJECTIVE:To analyze the overall survival (OS) of elderly acute myeloid leukemia (AML) patients treated with oral arsenic-containing Qinghuang Powder (, QHP) or low-intensity chemotherapy (LIC). METHODS:Forty-two elderly AML patients treated with intravenous or subcutaneous LIC (1 month for each course, at least 3 courses) or oral QHP (3 months for each course, at least 2 courses) were retrospectively analyzed from January 2015 to December 2017. The main endpoints of analysis were OS and 1-, 2-, 3-year OS rates of patients, respectively. And the adverse reactions induding bone marrow suppression, digestive tract discomfort and myocardia injury were observed. RESULTS:Out of 42 elderly AML patients, 22 received LIC treatment and 20 received QHP treatment, according to patients' preference. There was no significant difference on OS between LIC and QHP patients (13.0 months vs. 13.5 months, >0.05). There was no significant difference on OS rates between LIC and QHP groups at 1 year (59.1% vs. 70.0%), 2 years (13.6% vs. 15%), and 3 years (4.6% vs. 5.0%, all >0.05). Furthermore, there was no significant difference of OS on prognosis stratification of performance status > 2 (12 months vs. 12 months), age> 75 year-old (12.0 months vs. 12.5 months), hematopoietic stem cell transplant comorbidity index >2 (12 months vs. 13 months), poor cytogenetics (12 months vs. 8 months), and diagnosis of secondary AML (10 months vs. 14 months) between LIC and QHP patients (>0.05). CONCLUSION:QHP may be an alternative treatment for elderly AML patients refusing LIC therapy.
Outcome of elderly patients after failure to hypomethylating agents given as frontline therapy for acute myeloid leukemia: Single institution experience.
Nanah Rama,McCullough Kristen,Hogan William,Begna Kebede,Patnaik Mrinal,Elliott Michelle,Litzow Mark,Al-Kali Aref
American journal of hematology
Outcomes of acute myeloid leukemia (AML) in elderly patients unfit for intensive chemotherapy is challenging. Hypomethylating agents (HMAs) can be effective in these patients but responses are usually short-lived. The majority of patients will either have stable disease or progress through therapy. We hereby describe the outcome of these patients at our institution after they fail HMAs. The data on 56 AML patients at Mayo Clinic, Rochester were reviewed. Patients were considered for our study if they received HMA as frontline therapy for their AML. Out of 56 patients, 15 (27%) patients received azacitidine (AZA) and 41 (73%) received decitabine. Complete remission was found in 10 (18%), with overall response of 28% and median response duration of 10 months. Thirteen (81%) out of 16 responders relapsed. Therefore 53 patients were included in the primary or secondary failure analysis with a median overall survival (OS) of 2 months after the date of failure. Out of 53 patients, 12 (23%) received subsequent treatments. None of the 12 patients who got first salvage therapy achieved remission. Five out of the 12 patients received second salvage therapy, 2 (40%) of which achieved CR. Median OS for patients who received subsequent salvage therapies was better than those who did not receive any subsequent therapy after failing HMA (9.5 vs. 2 months, P = .0009). Outcome for patients who have primary or secondary failure is very poor. Our study provides important historical data for future novel therapies, which are sorely needed for these patients.
Low-dose lenalidomide plus cytarabine in very elderly, unfit acute myeloid leukemia patients: Final result of a phase II study.
Visani Giuseppe,Ferrara Felicetto,Di Raimondo Francesco,Loscocco Federica,Fuligni Fabio,Paolini Stefania,Zammit Valentina,Spina Eleonora,Rocchi Marco,Visani Axel,Piccaluga Pier Paolo,Isidori Alessandro
Outcome for elderly patients with acute myeloid leukemia (AML) is extremely poor. Intensive induction chemotherapy is often unsuitable. Sixty-six newly diagnosed AML patients (median age: 76years), ineligible for standard therapy, were consecutively treated with low-dose lenalidomide (10mg/day orally, days 1-21) plus 10mg/m low-dose cytarabine, subcutaneously, twice a day (days 1-15) every six weeks, up to 6 cycles. Complete remission (CR) rate was 36.3% according to intention-to-treat. Responding patients had a longer median overall survival than non-responders (517 vs. 70days, P<0.001). The achievement of CR was not predicted by bone marrow blast count, cytogenetics, molecular markers, prior MDS, white blood cell count. Conversely, by studying the global gene expression profile, we identified a molecular signature, including 309 genes associated with clinical response (CR versus no CR). Based on the expression of a minimal set of 16 genes, we developed an algorithm to predict treatment response, that was successfully validated by showing an overall accuracy of 88%. We met the primary endpoint of the study, by beating the estimated successful CR rate (P1) fixed at 30%. Moreover, CR induced by this 2-drug combo was efficiently predicted by genetic profiling, identifying a biomarker that warrants validation in independent series.
