Antibody-based therapy for acute myeloid leukemia: a review of phase 2 and 3 trials.

INTRODUCTION: Despite recent advances in the treatment of adult acute myeloid leukemia (AML), the clinical outcome of patients continues to be unsatisfactory especially among older patients, those with a high-risk profile, and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments. AREAS COVERED: The current paper reviews the clinical development of monoclonal antibody-based therapies in AML, their current status and phases 2 and 3 prospective trials. EXPERT OPINION: Monoclonal antibody-based therapies demonstrated efficacy and tolerability in several clinical trials, especially when used in combination either with '3 + 7' chemotherapy or with low-intensity treatments. Additional studies are needed to determine new antigens for antibody-based therapies that target leukemia stem cells and spare normal hematopoiesis. Phase 2 and 3 additional clinical trial data are needed to assess the promise of first trials, especially regarding chimeric antigen receptor T cells redirected against myeloid antigens and immune checkpoint inhibitor therapies.

Successful pregnancies in patients with BCR-ABL-positive leukemias treated with interferon-alpha therapy during the tyrosine kinase inhibitors era.

BACKGROUND: Management of pregnant patients with BCR-ABL-positive leukemia is challenging. Managing a patient who has been diagnosed while pregnant requires a different approach as compared to a patient who plans to become pregnant while on the treatment with tyrosine kinase inhibitor (TKI). Interferon (IFN)-alpha is a useful option in both situations due to teratogenic potential of TKIs. METHODS: We presented a series of 12 successful pregnancies in 11 women with BCR-ABL-positive leukemia, whose leukemia was managed with IFN-alpha throughout their pregnancy. RESULTS: All children have normal growth and development. All patients remained at least in hematological response and could start or resume TKI after delivery or breastfeeding. CONCLUSION: Because of the increased risk of teratogenicity and spontaneous abortion in female patient with pregnancy, when receiving TKI, IFN-alpha can be considered a safe drug to be administered throughout pregnancy and could represent the drug of choice in this situation during the era of TKI therapy.

Acute myeloid leukemia in the elderly (age 70 yr or older): long-term survivors.

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.

Transfusion dependency at diagnosis and transfusion intensity during initial chemotherapy are associated with poorer outcomes in adult acute myeloid leukemia.

Blood transfusions can modify host immunity and clinical outcomes in hematological malignancies. One thousand sixty-seven patients with acute myeloid leukemia (AML) were studied for their transfusion dependency at initial presentation and transfusion frequency during induction chemotherapy. Three hundred five patients (29 %) showed initial dependence to red blood cell (RBC) transfusion and 109 (10 %) to platelet transfusion. Transfusion dependency at presentation was associated with a poorer prognosis. Both initial RBC and platelet transfusion needs were associated with lower response rates (P = 0.04 and P = 0.03). Median overall survival (OS) was 10.8 months for patients with RBC need vs 18.8 months for the other patients (P = 0.02) and 6.8 months for patients with platelet transfusion need vs 13.6 months for the others (P = 0.01). Similarly, transfusion intensity during induction therapy influenced negatively treatment outcome. Median transfusion burden per week was 2.5 (range 0-25.7) RBC units and 1.6 (range 0-15.7) platelet concentrates (PCs). Both high RBC and PC transfusion intensities were associated with lower response rates (P = 0.003 and P < 0.0001). Median OS was 9.08 months for patients with RBC transfusions >3/week vs 18.29 months for those with RBC transfusions ≤3/week (P = 0.0003) and 10.75 months for patients with PC transfusions >2/week vs 19.96 months for those with PC ≤2/week (P = 0.0003). RBC and platelet transfusion intensities during induction therapy remained of prognostic value in multivariate analysis. Transfusion need at presentation and the frequency of transfusions during induction chemotherapy appear as strong prognostic factors.

Is There any Relationship Between the Repeated Complications of Sickle Cell Disease and the Potential Development of Acute Leukemia?

