Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome.

PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.     

Glasdegib with intensive/nonintensive chemotherapy in Japanese patients with untreated acute myeloid leukemia or high-risk myelodysplastic syndromes

Glasdegib is a potent, selective, oral inhibitor of the hedgehog signaling pathway. In this phase I study, previously untreated Japanese patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes were treated with glasdegib (100 mg once daily) combinations: low-dose cytarabine (20 mg twice daily; cohort 1, n = 6; expansion cohort, n = 15); daunorubicin and cytarabine (60 mg/m² i.v.; cohort 2, n = 6); or azacitidine (100 mg/m² i.v.; cohort 3, n = 6). Patients, except cohort 2, were ineligible for intensive chemotherapy. The primary end-point was dose-limiting toxicity in cohorts 1–3 and disease-modifying response in the expansion cohort. Disease-modifying response rate was tested with the null hypothesis of 6.8%, which was set based on the results from the phase II BRIGHT AML 1003 study (NCT01546038). No dose-limiting toxicities were observed in cohorts 1 or 3; one patient in cohort 2 experienced a dose-limiting toxicity of grade 3 erythroderma. The most common grade ≥3 treatment-related adverse events were neutropenia and thrombocytopenia (66.7% each) in cohort 1 and thrombocytopenia (60.0%) in the expansion cohort. In the expansion cohort, the disease-modifying response rate was 46.7% (90% confidence interval, 24.4–70.0; p < 0.0001), with all patients achieving either a complete response or complete response with incomplete blood count recovery. Median overall survival was 13.9 months. In this study, the primary disease-modifying response end-point with glasdegib plus low-dose cytarabine was met. The study confirms the safety and efficacy of glasdegib plus low-dose cytarabine in Japanese patients with AML ineligible for intensive chemotherapy.     

Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes

BACKGROUND: It is unclear whether intensive chemotherapy is beneficial to patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) if they are aged >/=60 years. METHODS: The authors studied 160 patients with a median age of 67 years who received intensive chemotherapy for MDS or AML with cytosine arabinoside and an anthracycline. RESULTS: At diagnosis, cytogenetic analysis was available in 146 patients. Karyotype was normal in 78 patients and abnormal in 68 patients. Of the abnormal karyotypes, 32 belonged to the high-risk category, ie, they involved either >/=3 chromosomes or chromosome 7. Complete remission (CR) was achieved by 94 patients (56%). CR rates were 70% among the patients who had a normal karyotype, 69% among the patients who had an abnormal (noncomplex) karyotype, but only 46% among the patients ho had a high-risk karyotype. The median survival was 9.5 months in the entire group, 18 months in patients with normal karyotype, 6 months in patients with abnormal, and 4 months in patients with a high-risk karyotype. A poor prognosis was attributable to low rates of CR and a high risk of early recurrence. CONCLUSIONS: According to the current data, elderly patients with AML or advanced MDS do not benefit from intensive chemotherapy if they show karyotype anomalies, especially those in the high-risk category.     

Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia,high-risk myelodysplastic syndrome,and myeloproliferative disorders

BACKGROUND: Imatinib mesylate is a selective tyrosine kinase inhibitor of c-abl, bcr/abl, c-kit, and platelet-derived growth factor-receptor (PDGF-R). c-kit is expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD). METHODS: The authors investigated the efficacy of imatinib in patients with these disorders. Forty-eight patients with AML (n = 10), MDS (n = 8), myelofibrosis (n = 18), atypical chronic myeloid leukemia (CML; n = 7), chronic myelomonocytic leukemia (CMML; n = 3), or polycythemia vera (n = 2) were treated with imatinib 400 mg daily. RESULTS: None of the patients with AML or MDS responded. Among patients with myelofibrosis, 10 of 14 patients with splenomegaly (71%) had a 30% or greater reduction in spleen size, 1 patient had trilineage hematologic improvement, 2 had erythroid hematologic improvement, and 1 had improvement in platelet count. One patient with atypical CML had erythroid hematologic improvement. Both patients with polycythemia vera needed fewer phlebotomies (from 2-3 per year to none during the 8 months of therapy and from 3-6 per year to 1 during 9 months of therapy). None of the three patients with CMML responded. Treatment was well tolerated. The side effects were similar to those observed in patients with CML. CONCLUSIONS: Within these small subgroups of disease types, single-agent imatinib did not achieve a significant clinical response among patients with AML, MDS, atypical CML, or CMML without PDGF-R fusion genes. Preliminary data on polycythemia vera are promising and deserve further investigation. Responses among myelofibrosis patients were minor. Therefore, a combination treatment regimen including imatinib may be more effective.     

Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome

BACKGROUND:

Secondary acute myeloid leukemia (AML) from an antecedent myelodysplastic syndrome (MDS)/myeloproliferative neoplasm is associated with a poor prognosis. The authors evaluated predictive factors in patients with secondary AML treated with anthracycline‐based induction therapy.

METHODS:

This was a retrospective review of secondary AML patients treated with induction therapy. Age, International Prognostic Scoring System, Eastern Cooperative Oncology Group performance status, cytogenetics, duration of MDS/myeloproliferative neoplasm, and prior MDS/myeloproliferative neoplasm treatment were evaluated for their impact on complete response (CR), CR with low platelets, and overall survival (OS).

RESULTS:

The authors evaluated 61 secondary AML patients who received induction chemotherapy; 59% (36 patients) achieved CR/CR with low platelets (95% confidence interval [CI], 46%‐71%), and median OS was 6.5 (95% CI, 3.9‐8.1) months. Three factors were associated with lower CR/CR with low platelets and OS: poor risk cytogenetics, prior treatment with hypomethylating agents or lenalidomide, and longer time to transformation to AML. Of those treated with hypomethylating agents or lenalidomide, 32% achieved CR/CR with low platelets versus 78% in the group not treated with a hypomethylating agent or lenalidomide (odds ratio [OR], 0.13; 95% CI, 0.04‐0.42). Median OS for those treated with a hypomethylating agent or lenalidomide was 3.7 versus 10.5 months for those not treated with a hypomethylating agent or lenalidomide (P < .0001). The CR/CR with low platelets rate for those with intermediate risk cytogenetics was 70% versus 35% for those with poor risk (OR, 4.33; 95% CI, 1.38‐13.6). Those with poor risk cytogenetics had a median OS of 2.8 versus 7.5 months for those with intermediate risk (P = .01).

CONCLUSIONS:

Prior treatment with hypomethylating agents or lenalidomide, poor risk cytogenetics, and longer time to transformation to AML are independent negative predictive factors for response and OS in patients with secondary AML after induction therapy. Cancer 2011. © 2010 American Cancer Society.     

Prognostic relevance of achieving cytogenetic remission in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome following induction chemotherapy

Cytogenetic findings at diagnosis have influence on prognosis in patients with acute myelogenous leukaemia (AML) or MDS who undergo induction chemotherapy. Assessment of remission and treatment decisions are based on cytological findings. We analyzed the prognostic impact of cytogenetic remission status in 118 patients with abnormal karyotype who received induction chemotherapy. Initial cytogenetics were: 28 good-risk (14× t(15;17), 9× t(8;21), 5× inv(16)), 44 intermediate-risk, and 46 high-risk karyotypes. Eighty-three patients achieved complete remission (CR) and 20 achieved partial remission. Twenty-six of the patients who reached cytological CR retained an abnormal karyotype after induction, 13 of whom had been classified as standard-risk and therefore did not receive intensified consolidation. Sixty-one patients achieved cytogenetic CR (CCR), including 24 out of 28 (86%) patients with low-risk cytogenetics. The CCR rate was lower in patients with intermediate-risk (48%) or poor-risk cytogenetics (28%). Median survival (excluding patients with AML M3) of the CCR group was 37 months, as compared to 11 months in patients with persistence of abnormal karyotype (p < 0.0001). This difference remained statistically significant when calculated only for patients with intermediate-risk karyotypes (p = 0.03).Cytogenetic analysis after induction chemotherapy provides meaningful information especially in patients with intermediate-risk karyotypes. Patients with a persisting abnormal karyotype must be regarded as high-risk patients who should receive intensified treatment.     

