Philadelphia chromosome-positive (Ph+) AML is a controversial diagnosis,
as others propose it represents CML in blast phase (CML-BP).
NPM1 mutations occur in 25-35% of AML but are absent in CML
patients. Conversely, ABL1 mutations occur in 25% of
Imatinib-naïve CML-BP but are not described in AML patients. We analyzed
for NPM1 and ABL1 mutations in 9 Ph+ AML and 5
CML-BP patients initially presented in BP. In 6 Ph+ AML cases, we screened for a
panel of gene mutations using Sequenome®-based methods including
AKT1, AKT2, AKT3, BRAF,
EGFR, GNAQ, GNAS,
IDH1, IDH2, KRAS,
MET, NRAS, PIK3CA, and
RET. Two of 9 (22%) Ph+ AML patients had
NPM1 mutations and were alive 36 and 71 months after
diagnosis. All Ph+ AML were negative for ABL1 and other gene
mutations. One (20%) CML-BP patients had ABL1 mutation; no
patients had NPM1 mutations. These data suggest that Ph+ AML is
distinct from CML-BP.
acute myeloid leukemia; BCR-ABL1; blast phase; chronic myelogenous leukemia; NPM1; Philadelphia chromosome
This report describes the final results of a Phase II clinical trial investigating the efficacy of rabbit antithymocyte globulin (rATG), ciclosporin, steroids, and granulocyte colony-stimulating factor (GCSF) in patients with untreated aplastic anaemia (AA), or low to intermediate-risk and hypocellular myelodysplastic syndrome (MDS). We treated 24 patients each with AA and MDS with rATG (3.5 mg/kg/day × 5; reduced to 2.5 mg/kg/d × 5 in patients with MDS ≥55 years), ciclosporin (5 mg/kg orally daily × 6 months), steroids (1 mg/kg daily, tapered off over 1 month), and GCSF. The overall response rate in AA patients was 64% compared to 25% in MDS patients. The median time to response was 3 months in AA patients and 4 months in MDS patients. Pretreatment clinical characteristics, such as age, sex, blood counts, cellularity, cytogenetics, or HLA-DR15 status, did not predict for response. Response to therapy, however, predicted for improved overall survival (OS), with a 3-year OS of 89% vs. 43% in responders vs. non-responders, respectively (P<0.001). Infusion reactions occurred in about half the patients and were manageable. Myelosuppression, elevation in liver enzymes, and infections were common. The early mortality in MDS patients was 13% vs. 0% in AA patients with.
thymoglobulin; immunotherapy; hypoplastic
We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P =0.01) and 17 vs. 62 months (P =0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR=1.40; P = 0.03) or death (HR=1.45; P = 0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR= 5.26; P<0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS.
Anemia is an expected consequence of intensive chemotherapy regimens administered to acute leukemia patients. This study was designed to determine if epoetin alfa would decrease the number of transfusion events and units of packed red blood cells (PRBCs) transfused, and secondarily, to study its effects on quality of life (QOL) and complete remission (CR) rates.
Patients and Methods
Patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), or Burkitt’s lymphoma (BL) receiving frontline myelosuppressive chemotherapy were randomized to receive epoetin alfa or no epoetin during the first 6 cycles of their planned chemotherapy. QOL was assessed by Edmonton Symptom Assessment Scale (ESAS) and FACT-Anemia questionnaires.
Fifty five patients were randomized to epoetin alfa and 54 to no epoetin. Transfusion data was available in 79 of the 81 (98%) evaluable patients who completed the treatment/observation period. The trial was stopped early due to poor accrual before the target of 123 evaluable patients was met. A mean of 10.6 units of PRBCs over 5 months were administered to those receiving epoetin alfa compared to 13 units for those who did not (p=0.04). There was no significant difference in QOL as assessed by FACT-Anemia or ESAS. The CR rate and 3-year CR duration were not adversely affected by use of epoetin alfa.
Epoetin alfa decreases the number of PRBC transfusions and does not appear to negatively impact remission duration. No difference in QOL was observed.