Sickle cell disease (SCD) is a severe monogenic hereditary hemoglobinopathy that is characterized by repeated clinical and biological manifestations able to generate stress erythopoiesis. A clonal hematopoiesis involving mainly variants of TP53, DNMT3A, ASXL1, and/or TET2 may be more prevalent in patients with SCD, suggesting that mutations in these genes may lead to an increased risk of leukemia. An increased prevalence of leukemia in patients with SCD has been confirmed by an increasing number of acute myeloid leukemia cases with myelodysplastic features reported in this patient population even in the absence of disease-modifying treatments. This leads to the hypothesis of a mechanism involving multifactorial causes through the pathophysiologic manifestations of SCD, in which cells are undergoing constant hematopoietic hyperplasia, inducing genomic damage and somatic mutations.

Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study.

To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high-dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association-9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1(+) or CEBPA(+) and FLT3-ITD(-) had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243.

Emerging pharmacotherapies for elderly acute myeloid leukemia patients.

INTRODUCTION: Acute myeloid leukemia (AML) is a disease mainly seen in the elderly, for which treatment is undergoing rapid changes. Although recent studies have supported the survival benefit of induction chemotherapy in fit patients and that of hypomethylating agents (HMAs) in non-induction candidates, treatment of this patient age population remains a significant challenge for the treating oncologist. AREAS COVERED: In this review, we will examine effectiveness and safety outcomes of upcoming novel treatment strategies in elderly (≥60 years old) patients with AML, highlight the current literature and ongoing trials able to maximize therapeutic options in this heterogeneous patient population. EXPERT OPINION: Current developments including new chemotherapeutic strategies and combinations of HMAs with novel drugs targeting epigenetic or immunomodulatory pathways are underway to improve patient survival and quality of life.

Lyon-University Hospital Experience with Gemtuzumab Ozogamicin Therapy in Acute Myeloid Leukemia: a 'Real-Life' Study.

Ninety-four adults with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML) were treated with fractionated doses of gemtuzumab ozogamicin (GO) at one-single French center over ten years. We attempted to define predictive factors for response and survival. The overall response rate was 70% (86% in newly diagnosed and 65% in relapsed/refractory AML). Mortality during induction was 6%. Disease-free survival (DFS) and overall survival at three years after GO treatment was 36% and 31%, respectively. Median DFS in relapsed/refractory patients was eight months with a 3-year DFS at 34%. Among remitters, allogeneic hematopoietic stem cell transplantation (HSCT) can be performed in 28 cases (42%), including two patients in first-line therapy and 26 in further line. In relapsed/refractory patients undergoing allogeneic HSCT after responding to GO therapy, the median DFS was not reached. Incidences of transplant-related mortality, grade ≥ 3 acute graft-versus-host (GvH) disease, and extensive chronic GvH disease were 11%, 14%, and 25%, respectively. No sinusoidal obstruction syndromes were reported among allografted patients as among the other patients in the studied cohort. GO-based chemotherapy is a viable option for the treatment of relapsed/refractory AML patients and is a feasible schedule as a bridge to allogeneic transplant.

Clofarabine for the treatment of adult acute myeloid leukemia.

Clofarabine, a next-generation deoxyadenosine analog, has demonstrated significant activity in patients with acute myeloid leukemia (AML). The single-agent activity compares favorably with that demonstrated by the current standard antileukemia agents. Clofarabine has been safely and effectively combined with other agents and will probably become an integral part of induction and/or consolidation regimens in AML. Current studies are underway to better define the role of clofarabine in younger and elderly patients with AML, and also explore development strategies for an oral formulation.

Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1.

INTRODUCTION: EVI1 (MECOM)-positive acute myeloid leukemia (AML) cells have shown in vitro sensitivity to all-trans-retinoic acid (ATRA) by inducing differentiation, cell death, and decreased leukemic engraftment. METHODS: In this pilot study, we investigated the response to ATRA in 13 high-risk AML patients with overexpression of EVI1. RESULTS: Seven of the 13 patients (53.8%) achieved complete remission (CR), and response can be combined with a decreased of the leukemia stem cell pool. CONCLUSION: These primary results tend to confirm in vitro results and suggest that addition of ATRA might be of benefit in the treatment of patients with EVI1-positive AML.

Elderly Patients (Age 70 Years or Older) With Secondary Acute Myeloid Leukemia or Acute Myeloid Leukemia Developed Concurrently to Another Malignant Disease.