Treatment outcome in older patients with childhood acute myeloid leukemia

BACKGROUND.

Older age has historically been an adverse prognostic factor in pediatric acute myeloid leukemia (AML). To the authors' knowledge, the impact of age relative to that of other prognostic factors on the outcome of patients treated in recent trials is unknown.

METHODS.

Clinical outcome and causes of treatment failure of 351 patients enrolled on 3 consecutive protocols for childhood AML between 1991 and 2008 were analyzed according to age and protocol.

RESULTS.

The more recent protocol (AML02) produced improved outcomes for patients aged 10 years to 21 years compared with 2 earlier studies (AML91 and AML97), with 3‐year rates of event‐free survival (EFS), overall survival (OS), and cumulative incidence of refractory leukemia or recurrence (CIR) for this group being similar to those of patients aged birth to 9 years: EFS: 58.3% ± 5.4% versus 66.6% ± 4.9% (P = .20); OS: 68.9% ± 5.1% versus 75.1% ± 4.5% (P = .36); and CIR: 21.9% ± 4.4% versus 25.3% ± 4.2% (P = .59). The EFS and OS estimates for patients aged 10 to 15 years overlapped those for patients aged 16 to 21 years. However, the cumulative incidence of toxic death was significantly higher for patients aged 10 to 21 years compared with younger patients (13.2% ± 3.6% vs 4.5% ± 2.0%; P = .028).

CONCLUSIONS.

The survival rate for older children with AML has improved on the results of a recent trial and is now similar to that of younger patients. However, deaths from toxicity remain a significant problem for patients in the older age group. Future trials should focus on improving supportive care while striving to develop more effective antileukemic therapy. Cancer 2012. © 2012 American Cancer Society.     

Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome.

Older patients with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (aMDS) must decide between receiving intensive induction chemotherapy (IC) or nonintensive chemotherapy/best supportive care (NIC). Little information exists about what factors influence treatment decisions and what quality of life (QOL) is associated with treatment choices. We prospectively examined 43 patients 60 years or older who were interviewed at diagnosis and periodically over 1 year. IC choice was associated with younger age (66 vs 76 years, P=0.01) and AML diagnosis, but not with performance status, comorbidities, or QOL. In total, 63% of all patients reported not being offered other treatment options despite physician documentation of alternatives. Patient and physician estimates of cure differed significantly: 74% of patients estimated their chance of cure to be 50% or greater, yet for 89% of patients physician estimates of cure were 10% or less. IC patients experienced decreased QOL at 2 weeks, but rebounded to baseline and to NIC levels by 6 weeks. Initial QOL is not associated with treatment choice in older AML and aMDS patients. Regardless of treatment choice, patients report not being offered treatment options and overestimate their chances of cure. In IC patients, QOL decreases during hospitalization but rebounds after discharge.     

A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment

BACKGROUND: The survival of older patients with acute myeloid leukemia has not improved. Few clinical trials have been available for older patients who are not considered fit for an intensive chemotherapy approach. METHODS: Between December 1998 and November 2003, as part of National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients, who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (Ara-C) (20 mg twice daily for 10 days) or hydroxyurea with or without all-trans retinoic acid (ATRA). RESULTS: Low-dose ara-C produced a better remission rate (18% vs 1%; odds ratio [OR], 0.15; 95% confidence interval [95% CI], 0.06-0.37; P = .00006) and better overall survival (OR, 0.60; 95% CI, 0.44-0.81; P = .0009), which was accounted for by the achievement of complete remission (CR) (duration of CR: 80 weeks vs 10 weeks for patients with no CR). Patients who had adverse cytogenetics did not benefit. ATRA had no effect. Toxicity scores or supportive care requirements did not differ between the treatment arms. CONCLUSIONS: Older, less fit patients have a poor outcome, and few trials have been conducted in this patient group. Low-dose ara-C treatment was superior to best supportive care and hydroxyurea because it had greater success in achieving CR, and it could represent standard care against which new treatments may be compared in this patient group.     