Anemia; epoetin; leukemia
Compared with younger patients, older adults with acute myeloid leukemia (AML) generally have poorer survival outcomes and less benefit from clinical trials. A recent phase 3 trial demonstrated a trend toward improved overall survival (OS) with decitabine, a hypomethylating agent, compared with treatment choice of either cytarabine or supportive care (7.7 months, 95% CI: 6.2–9.2 vs 5.0 months, 95% CI: 4.3–6.3, respectively) in older adults with newly diagnosed AML. The current analyses investigated prognostic factors for outcomes in this trial and examined OS and responses in prespecified subgroups.
A multivariate Cox proportional hazards model was used to investigate effects of demographic and baseline characteristics, including age, sex, cytogenetic risk, AML type, ECOG Performance Status, geographic region, bone marrow blasts, platelets, and white blood cells on OS, based on mature data. Similar analyses were conducted with a logistic regression model to predict response rates. Prespecified subgroup analyses were performed for OS and response rates, also using mature data.
Patient characteristics that appeared to negatively influence OS included more advanced age (hazard ratio [HR] 1.560 for ≥75 vs <70 years; p = 0.0010), poorer performance status at baseline (HR 0.771 for 0 or 1 vs 2; p = 0.0321), poor cytogenetics (HR 0.699 for intermediate vs poor; p = 0.0010), higher bone marrow blast counts (HR 1.355 for >50% vs ≤50%; p = 0.0045), low baseline platelet counts (HR 0.775 for each additional 100 × 109/L; p = 0.0015), and high white blood cell counts (HR 1.256 for each additional 25 × 109/L; p = 0.0151). Regarding geographic regions, patients from Western Europe had the longest median OS. Response rates favored decitabine for all subgroups investigated, including patients ≥75 years (odds ratio 5.94, p = 0.0006).
Response to decitabine in AML is associated with known prognostic factors related to both patient demographics and disease characteristics.
ClinicalTrials.gov identifier NCT00260832
Decitabine; Acute Myelocytic Leukemia; Elderly; Treatment
While most patients with myelodysplastic syndrome (MDS) exhibit bone marrow hypercellularity, a subset of them presents with a hypocellular bone marrow. Specific factors associated with poor prognosis have not been investigated in patients with hypocellular MDS. We studied a cohort of 253 patients with hypocellular MDS diagnosed at MD Anderson Cancer Center between 1993 and 2007 and a cohort of 1725 patients with hyper/normocelluar MDS diagnosed during the same time period. Patients with hypocellular MDS presented more frequently with thrombocytopenia (p<0.019), neutropenia (p<0.001), low serum β-2 microglobulin (p<0.001), increased transfusion dependency (p<0.001), and intermediate-2/high risk disease (57% vs. 42%, p=0.02) compared to patients with hyper/normocellular MDS. However, no difference in overall survival was observed between the two groups (p=0.28). Multivariate analysis identified poor performance status (ECOG ≥2), low hemoglobin (<10 g/dl), unfavorable cytogenetics (−7/7q or complex), increased bone marrow blasts (≥5%) and high serum LDH (>600 IU/l) as adverse independent factors for survival. A new prognostic model based on these factors was built that segregated patients into three distinct risk categories independent of IPSS score. Such model is independent from IPSS, further refines IPSS-based prognostication, and may be used to develop of risk-adapted therapeutic approaches for patients with hypocellular MDS.
Hypocellular; myelodysplastic syndrome (MDS); prognostic score; IPSS
We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches.
acute myeloid leukemia; bone marrow microenvironment; hypoxia; GDC-0941; sorafenib
A cross-sectional survey of board certified hematologists/oncologists was conducted to describe current chronic myeloid leukemia (CML) practice patterns and compare these self-reported practices with the clinical guidelines. Overall, the reported practice patterns regarding CML treatment were in accordance with guidelines; however, decisions also appear to be based on the attitudes, beliefs, and personal experience of the responding physicians.