INTRODUCTION: Secondary acute myeloid leukemia (sAML) remains a therapeutic challenge. In elderly patients with AML, it is unclear whether sAML displays an inferior outcome compared with de novo AML. PATIENTS AND METHODS: We studied AML with an antecedent of hematologic disease, treatment-related AML, or AML occurring concurrently to another malignancy in a single-center cohort of patients aged 70 and older with AML. The study included 169 patients who were compared with a cohort of patients with de novo AML, without any prior history of malignant disorders, seen during the same period of time. RESULTS: Hematologic antecedents or presence of prior/concurrent solid malignancy did not impact complete remission rates and overall survival. In multivariate analysis, sAML appeared without independent prognostic value in the elderly. CONCLUSION: Our results support that sAML and de novo AML in elderly patients are not prognostically distinct entities. They should therefore not be considered separately when investigating outcomes and new treatment strategies.

Trisomy 8 as sole anomaly or with other clonal aberrations in acute myeloid leukemia: impact on clinical presentation and outcome.

One hundred and fifty-four acute myeloid leukemia patients with trisomy 8 were studied for their clinical and biological characteristics, and treatment outcome. Forty-seven patients presented with trisomy 8 as the sole aberration, 107 with trisomy 8 associated with other cytogenetic abnormalities (13 with favorable, 54 with intermediate, and 40 with unfavorable risk cytogenetics). Overall complete remission (CR) proportion was 48%. Median disease-free survival (DFS) and overall survival (OS) were 7.8 and 8.3 months, respectively. In multivariate analysis, age >or=60 years (P<0.0001) and association with unfavorable karyotype (P=0.03) were of poor prognostic value for CR achievement. Age >or=60 years (P<0.0001) and antecedents of dysmyelopoiesis (P=0.02) were of poor prognostic value for OS. Patients with trisomy 8 alone did not show any difference in terms of outcome as compared with those in whom trisomy 8 was associated to intermediate risk cytogenetics (P=0.0002). Trisomy 8 in addition to favorable karyotype maintained a good clinical outcome, while trisomy 8 in addition to unfavorable cytogenetics showed the worst prognosis.

Treatment patterns and comparative effectiveness in elderly acute myeloid leukemia patients (age 70 years or older): the Lyon-university hospital experience.

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).

High frequency of CD34+CD38-/low immature leukemia cells is correlated with unfavorable prognosis in acute myeloid leukemia.

AIM: To evaluate the importance of the CD34+CD38- cell population when compared to the CD34+CD38+/low and CD34+CD38+/high leukemic cell sub-populations and to determine its correlations with leukemia characteristics and known prognostic factors, as well as with response to therapy and survival. METHODS: Two hundred bone marrow samples were obtained at diagnosis from 200 consecutive patients with newly diagnosed acute myeloid leukemia (AML) were studied between September 2008 and December 2010 at our Institution (Hematology Department, Lyon, France). The CD34/CD38 cell profile was analyzed by multiparameter flowcytometry approach using 8C panels and FACS CANTO and Diva software (BD Bioscience). RESULTS: We analyzed CD34 and CD38 expression in bone marrow samples of 200 AML patients at diagnosis, and investigated the prognostic value of the most immature CD34+CD38- population. Using a cut-off value of 1% of CD34+CD38- from total "bulk leukemic cells" we found that a high (> 1%) level of CD34+CD38- blasts at diagnosis was correlated with advanced age, adverse cytogenetics as well as with a lower rate of complete response after induction and shorter disease-free survival. In a multivariate analysis considering age, leukocytosis, the % of CD34+ blasts cells and the standardized cytogenetic and molecular risk subgroups, a percentage of CD34+CD38- leukemic cells > 1% was an independent predictor of DFS [HR = 2.8 (1.02-7.73), P = 0.04] and OS [HR = 2.65 (1.09-6.43), P = 0.03]. CONCLUSION: Taken together, these results show that a CD34/CD38 "backbone" for leukemic cell analysis by multicolour flowcytometry at diagnosis provides useful prognostic information.

Treatment with Low-Dose Cytarabine in Elderly Patients (Age 70 Years or Older) with Acute Myeloid Leukemia: A Single Institution Experience.

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.

Adoptive immunotherapy for acute leukemia: New insights in chimeric antigen receptors.

Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells (LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despite the introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors (CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term anti-tumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.

Effect of Initial Body Mass Index on Survival Outcome of Patients With Acute Leukemia: A Single-Center Retrospective Study.