Immunotherapy of elderly acute myeloid leukemia: light at the end of a long tunnel?
Rafelson William M,Reagan John L,Fast Loren D,Lim Seah H
Leukemia & lymphoma
Although it is possible to induce remission in the majority of the patients with acute myeloid leukemia (AML), many patients still die due to disease relapse. Immunotherapy is an attractive option. It is more specific. The memory T cells induced by immunotherapy may also provide the long-term tumor immunosurveillance to prevent disease relapse. Although immunotherapy of AML started in the early 1970s, its clinical impact has been disappointing. Recent advances in tumor immunology and immunotherapeutic agents have rekindled interest. Here, we provide a review of the history of AML immunotherapy, discuss why AML is well suited for immunotherapeutic approaches and present the biological obstacles that affect the success of immunotherapy. Finally, we put forward a new paradigm of AML immunotherapy that utilizes a combination of immunotherapeutic agents sequentially to enhance the in vivo tumor immunogenicity and effective priming and propagation of tumor-specific cytotoxic T cells.
Therapeutic decision-making in elderly patients with acute myeloid leukemia: conventional intensive chemotherapy versus hypomethylating agent therapy.
Oh Sang-Bo,Park Sung-Woo,Chung Joo-Seop,Lee Won-Sik,Lee Ho-Seop,Cho Su-Hee,Choi Yoon-Suk,Lim Sung-Nam,Shin Ho-Jin,
Annals of hematology
Standards of care for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy remain undefined. We aimed to compare outcomes of hypomethylating agent (HMA) therapy and intensive chemotherapy (IC) in elderly AML patients and identify the subgroup of patients who are eligible for HMA therapy. We reviewed data on the outcomes of 86 AML patients aged ≥ 65 years, who had undergone treatment between 2010 and 2015. These treatments included IC (25 patients, 29.1%) or therapy using HMA including azacitidine or decitabine (61 patients, 70.9%). The overall response rates were 32 and 19.7%, respectively. Median overall survival (OS) (8 vs. 8 months) and progression-free survival (PFS) (6 vs. 7 months) durations were similar in the two groups. Patients in the HMA group with less than 10% peripheral blood (PB) blasts achieved significantly better OS duration than patients in the IC group (P = 0.043). Patients in the IC group with PB blasts and bone marrow blast of ≥ 10 and ≥ 50%, respectively, achieved better PFS durations than the corresponding patients in the HMA group (P = 0.038). Multivariate analysis identified the hematologic improvement-platelet (HI-P) as an independent prognostic factor for survival in the HMA group (P = 0.005). Our results showed that HMA therapy and IC were associated with similar survival duration in elderly AML patients. This study was noteworthy because it assessed prognostic factors that would help to select elderly patients who could expect actual benefits from undergoing the different therapeutic options available, especially HMA therapy.
[Acute myeloid leukemia of the elderly: recent progresses in therapy].
[Rinsho ketsueki] The Japanese journal of clinical hematology
Therapeutic modalities for acute myeloid leukemia (AML) in elderly include intensive chemotherapy, less-intensive chemotherapy, and best supportive care. The choice of treatment is based on patients' general physical condition, leukemic prognostic factors, preference of the patient/family, and the available social support. Findings of comprehensive geriatric assessment and comorbidities are considered while selecting therapeutic modalities. AML score may suggest the appropriateness of the use of intensive chemotherapy. When intensive chemotherapy is tolerable, enocitabine or cytarabine + daunorubicin is used as remission induction chemotherapy. Consolidation chemotherapy comprising three courses of cytarabine-based regimens is administered after complete remission. When intensive chemotherapy is not tolerable, low-dose cytarabine is used. CPX351, a novel antileukemic agent, is a liposomal formulation of asynergistic 5 : 1 molar ratio of cytarabine and daunorubicin. In a randomized phase 2 trial in older patients with AML, CPX351 showed better response rate and survival than cyarabine + daunorubicin regimen.
A multicenter, retrospective analysis of elderly patients with acute myeloid leukemia who were treated with decitabine.
Yi Jun Ho,Park Silvia,Kim Jung Han,Won Young-Woong,Lim Do Hyoung,Han Boram,Uhm Jieun,Kim Hae Su,Jung Chul Won,Jang Jun Ho
Decitabine is widely accepted as the treatment options for elderly acute myeloid leukemia (AML) patients. However, the efficacy has yet been assessed in Asian population. We retrospectively analyzed the outcomes of 80 Korean elderly AML patients who were treated with decitabine. The median age was 74 years (range, 64 to 86 years) and 6 (7.5%), 48 (60.0%), and 25 (31.3%) patients were categorized to favorable, intermediate, and poor risk group, respectively. The median OS was 10.2 months (95% CI 5.0-15.4). Given that decitabine treatment demonstrated improved clinical outcomes, it could be considered as one of the first-line treatment for Korean elderly AML patients.