A previous survey of physician self-reported practice patterns in the management of CML was conducted in 2005. The National Comprehensive Cancer Network and European LeukemiaNet guidelines now include nilotinib and dasatinib in their treatment algorithms for CML. To assess these new guidelines, a cross-sectional survey of US hematologists and/or oncologists was conducted in December 2010 through an online survey.
Materials and Methods
The survey had 43 questions consisting of items updated from the 2005 survey to reflect changes in clinical practice, tyrosine kinase inhibitor therapy, and current guidelines.
Analysis of the responses from 507 board certified medical oncologists/hematologists suggests that the use of imatinib 400 mg as an initial treatment option had decreased from 62% in 2005 to 52% in the 2010 survey. Currently, nearly 40% of physicians would choose either nilotinib or dasatinib as first-line treatment. From the surveyed physicians, achievement of at least a major molecular response (MMR) is the predominant treatment goal in chronic phase CML.
This survey emphasizes the need for continued updates and education regarding optimal therapy, monitoring practices, and therapeutic end points in CML.
CML; Guidelines; Practice patterns; Survey; Tyrosine kinase inhibitors
Standard therapy for older patients with AML has a poor outcome. We have designed a combination of clofarabine plus low-dose cytarabine followed by a prolonged consolidation alternating with decitabine.
Sixty patients with a median age of 70 years (range 60-81) with newly diagnosed AML were included. They received clofarabine 20mg/m2 intravenously daily × 5 days plus cytarabine 20mg subcutaneously twice daily × 10 days. Responding patients continued for up to 17 courses of consolidation therapy including decitabine.
Forty of 59 evaluable patients responded (66%). Complete remission rate was 58%. Median relapse-free survival (RFS) was 14.1 (95% CI: 6.9-not estimable) and median overall survival (OS) 12.7 months (95% CI: 8.8-not estimable). Median OS of responding patients (CR/CRp) was 24.2 months (95% CI: 17-not estimable). Compared to a historical group of patients who received clofarabine plus low-dose cytarabine with a shorter consolidation, RFS was not statistically different. Induction mortality was low (7% at 8 weeks) and toxicities manageable.
Clofarabine plus low-dose cytarabine alternating with decitabine in consolidation is active in older patients with newly diagnosed AML. The benefits of a prolonged consolidation remain unproven.
acute myeloid leukemia; clofarabine; decitabine; cytarabine; induction therapy
Splenectomy may be an effective therapeutic option for treating massive splenomegaly in patients with myeloproliferative neoplasms (MPNs). There is still limited data on its short- and long-term benefits and risks.
Efficacy and short-term complications were analyzed in 94 patients with different MPNs who underwent splenectomy at MD Anderson. The long-term impact of splenectomy on overall survival (OS) and transformation free survival (TFS) was evaluated in 461 patients with myelofibrosis (MF) seen at MD Anderson including 50 who underwent splenectomy during disease evolution.
Splenectomy improved anemia and thrombocytopenia in 47% and 66% of patients, respectively. Most common complications were leukocytosis (76%), thrombocytosis (43%), and venous thromboembolism (16%). Post-operative mortality was 5%. Among patients with MF, splenectomy during disease evolution was associated with decreased OS (Hazard Ratio [HR] =2.17, p<0.0001) and TFS (HR=2.17, p<0.0001). This effect was independent of the Dynamic International Prognostic Scoring System.
Splenectomy is a possible therapeutic option for patients with MF and other MPNs, and its greatest benefits are related to improvement in spleen pain and discomfort, anemia and thrombocytopenia. However, in patients with MF it appears to be associated with increased mortality.
Myelofibrosis; Myeloproliferative Neoplasms; Splenectomy; Survival; Acute Myeloid Leukemia
Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.
Patients and methods
COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 109/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100–200 × 109/L and >200 × 109/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).
The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8–12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.
This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.