BACKGROUND: Obesity is associated with an increased risk of mortality from cardiovascular causes and occurrence of malignancies. However, the effect of body mass index (BMI) on survival outcome remains controversial in acute leukemia (AL) patients. PATIENTS AND METHODS: A total of 531 adults with AL who entered clinical trials in our institution between 1994 and 2012 were analyzed retrospectively for the effect of BMI at diagnosis on outcome. The median follow-up was 4.7 years (95% confidence interval [CI], 4.0-5.1). RESULTS: BMI had no significant effect on complete response rate, disease-free survival (DFS), or overall survival (OS) in patients from the whole cohort when considering a cutoff value for BMI of 25, and when analyzed according to age, or initial cytogenetics. In T-acute lymphoblastic leukemia (T-ALL) patients with BMI > 25, median DFS was not reached with a 3-year DFS at 76%, and median DFS was 16.1 months with 3-year DFS at 13% for those with BMI ≤ 25 (P = .005). Median OS was not reached in T-ALL patients with BMI > 25 versus 28.3 months in those with BMI ≤ 25 (3-year OS: 78% vs. 41%; P = .04). Multivariate analyses confirmed the prognostic value of BMI (> 25 vs. < 25) in T-ALL, but only in terms of DFS (hazard ratio, 0.25; 95% CI, 0.05-0.87; P = .037). However, in a validation cohort of 211 T-ALL patients, these results were not confirmed. CONCLUSION: Results from the literature are very heterogeneous and contradictory regarding the effect of BMI on leukemia outcome. Even if nutritional status during chemotherapy courses is critical, these findings provide further evidence that initial body size does not have a major prognostic effect on survival in AL patients.

Effect of Age on Treatment Decision-Making in Elderly Patients With Acute Myeloid Leukemia.

BACKGROUND: Patients aged ≥ 70 years with acute myeloid leukemia (AML) have a poorer prognosis than those aged 60 to 69 years. PATIENTS AND METHODS: We retrospectively analyzed the cases of 183 patients aged ≥ 70 years with a performance status of ≤ 2 treated at our institution from 2000 to 2014. Treatment consisted of anthracycline- and cytarabine-based chemotherapy for 93 patients and lower intensity therapy with low-dose cytarabine or hypomethylating agent cycles for 90 patients. RESULTS: A total of 57 patients (61%) achieved complete remission in the intensive chemotherapy group versus only 11 (12%) in the lower intensity treatment group (P < .0001). The median overall survival (OS) was 14.5 months and 11.7 months with a 3-year OS rate of 34% and 18% (P = .005) for the intensive and lower intensity groups, respectively. The difference remained significant when considering patients aged ≤ 75 years, but not for patients aged > 75 years. Similarly, a significant difference was only observed when considering favorable and intermediate cytogenetic factors (P = .007) but not unfavorable karyotypes. On multivariate analysis, age did not appear as an independent prognostic factor. CONCLUSION: With intensive chemotherapy, the median OS significantly increased after the introduction of an improved supportive care policy compared with historical controls (14 vs. 5.4 months, with a 3-year OS rate of 33% vs. 8%). After 2006, a more "personalized" therapeutic approach tended to erase the difference in terms of OS, especially in patients aged > 75 years.

Higher percentage of CD34 + CD38- cells detected by multiparameter flow cytometry from leukapheresis products predicts unsustained complete remission in acute myeloid leukemia.

Relapse in acute myeloid leukemia (AML) after chemotherapy reflects the persistence of resistant leukemia stem cells (LSCs). These cells have been described in the CD34 + CD38- cell fraction. Leukapheresis products were harvested in 123 patients in morphological complete remission and analyzed by multiparameter flow cytometry. The CD34 + CD38- cell population showed a prognostic impact on survival. Median event-free survival (EFS) was 8.2 months (3-year EFS: 29%) for those with a higher percentage of CD34 + CD38- versus 91.9 months (3-year EFS: 62%) for those with a lower percentage for the entire cohort. These differences were confirmed in patients undergoing autologous stem cell transplant, with median EFS of 7.3 months versus 91.1 months (3-year EFS: 31% vs. 70%). Higher proportions of CD34 + CD38- cells were associated with adverse cytogenetics and with earlier relapses. Higher percentages of CD34 + CD38- cells in apheresis products reflect inadequate in vivo purging and reliably distinguish samples enriched in LSCs from those involving mainly normal cells.