The synergy of Vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia.
Zhao Huihui,Zhu Huayuan,Huang Jiayu,Zhu Yu,Hong Ming,Zhu Han,Zhang Jingjing,Li Shan,Yang Lijia,Lian Yun,Wang Shuai,Mao Jianping,Chen Yaoyu,Li Jianyong,Qian Sixuan
BACKGROUND:Decitabine is widely used in the treatment of acute myeloid leukemia (AML) in elderly patients. Low-dose Vitamin C has also been indicated to induce DNA demethylation at the cellular level. However, little is known whether low-dose Vitamin C has a synergistic effect with decitabine in clinic. METHODS:The effect of combined low-dose Vitamin C and decitabine on cell proliferation, the cell cycle, apoptosis and the expression level and activity of TET2 was investigated in HL60 and NB4 human leukemic cells. Additionally, we analyzed the clinical outcomes of 73 elderly AML patients who received A-DCAG (intravenous Vitamin C [IVC] plus DCAG [n = 39]) or DCAG (n = 34) treatment. RESULTS:We found that low-dose Vitamin C and decitabine has a synergistic efficacy on proliferation, apoptosis, TET2 expression and activity, compared to drug-alone treatment in HL60 and NB4 cell lines in vitro. In clinic, feasibility and safety evaluations revealed that patients who received A-DCAG regimen have a higher complete remission (CR) rate than those who received the DCAG regimen (79.92% vs. 44.11%; P = 0.004) after one cycle of chemotherapy. The median overall survival (OS) was better in the A-DCAG group compared with the DCAG group (15.3 months vs. 9.3 months, P = 0.039). Patients with adverse cytogenetics did benefit from CR. There was no clinically significant additional toxicity observed with the addition of IVC. CONCLUSION:On the basis of these results, the addition of IVC at low doses to DCAG appeared to improve CR and prolong OS, compared with DCAG, in elderly patients with AML.
Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients.
Röllig C,Kramer M,Gabrecht M,Hänel M,Herbst R,Kaiser U,Schmitz N,Kullmer J,Fetscher S,Link H,Mantovani-Löffler L,Krümpelmann U,Neuhaus T,Heits F,Einsele H,Ritter B,Bornhäuser M,Schetelig J,Thiede C,Mohr B,Schaich M,Platzbecker U,Schäfer-Eckart K,Krämer A,Berdel W E,Serve H,Ehninger G,Schuler U S,
Annals of oncology : official journal of the European Society for Medical Oncology
Background:The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients and methods:Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results:Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33-45] versus 55% (95% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). Conclusion:The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.
Immunosenescence and Immunotherapy in Elderly Acute Myeloid Leukemia Patients: Time for a Biology-Driven Approach.
Isidori Alessandro,Loscocco Federica,Ciciarello Marilena,Corradi Giulia,Lecciso Mariangela,Ocadlikova Darina,Parisi Sarah,Salvestrini Valentina,Amadori Sergio,Visani Giuseppe,Curti Antonio
Acute myeloid leukemia (AML) is a disease, which mainly affects the elderly population. Unfortunately, the prognosis of patients aged >65 years is dismal, with 1-year overall survival approaching 10% with conventional therapies. The hypothesis of harnessing the immune system against cancer, including leukemia, has been postulated for a long time, and several clinical attempts have been made in this field. In the last years, we increased our knowledge about the interplay between AML and immune cells, but no major improvement has been translated, up to now, from bench to bedside. However, the outstanding results coming from the modern immuno-oncology trials with new drugs have granted a new interest for immunotherapy in AML. Accordingly, the elderly population represents an ideal target, given the low percentage of patients eligible for allogeneic stem cell transplant. With that in mind, in the era of immunotherapy, we consider immunosenescence as the optimal background to start investigating a biology-driven approach to AML therapy in the elderly. By taking into account the physiological age-related changes of immune response, more personalized and tailored use of the new drugs and strategies harnessing the immune system against AML, has the potential to increase their efficacy and impact on clinical outcomes.
Effectiveness and Safety of Therapeutic Regimens for Elderly Patients With Acute Myeloid Leukemia: A Systematic Literature Review.