COMFORT-I; dose titration; JAK2 inhibitor; myelofibrosis; ruxolitinib; treatment-related cytopenias
We evaluated the efficacy and safety of the combination of twice-daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). One hundred seven patients were enrolled. Overall, 27 (26%) patients responded with a complete remission (CR) rate of 21% and CR without platelet recovery (CRp) of 5%. The overall 4-week mortality rate was 9%. In conclusion, BIDFA is active and safe in heavily pretreated patients with myeloid malignancies.
The purpose of this study was to evaluate the efficacy and safety of the combination of twice-daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP).
Patients and Methods
One hundred seven patients with refractory/relapsed AML, intermediate and high-risk MDS, and CML-BP, with a performance status of 3 or less and normal organ function were treated. Patients received fludarabine 15 mg/m2 intravenously (IV) every 12 hours on days 1 to 5 and cytarabine 0.5 g/m2 IV over 2 hours every 12 hours on days 1 to 5. Gemtuzumab ozogamicin (GO) was administered at 3 mg/m2 IV on day 1 in the first 59 patients. Patients with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors.
Overall, 27 (26%) patients responded with a complete remission (CR) rate of 21% and CR without platelet recovery of 5%. The overall 4-week mortality rate was 9%. The CR rates for patients with relapsed AML with first CR duration greater than or equal to 12 months, relapsed AML with first CR duration less than 12 months, and refractory/relapsed AML beyond first salvage were 56%, 26%, and 11%, respectively. With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission CR duration rates were 18%, 35%, and 70%, respectively.
BIDFA is active with an overall response rate of 26% in a heavily pretreated population. This combination is safe with a low 4-week mortality rate of 9%.
Acute myeloid leukemia; Efficacy; Refractory; Safety
We analyzed 133 patients with polycythemia vera (PV) that were followed at our institution (median 7.5 years) and had adequate cytogenetic information. The 5-, 10-, and 15-year survival rates were 93%, 79%, and 64%, respectively, with the median projected overall survival of 24 years. Nineteen patients (14%) had abnormal cytogenetics at any time during the disease course (no survival difference). Sixteen patients (12%) transformed during follow up, after a median of 8.5 years, to myelofibrosis (11), acute myeloid leukemia (4), or myelodysplastic syndrome (1); 8 had cytogenetic abnormalities. Among 133 patients, 39 were newly diagnosed: 33 with normal and 6 with abnormal cytogenetics (no survival difference); 9 transformed (6 with normal and 3 with abnormal cytogenetics at diagnosis). In keeping with other smaller series, the presence of chromosomal abnormalities may have a role in the transformation of patients with PV; survival was not affected likely due to short follow up.
polycythemia vera; cytogenetic abnormality; survival; transformation
Little information exists regarding the prevalence and natural history of pericardial disease in patients with leukemia. Recently, it has been reported that the use of histone deacytelase inhibitors (HDACi) is associated with an increased incidence of pericardial effusions (PEfs). To study the characteristics and treatment relationships of PEfs in patients with leukemia, we retrospectively analyzed a cohort of patients with leukemia evaluated at a single center.
We reviewed 2592 patients with acute myeloid leukemia (AML, N= 1282, 49%), acute lymphocytic leukemia (ALL, N= 336, 13%), or myelodysplastic syndrome (MDS, N=974, 38%), who were evaluated from 8/2003 to 7/2008. Electronic medical records were reviewed to select patients that had underwent at least one echocardiographic evaluation. Data regarding diagnosis, timing, effusion size, survival, and prior therapy was collected in the patients that had echocardiographic evidence of PEfs.
PEfs were detected in 325 (20%) of the patients who had echocardiograms: 21% in AML, 23% in ALL, and 18% in MDS patients. Only a small portion of PEfs were detected prior to the initiation of therapy: 26% in AML, 25% ALL, and 15% in MDS. Most PEfs were of minimal size (70%) overall. No significant differences in effusion characteristics, including severity, were observed among different types of therapies. The presence of PEfs had no impact on the survival of patients evaluated.