Advance care planning in older patients with acute myeloid leukemia and myelodysplastic syndromes

IntroductionOlder patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) have worse survival rates compared to younger patients, and experience more intense inpatient healthcare at the end of life (EOL) compared to patients with solid tumors. Advance care planning (ACP) has been shown to limit aggressive and burdensome care at EOL for patients with AML and MDS. The purpose of this study was to better understand ACP from the perspective of clinicians, older patients with AML and MDS, and their caregivers.Materials and MethodsWe conducted semi-structured interviews with 45 study participants. Interviews were audio-recorded and transcribed. Open coding and focused content analysis were used to organize data and develop and contextualize categories and subcategories.ResultsGuided by our specific aims, we developed four themes: (1) The language of ACP and medical order for life-sustaining treatment (MOLST) does not resonate with patients, (2) There is no uniform consensus on when ACP is currently happening, (3) Oncology clinician-perceived barriers to ACP (e.g., patient discomfort, patient lack of knowledge, and lack of time), and (4) Patients felt that they are balancing fear and hope when navigating their AML or MDS diagnosis.DiscussionThe results of this study can be used to develop interventions to promote serious illness conversations for patients with AML and MDS and their caregivers to ensure that patient care aligns with patient values.     

White blood cell count nadir following remission induction chemotherapy is predictive of outcome in older adults with acute myeloid leukemia

Kinetics of white blood cell (WBC) elimination following induction chemotherapy for older adults with acute myeloid leukemia (AML) may serve as a surrogate for its effectiveness and safety by enabling real-time prognostication. We reviewed 122 older adults with AML treated at the Cleveland Clinic. Recursive partitioning analysis was used to identify optimal cut points in nadir WBC count and time to WBC nadir that correlate with survival. Multivariable analysis identified time to WBC nadir less than or equal to 10 days (HR 2.15, 95%CI 1.12 - 4.12, p = 0.02), low WBC nadir (less than 0.04×10⁹/l, HR 2.68, 95%CI 1.15 - 6.23, p = 0.02) and high WBC nadir (greater than 0.12×10⁹/l HR 1.5, 95%CI 0.96 - 2.37, p = 0.08), as predictors of worse outcomes. Time to WBC nadir predicts survival. The absolute WBC nadir value follows a J-curve, with lower value indicating a worse outcome.     

Results of a multicenter phase II trial for older patients with c-Kit-positive acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) using low-dose Ara-C and Imatinib

BACKGROUND: Imatinib (IM) is a potent tyrosine kinase inhibitor of c-Kit. c-Kit is expressed in the majority of patients with acute myeloid leukemia (AML). Whereas clinical trials evaluating monotherapy with IM in AML revealed low response rates, Ara-C and IM showed synergistic effects in vitro. This suggested evaluation of a combination treatment. METHODS: Low-dose Ara-C (LDAC) combined with IM was tested to determine the efficacy and safety of this regimen. Forty patients from 4 centers with c-Kit-positive AML (n = 34) and high-risk myelodysplastic syndrome (HR-MDS) (n = 6) with a median age of 73 years were enrolled. They were either not eligible for myelosuppressive therapy and/or had recurring/refractory disease. RESULTS: Thirty-eight patients were evaluable for analysis. In 6 of 38 patients a blast response was observed. Eight of 38 patients showed stable disease for more than 2 months. The objective hematologic response rate was low (11%), with 2 patients showing hematologic improvement and 1 each with a partial response (PR) or complete response (CR). Median overall survival was 138 days, with 20% of patients alive after an observation period of 600 days. Study medication was applied in an ambulatory setting with minimal hospitalization time, an early mortality rate of only 18.9%, and a low toxicity rate. CONCLUSIONS: LDAC plus IM does not appear to be inferior in older AML patients incomparison with historic controls receiving myelosuppressive therapy. However, this trial also shows that LDAC/IM does not appear to be more effective than LDAC monotherapy in a patient population not selected for appropriate molecular markers.     