Bell Jill A,Galaznik Aaron,Huelin Rachel,Stokes Michael,Guo Yelan,Fram Robert J,Faller Douglas V
Clinical lymphoma, myeloma & leukemia
Acute myeloid leukemia (AML) is the second most common leukemia among adults. Although the median age at diagnosis is 67 years, with approximately one third of patients aged 75 years or older, limited treatment options exist for the elderly, who have 5-year survival rates of only 5%. A systematic review was conducted to examine effectiveness and safety outcomes of treatment regimens in elderly (≥60 years old) patients with AML. Published literature on the topic was scant, and the review included only 22 articles examining outcomes. Twelve studies examined treatment-specific outcomes; most of these examined azacitidine or intensive chemotherapy (IC). An international randomized controlled trial found that azacitidine significantly improved overall survival relative to conventional regimens including IC and low-dose cytarabine in patients aged > 65 years. Similar results in favor of azacitidine were demonstrated in 2 other studies. IC was generally associated with longer survival versus lower-intensity therapy or best supportive care. Findings suggest that azacitidine is a viable option for elderly AML patients who are ineligible for IC, and emerging agents used in combination with azacitidine could have a major impact in this difficult-to-treat population.
A novel allogeneic off-the-shelf dendritic cell vaccine for post-remission treatment of elderly patients with acute myeloid leukemia.
van de Loosdrecht Arjan A,van Wetering Sandra,Santegoets Saskia J A M,Singh Satwinder Kaur,Eeltink Corien M,den Hartog Yvonne,Koppes Malika,Kaspers Jorn,Ossenkoppele Gert J,Kruisbeek Ada M,de Gruijl Tanja D
Cancer immunology, immunotherapy : CII
In elderly acute myeloid leukemia (AML) patients post-remission treatment options are associated with high comorbidity rates and poor survival. Dendritic cell (DC)-based immunotherapy is a promising alternative treatment strategy. A novel allogeneic DC vaccine, DCP-001, was developed from an AML-derived cell line that uniquely combines the positive features of allogeneic DC vaccines and expression of multi-leukemia-associated antigens. Here, we present data from a phase I study conducted with DCP-001 in 12 advanced-stage elderly AML patients. Patients enrolled were in complete remission (CR1/CR2) (n = 5) or had smoldering disease (n = 7). All patients were at high risk of relapse and ineligible for post-remission intensification therapies. A standard 3 + 3 dose escalation design with extension to six patients in the highest dose was performed. Patients received four biweekly intradermal DCP-001 injections at different dose levels (10, 25, and 50 million cells DCP-001) and were monitored for clinical and immunological responses. Primary objectives of the study (feasibility and safety) were achieved with 10/12 patients completing the vaccination program. Treatment was well tolerated. A clear-cut distinction between patients with and without detectable circulating leukemic blasts during the vaccination period was noted. Patients with no circulating blasts showed an unusually prolonged survival [median overall survival 36 months (range 7-63) from the start of vaccination] whereas patients with circulating blasts, died within 6 months. Long-term survival was correlated with maintained T cell levels and induction of multi-functional immune responses. It is concluded that DCP-001 in elderly AML patients is safe, feasible and generates both cellular and humoral immune responses.
Improved Survival of Elderly-fit Patients With Acute Myeloid Leukemia Requiring Intensive Therapy: 3-Year Multicenter Analysis From TALWG.
Owattanapanich Weerapat,Utchariyaprasit Eakkapol,Tantiworawit Adisak,Rattarittamrong Ekarat,Niparuck Pimjai,Puavilai Teeraya,Julamanee Jakrawadee,Saelue Pirun,Chanswangphuwana Chantiya,Polprasert Chantana,Limvorapitak Wasithep,Kanitsap Nonglak,Wanitpongpun Chinadol,Nakhakes Chajchawan,Sriswasdi Chantarapa,Prayongratana Kannadit
Clinical lymphoma, myeloma & leukemia
BACKGROUND:Elderly patients with acute myeloid leukemia (AML) have a poorer prognosis than younger ones. Several factors contribute to the poor outcomes for this patient group. PATIENTS AND METHODS:This study investigated the epidemiology, clinical characteristics, treatment, and clinical outcomes of elderly Thai patients with AML. This 3-year, prospective, multicenter study was focused on Thai patients with AML aged over 60 years who were diagnosed between 2014 and 2016. RESULTS:Of 680 patients with AML, 235 elderly patients with AML (34.6%) were identified, with a mean age of 70 ± 8 years. Using a 3-group cytogenetic risk classification (favorable, intermediate, and adverse risk), the proportions of patients in each category were 3.6%, 73.8%, and 22.6%, respectively. The median follow-up time for surviving patients was 846 days. The median overall survival (OS) of the patients was 128.2 days (range, 0-1205 days), with a 1-year OS of 13%. From a multivariate analysis, the significant factors associated with an improved long-term OS were patients with an Eastern Cooperative Oncology Group performance status 0 to 2 and those receiving intensive therapy. CONCLUSION:Our study confirms the high prevalence of AML in elderly patients with generally poor outcomes. Selected patients with a good performance status and those who received intensive induction treatment could have a long-term survival.