PEfs are relatively common in patients with leukemia and do not appear to be related to specific types of therapy or to survival.
leukemia; pericardial effusions; histone deacetylase inhibitors
The term epigenetics refers to the study of a number of biochemical modifications of chromatin that have an impact on gene expression regulation. Aberrant epigenetic lesions, in particular DNA methylation of promoter associated CpG islands, are common in acute lymphocytic leukemia (ALL). Recent data from multiple laboratories indicates that several hundred genes, involving dozens of critical molecular pathways, are epigenetically suppressed in ALL. Because these lesions are potentially reversible, the reactivation of these pathways using, for instance, hypomethylating agents may have therapeutic potential in this disease. Furthermore, the analysis of epigenetic alterations in ALL may allow: 1) the identification of subsets of patients with poor prognosis when treated with conventional therapy; 2) development of new techniques to evaluate minimal residual disease; 3) better understanding of the differences between pediatric and adult ALL; and 4) new therapeutic interventions by incorporating agents with hypomethylating activity to conventional chemotherapeutic programs. In this review, we desribe the role of epigenetic alterations in ALL from a translational perspective.
Acute lymphocytic leukemia; DNA methylation; epigenetics
Activating mutations in RAS are frequently present in patients with AML, but their overall prognostic impact is not clear.
A retrospective analysis was done to establish the clinical characteristics of patients with RASmut AML, to analyze their outcome by therapy, and to describe the proteomic profile of RASmut relative to RASWT AML.
Out of 609 patients with newly diagnosed AML, 11% had mutated RAS. Compared with RASWT, patients with RASmut AML were younger (median 54 vs. 63 yrs, p=0.001), had a higher WBC (16 vs. 4.2, p<0.001) and marrow blast percentage (56% vs. 42%, p=0.01) at diagnosis, and less likely to have an antecedent hematologic disorder (36% vs. 50%, p=0.03). The inv(16) karyotype was overrepresented in patients with RASmut and -5 and/or -7 karyotype was underrepresented. RAS mutation had no prognostic impact on OS or DFS overall or within cytogenetic subgroups. There was a suggestion that patients with RASmut benefited from AraC-based therapy. Proteomic analysis revealed simultaneous upregulation of the RAS-Raf-MAP kinase and PI3K signaling pathways in patients with RASmut.
RAS mutations in AML may delineate a subset of patients who benefit from AraC-based therapy and who may be amenable to treatment with inhibitors of RAS and PI3K signaling pathways.
AML; RAS; signal transduction
To define the mutation spectrum in non-Down syndrome acute megkaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL leukemia samples. Our analysis identified a cryptic chromosome 16 inversion [inv(16)(p13.3q24.3)] in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.
A subset of patients with myelodysplastic syndromes (MDS) who are predicted to have lower-risk disease as defined by the International Prognostic Scoring System (IPSS) demonstrate more aggressive disease and shorter overall survival than expected. The identification of patients with greater-than-predicted prognostic risk could influence the selection of therapy and improve the care of patients with lower-risk MDS.
Patients and Methods
We performed an independent validation of the MD Anderson Lower-Risk Prognostic Scoring System (LR-PSS) in a cohort of 288 patients with low- or intermediate-1 IPSS risk MDS and examined bone marrow samples from these patients for mutations in 22 genes, including SF3B1, SRSF2, U2AF1, and DNMT3A.
The LR-PSS successfully stratified patients with lower-risk MDS into three risk categories with significant differences in overall survival (20% in category 1 with median of 5.19 years [95% CI, 3.01 to 10.34 years], 56% in category 2 with median of 2.65 years [95% CI, 2.18 to 3.30 years], and 25% in category 3 with median of 1.11 years [95% CI, 0.82 to 1.51 years]), thus validating this prognostic model. Mutations were identified in 71% of all samples, and mutations associated with a poor prognosis were enriched in the highest-risk LR-PSS category. Mutations of EZH2, RUNX1, TP53, and ASXL1 were associated with shorter overall survival independent of the LR-PSS. Only EZH2 mutations retained prognostic significance in a multivariable model that included LR-PSS and other mutations (hazard ratio, 2.90; 95% CI, 1.85 to 4.52).