The prognostic significance of cytokine levels in newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndromes

BACKGROUND.

Tumor necrosis factor (TNF)‐α and other cytokines are involved in the pathogenesis of acute myeloid leukemia (AML) and high‐risk myelodysplastic syndromes (MDS), but their prognostic significance in these diseases is unknown. In the current study, the authors assessed the association between serum levels of various cytokines and clinical outcomes in patients with untreated AML or high‐risk MDS.

METHODS.

Serum levels of TNF‐α, interleukin (IL)‐1 receptor antagonist, IL‐6, IL‐10, and endostatin were measured in patients with AML or high‐risk MDS who presented for treatment at The University of Texas M. D. Anderson Cancer Center from September 1994 through January 2001. Univariate and multivariate analyses were performed to test for correlations with clinical outcomes.

RESULTS.

Higher TNF‐α levels were found to correlate with poorer performance status; higher leukocyte counts; higher levels of β₂‐microglobulin, creatinine, uric acid, and alkaline phosphatase; lower levels of creatinine clearance and albumin; baseline infection; and M4‐M5 AML subtypes. TNF‐α levels <10 pg/mL were associated with higher rates of complete remission (P = .003), survival (P = .0003), and event‐free survival (EFS) (P = .0009). However, on multivariate analyses, TNF‐α level ≥10 pg/mL was not found to be an independent factor predicting clinical outcomes, but became statistically significant when leukocyte count was excluded from the models. The other cytokines were not found to be predictive of clinical outcomes.

CONCLUSIONS.

High serum TNF‐α level is an adverse prognostic factor for survival and EFS in patients with untreated AML or high‐risk MDS. Cancer 2008. © 2008 American Cancer Society.     

Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid

BACKGROUND: The authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all-trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). METHODS: Twenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45-100 microg/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for > or = 2 months were considered evaluable. RESULTS: Hematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63-550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone. CONCLUSIONS: Differentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life.     

NF-kappaB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia

CD34(+) bone marrow blasts from high-risk myelodysplastic syndrome (MDS) patients as well as MDS patient-derived cell lines (P39 and MOLM13) constitutively activate the nuclear factor-kappaB (NF-kappaB) pathway and undergo apoptosis when NF-kappaB is inhibited. Here, we show that the combination of conventional chemotherapeutic agents (daunorubicin, mitoxantrone, 5-azacytidine or camptothecin) with the NF-kappaB inhibitor BAY11-7082 did not yield a synergistic cytotoxicity. In contrast, BAY11-7082 (which targets the NF-kappaB-activating I-kappaB kinase (IKK) complex) or knockdown of essential components of the NF-kappaB system (such as the IKK1 and IKK2 subunits of the IKK complex and the p65 subunit of NF-kappaB), by small interfering RNAs sensitized MDS cell lines to starvation-induced apoptosis. The combination of BAY11-7082 and nutrient depletion synergistically killed the acute myeloid leukemia (AML) cell line U937 as well as primary CD34(+) bone marrow blasts from AML and high-risk MDS patients. The synergistic killing by BAY11-7082, combined with nutrient depletion, led to cell death accompanied by all hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential, the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria, activation of caspase-3, phosphatidylserine exposure on the plasma membrane surface and nuclear chromatin condensation. Transmission electron microscopy revealed the presence of numerous autophagic vacuoles in the cytoplasm before cells underwent nuclear apoptosis. Nonetheless, cell death was neither inhibited by the pan-caspase inhibitor z-VAD-fmk nor by knockdown of AIF or of essential components of the autophagy pathway (ATG5, ATG6/Beclin-1, ATG10, ATG12). In contrast, external supply of glucose, insulin or insulin-like growth factor-I could retard the cell death induced by BAY11-7082 combined with starvation. These results suggest that in MDS cells, NF-kappaB inhibition can precipitate a bioenergetic crisis that leads to an autophagic stress response followed by apoptotic cell death.