[Efficacy of Decitabine Combined with Pre-Excitation Chemotherapy in the Treatment of Middle-Aged and Elderly MDS Transformed Acute Myeloid Leukemia].
Li Zhang-Kun,Lai Ying-Chang,Li Kun,He Ji-Xiang,Jiang Yi-Rong,Liu Shu-Yang
Zhongguo shi yan xue ye xue za zhi
OBJECTIVE:To investigate the efficacy of domestic decitabine (D) combined with pre-excitation chemotherapy consisted of Ara-c, THP and G-CSF(CTG) in treatment of middle-aged and elderly patients with MDS-transformed AML and prognosis-related factors. METHODS:Seventy-six patients with MDS-transformed AML treated in our hospital from June 2013 to June 2015 were selected according to treatment regimens, 76 patients were divided into 2 groups: CTG group(36 cases) and D+CTG group(40 cases). The patients in CTG group received treatment with Ara-C, THP and G-CSF; the patients received the treatment with decitabine plus CTG. The patients in 2 groups all received 4 course treatment, then received maintaining treatment. The therapeutic efficacy and incidence of adverse reactions in 2 group were compared, at the same time, the risk factors affecting the prognos of patients treated with D+CTG were analyzed. RESULTS:There were no siginificant differences in age, sex, initial blood cell count, bone marrow blast ratio, disease types, chromosome karyotypes and FLT3-ITD gene mutation between 2 groups. The efficacy analysis showed that the efficacy of D+CTG was superior to CTG, ORR in D+CTG group was significantly higher than that in CTG group (72、52 vs 50%) (P<0.05), moreover, no significant differences in bone marrow inhibition digree infeetion, gastroinfestinal response and liver damage were found between 2 groups (P>0.05). The follow-np for 2 years showed that the median survival time in D+CTG group was significantly longer than that in CTG group (19.9 vs 11.0 months) (P<0.05). The multivariate analysis showed that the 1 course efficacy (RR=3.926, P=0.015) and FLT3-ITD gene mutation (RR=4.347, P=0.004) were independent risk factors affecting the efficacy of D+CTG treatment. CONCLUSION:The short-and long-term efficacy of domestic decitasine combined with preexcitation chenotherapy in treatment of middec-aged and eldery patients with MDS transformed AML is superior to single pre-excitation chenothrapy, moreover the incidence of adverse reactions did not increase. The 1 course efficacy and FLT-3 ITD gene mutation are the independent risk factors affecting the prognosis of patients. .
Intensive treatment and trial participation in elderly acute myeloid leukemia patients: A population-based analysis in The Netherlands.
Kalin Burak,Pijnappel Esther N,van Gelder Michel,Visser Otto,van de Loosdrecht Arjan A,Ossenkoppele Gert J,Cornelissen Jan J,Dinmohamed Avinash G,Jongen-Lavrencic Mojca
BACKGROUND:The paucity of population-based research indicates that the application of intensive chemotherapy (ICT) among elderly acute myeloid leukemia (AML) patients, as well as their accrual to randomized controlled trials (RCTs) remains low for several decades. Therefore, a contemporary, comprehensive apprehension on patient-, disease-, and treatment-specific characteristics of elderly AML patients at the population level can inform treatment choices and facilitate increased patient accrual in upcoming RCTs. OBJECTIVES:In this population-based study, we investigated patient- and disease-specific characteristics in elderly AML patients, and their association with treatment and survival. METHODS:We retrospectively obtained data on all over 65-year-old AML patients diagnosed between 2010-2013 in the referral area of two university hospitals in the Netherlands. Multivariable analyses were performed to assess factors associated with treatment choice and overall survival. RESULTS:Of all 356 patients, 77% received non-intensive therapy (NIT), and 15% and 8% received ICT within and outside a RCT, respectively. Cytogenetic (74%) and molecular (93%) analyses were not performed in most NIT recipients. Age and comorbidity were independently associated with NIT, whereas only comorbidity was associated with decreased trial participation. The adjusted risk of mortality among ICT recipients was not influenced by trial participation status. CONCLUSION:The application of ICT and accrual to RCTs remains staggeringly low in an elderly AML population. Since survival of ICT-treated patients was not affected by trial participation status, exclusion criteria might be relaxed in upcoming RCTs. Furthermore, appropriate management strategies can be accomplished by comprehensive comorbidity assessment and augmented genetic prognostication.
Acute myeloid leukemia in the elderly: therapeutic options and choice.
Webster Jonathan A,Pratz Keith W
Leukemia & lymphoma
Acute myeloid leukemia (AML) therapies are rapidly evolving with novel targeted therapies showing high-level responses in a notoriously difficult to treat group of patients - the elderly and unfit. This review will examine the outcomes of older AML patients (>60 years old) with conventional induction strategies, and published literature on risks of pursuit of induction. Low-intensity combination therapy response rates appear to be approaching that of induction regimens, and with lower toxicity, low-intensity therapy likely represents the future standard approach in this age group. Lastly, allogeneic transplant appears to have a role in increasing durable remissions regardless of age and should be considered in patients with limited comorbidities.
Maintenance therapy with alternating azacitidine and lenalidomide in elderly fit patients with poor prognosis acute myeloid leukemia: a phase II multicentre FILO trial.
Hunault-Berger M,Maillard N,Himberlin C,Recher C,Schmidt-Tanguy A,Choufi B,Bonmati C,Carré M,Couturier M-A,Daguindau E,Marolleau J-P,Orsini-Piocelle F,Delaunay J,Tavernier E,Lissandre S,Ojeda-Uribe M,Sanhes L,Sutton L,Banos A,Fornecker L M,Bernard M,Bouscary D,Saad A,Puyade M,Rouillé V,Luquet I,Béné M C,Hamel J-F,Dreyfus F,Ifrah N,Pigneux A
Blood cancer journal
How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia.
Jonas Brian A,Pollyea Daniel A
Acute myeloid leukemia (AML) is associated with poor outcomes, especially in older patients in whom the disease is most common. B-cell lymphoma 2 (BCL-2) is an antiapoptotic protein involved in the survival and maintenance of AML, and it is overexpressed in the leukemia stem cell population. Venetoclax is an oral BCL-2 protein inhibitor recently approved by the United States Food and Drug Administration (FDA) for use in combination with a hypomethylating agent (HMA) (azacitidine or decitabine) or low-dose cytarabine for front-line treatment of AML in older patients or those unfit for induction chemotherapy. Given that its mechanism of action is unique, it is not surprising that this widely effective therapy presents unique challenges, including but not limited to the rapidity of responses, the rate and depth of cytopenias, and issues related to drug-drug interactions. With the recent FDA approval and increasingly widespread use, we aim here to summarize, based on evidence and experience, emerging management strategies for the combination of HMAs and venetoclax in the treatment of AML.
Decitabine Versus Intensive Chemotherapy for Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia.
Choi Eun-Ji,Lee Je-Hwan,Park Han-Seung,Lee Jung-Hee,Seol Miee,Lee Young-Shin,Kang Young-Ah,Jeon Mijin,Woo Ji Min,Lee Kyoo-Hyung
Clinical lymphoma, myeloma & leukemia
BACKGROUND:Elderly patients with acute myeloid leukemia (AML) have generally had a poor prognosis with unfavorable clinical and biologic disease features. Hypomethylating agents have shown potential for treating medically unfit and elderly patients with AML. PATIENTS AND METHODS:We compared the outcomes of elderly patients with AML treated with decitabine and intensive chemotherapy (IC). RESULTS:The data from 107 patients with newly diagnosed AML aged ≥ 65 years were analyzed. The overall response rate was 38.6% and was significantly greater in the IC group than in the decitabine group (65.6% vs. 26.1%; P < .001). With a median follow-up duration of survivors of 14.8 months, the median overall survival (OS) and event-free survival were 12.3 months (95% confidence interval [CI], 10.0-14.7) and 2.0 months (95% CI, 2.0-2.0), respectively, which were not different between the 2 treatment groups. The FLT3-internal tandem duplication mutation (hazard ratio [HR], 2.637; 95% CI, 1.379-5.043; P = .003), complex karyotype (HR, 2.513; 95% CI, 1.258-5.020; P = .009), and peripheral blood blast percentage at diagnosis (HR, 1.983; 95% CI, 1.148-3.422; P = .014) were analyzed as independent prognostic factors for OS. A subgroup analysis for OS showed that IC was superior to decitabine for patients with the FLT3-internal tandem duplication mutation (P = .025) and poor risk cytogenetics, except for -7/del(7q) (P = .005), and decitabine was associated with longer OS for patients with -7/del(7q) (P = .077). CONCLUSION:Decitabine showed a similar OS to IC, despite the lower response rate in patients. The clinical outcomes of specific subgroups seemed to differ with different treatment options. Optimal therapeutic approaches for elderly patients with AML should be further examined.
Acute myeloid leukemia in the elderly (age 70 yr or older): long-term survivors.
Heiblig Maël,Elhamri Mohamed,Le Jeune Caroline,Laude Marie-Charlotte,Deloire Alexandre,Wattel Eric,Salles Gilles,Thomas Xavier
European journal of haematology
OBJECTIVE:Little data exist regarding long-term survival in elderly patients with acute myeloid leukemia (AML). METHODS:In view of the fact that most deaths occurred during the first 3 yr, this study examined long-term survival in this patient population, defined as overall survival for at least 3 yr with the aim to determine the number of long-term survivors and to identify factors that might impact on longer survival. RESULTS:The criterion for entry into this cohort was fulfilled by 57 patients among 302 seen over a 14-yr period (19%): 12 patients who never achieved complete remission (CR), 21 patients who relapsed after CR achievement, and 24 patients who achieved CR and did not relapse, including three patients who died while in CR and 21 patients still alive in first CR at the time of analysis. The pretreatment prognostic importance of cytogenetics was still apparent. However, some patients with secondary AML and/or unfavorable-risk markers belonged to long survivors. The cohort involved mainly patients treated by intensive chemotherapy, but also some patients receiving low-intensity therapies. CONCLUSION:Improved results should come from a better selection of patients to a more 'personalized' therapeutic approach combined with better supportive care assessment.
Treatment patterns and comparative effectiveness in elderly acute myeloid leukemia patients (age 70 years or older): the Lyon-university hospital experience.
Heiblig Maël,Le Jeune Caroline,Elhamri Mohamed,Balsat Marie,Tigaud Isabelle,Plesa Adriana,Barraco Fiorenza,Labussière Hélène,Ducastelle Sophie,Nicolini Franck,Wattel Eric,Salles Gilles,Thomas Xavier
Leukemia & lymphoma
The treatment of very elderly patients (≥70 years) with acute myeloid leukemia remains controversial. We present here 302 patients seen over a 14-year period in order to understand the real-world treatment patterns and outcomes in this patient population. Less than 25% of patients achieved a complete remission. The median overall survival was 12.4, 11.5 and 2.6 months, with a 3-year rates of 27%, 17% and 6%, for non-acute promyelocytic leukemia patients receiving intensive chemotherapy, lower-intensity therapy or best supportive care (BSC), respectively. In all ages, results were not significantly different among patients receiving low-intensity therapy and intensive chemotherapy, but significantly worse in those treated with BSC only. Similarly, intensive chemotherapy and low-intensity therapy gave better survival rates than BSC in patients with favorable- or intermediate-risk cytogenetics and in those with unfavorable cytogenetics (p < 0.0001 and p = 0.04, respectively).
Comparative analysis of azacitidine and intensive chemotherapy as front-line treatment of elderly patients with acute myeloid leukemia.
Maurillo Luca,Buccisano Francesco,Spagnoli Alessandra,Voso Maria Teresa,Fianchi Luana,Papayannidis Cristina,Gaidano Gian Luca,Breccia Massimo,Musto Pellegrino,De Bellis Eleonora,Del Principe Maria Ilaria,Lunghi Monia,Lessi Federica,Martinelli Giovanni,Venditti Adriano
Annals of hematology
The present observational study aimed to compare the efficacy of azacitidine (AZA) and intensive chemotherapy (IC) in elderly patients with untreated acute myeloid leukemia (AML), diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS), and disease-free survival (DFS). The AZA group included 89 patients; median age was 73 years (range 61-80) and median white blood cell count (WBCc) 2.5 × 10/L (range 0.27-83), 45% of the patients had BM blasts ≥ 30%, and 44 (49%) had a secondary AML (sAML). Karyotype was evaluable in 69 patients: 51 (74%) had intermediate-risk abnormalities and 18 (26%) an unfavorable risk karyotype. IC group consisted of 110 patients who received an induction course with mitoxantrone, cytarabine, and etoposide, followed by two consolidation cycles including idarubicin, cytarabine, and etoposide. Median age was 67 years (range 61-78) and median WBCc 8.0 × 10/L (range 0.69-258); 44 (40%) had a sAML. Karyotype was evaluable in 88 patients, 71 (81%) had intermediate risk, and 17 (19%) unfavorable risk karyotype. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 74 patient pairs. CR rate was significantly higher in IC vs AZA group (73 vs 25%, respectively) (p < 0.0001), but the 3-year OS rates and median OS were not significantly different (21.6 vs 11% and 15.8 vs 13 months, respectively). Our analysis suggests similar outcomes with AZA compared to IC. Controlled, randomized clinical trials are warranted to confirm this conclusion.
Venetoclax Synergistically Enhances the Anti-leukemic Activity of Vosaroxin Against Acute Myeloid Leukemia Cells Ex Vivo.
Liu Fangbing,Knight Tristan,Su Yongwei,Edwards Holly,Wang Guan,Wang Yue,Taub Jeffrey W,Lin Hai,Sun Liwei,Ge Yubin
BACKGROUND:The survival rate for acute myeloid leukemia remains unacceptably low, in large part owing to resistance to chemotherapy and high rates of relapse. There is an urgent need to develop new therapeutic modalities, in particular such that are tolerated by patients over the age of 60 years, who form the bulk of new acute myeloid leukemia diagnoses. Vosaroxin (SNS-595), a second-generation topoisomerase II inhibitor and DNA intercalating agent, shows promising preclinical and clinical activity against acute myeloid leukemia. Venetoclax (ABT-199), a selective Bcl-2 inhibitor, was recently approved for the treatment of acute myeloid leukemia. OBJECTIVE:The objective of this study was to determine the anti-leukemic activity and the underlying molecular mechanisms for the combination of venetoclax and vosaroxin in acute myeloid leukemia cell lines and primary patient samples ex vivo. PATIENTS AND METHODS:Using both acute myeloid leukemia cell lines and primary patient samples, annexin V/propidium iodide staining and flow cytometry analyses were used to quantify apoptosis induced by venetoclax or vosaroxin, alone or in combination, with subsequent western blotting analyses to assess levels of Bcl-2 family proteins. Alkaline comet assays were performed to quantify DNA damage induced by the two agents and to determine the effect of venetoclax on DNA repair. Finally, colony-forming assays were conducted on normal human CD34+ cord blood cells and primary acute myeloid leukemia patient samples to determine the effect of venetoclax and vosaroxin on normal hematopoietic and leukemic progenitor cells. RESULTS:We found that venetoclax and vosaroxin synergistically induced apoptosis in multiple acute myeloid leukemia cell lines. Although vosaroxin could partially abrogate the increase of Mcl-1 protein induced by venetoclax, it could not abrogate the increased binding of Bim to Mcl-1 induced by venetoclax. Cooperative induction of DNA damage occurred within 8 h of treatment with venetoclax plus vosaroxin. Moreover, repair of DNA damage induced by vosaroxin was significantly attenuated by venetoclax. The combination also synergistically induced apoptosis in primary acute myeloid leukemia patient samples and significantly reduced the colony formation capacity of acute myeloid leukemia progenitor cells, while sparing normal hematopoietic progenitor cells. CONCLUSIONS:Vosaroxin and venetoclax synergistically induce apoptosis in acute myeloid leukemia cells and cooperatively target acute myeloid leukemia progenitor cells while sparing normal hematopoietic progenitor cells. Our results support the clinical testing of vosaroxin in combination with venetoclax for treating patients with acute myeloid leukemia, especially in the elderly population.
Low-dose melphalan in elderly patients with relapsed or refractory acute myeloid leukemia: A well-tolerated and effective treatment after hypomethylating-agent failure.
Stratmann Jan,van Kann Elisabeth,Rummelt Christoph,Koschade Sebastian,Röllig Christoph,Lübbert Michael,Schaich Markus,Parmentier Stefani,Sebastian Martin,Chromik Joerg,Becker von Rose Aaron,Ballo Olivier,Steffen Björn,Serve Hubert,Brandts Christian,Shaid Shabnam
Relapsed or refractory (R/R) disease remains challenging in acute myeloid leukemia (AML), especially in elderly patients not considered eligible for intensive treatment options. We retrospectively evaluated the safety and efficacy of low-dose melphalan (LD-Mel) in a multicenter analysis in patients over 65 years with R/R AML, who previously had received ≥1 non-curative treatment line. The study included 31 patients (median age 77 years) with 1-4 previous treatment lines. Three patients (9.7%) achieved a complete remission. Two patients (6.5%) achieved a partial remission, nine patients (29.0%) had disease stabilization with reduction of peripheral or bone marrow blast burden, resulting in an overall response rate of 16.1% and 45.2% achieved clinical benefit. Responders showed a significantly longer median overall survival than non-responders (16.3 vs. 2.3 months, p < 0.001). Multivariate analysis identified complex karyotype as the only risk factor associated with inferior survival (p < 0.001), whereas prior treatment with hypomethylating agents (HMAs) in 25 of 31 patients was associated with superior OS, regardless of prior response to HMAs (p = 0.03). LD-Mel was well tolerated, with mild myelosuppressive side effects. Conclusively, LD-Mel is an effective treatment option in elderly patients with R/R AML, particularly after HMA therapy and in the absence of a complex karyotype.