Combining the LR-PSS and EZH2 mutation status identifies 29% of patients with lower-risk MDS with a worse-than-expected prognosis. These patients may benefit from earlier initiation of disease-modifying therapy.
Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.
In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).
Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.
Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.)
The authors have recently shown that a majority of patients with myelodysplastic syndrome (MDS) classified by the International Prognostic Scoring System as lower risk die without transformation to acute myelogenous leukemia (AML). The cause of death (COD) of these patients is not well understood. Identifying the COD could help to guide early therapy decisions.
The authors retrospectively analyzed the COD in a cohort of 273 deceased patients with lower-risk MDS according to the International Prognostic Scoring System at presentation to The University of Texas M. D. Anderson Cancer Center from 1980 to 2004. MDS-related death was defined as infection, bleeding, transformation to AML, or disease progression. Remaining CODs were classified as non–MDS-related.
Median age at presentation was 66 years (range, 19-88 years). Overall median survival was 59 weeks (range, 1-831 weeks). All French-American-British leukemia classification subgroups were represented. The percentage of International Prognostic Scoring System low and intermediate-1 groups were 21% and 79%, respectively. The most common cytogenetic abnormality (9%) was del(5q). Patients received supportive care only. The COD was identified as MDS-related in 230 of 273 (84%) patients. The most common disease-related CODs were infection (38%), transformation to AML (15%), and hemorrhage (13%). The most frequent non–disease-related COD was cardiovascular events (19 of 43 patients).
The majority of patients with low- or intermediate-1 risk MDS will die because of causes related to their underlying disease. Although these results need to be validated in different populations, early therapeutic intervention could be considered in the management of these patients to improve survival.
myelodysplastic syndrome; mortality; International Prognostic Scoring System; cause of death
Dasatinib is a dual Abl/Src tyrosine kinase inhibitor (TKI) designed as a prototypic short-acting BCR–ABL-targeted TKI that inhibits BCR–ABL with greater potency compared with imatinib, nilotinib, bosutinib, and ponatinib and has been shown to have potential immunomodulatory effects. Dasatinib is approved for the treatment of all phases of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to prior imatinib treatment and first-line treatment for CML in chronic phase. In this article, the development of dasatinib as a treatment for patients with CML is reviewed.
This is a review of the relevant literature regarding dasatinib development in CML (2003–2013).
Dasatinib demonstrates efficacy against most BCR–ABL mutations arising during imatinib therapy and is effective in treating patients with imatinib resistance due to other mechanisms. Randomized trial data show that first-line dasatinib provides superior responses compared with imatinib and enables patients to achieve early, deep responses correlated with improved longer-term outcomes. Dasatinib has a generally acceptable safety profile, with most adverse events (AEs) proving manageable and reversible. Cytopenias are commonly observed with dasatinib, and some nonhematologic AEs including pleural effusion have been consistently reported.
Dasatinib is an effective treatment option for patients with CML.
Dasatinib; Chronic myeloid leukemia; First-line treatment; Second-line treatment; Side effects; Early response
Overcoming resistance to chemotherapy is the main therapeutic challenge in the treatment of acute lymphocytic leukemia (ALL). Interactions between leukemia cells and the microenvironment promote leukemia cell survival and confer resistance to chemotherapy. Hypoxia is an integral component of bone marrow (BM) microenvironment. Hypoxia-inducible factor-1α (HIF-1), a key regulator of the cellular response to hypoxia, regulates cell growth and metabolic adaptation to hypoxia. HIF-1α expression, analyzed by Reverse Phase Protein Arrays in 92 specimens from newly diagnosed patients with pre-B-ALL, had a negative prognostic impact on survival (p = 0.0025). Inhibition of HIF-1α expression by locked mRNA antagonist (LNA) promoted chemosensitivity under hypoxic conditions, while pharmacological or genetic stabilization of HIF-1α under normoxia inhibited cell growth and reduced apoptosis induction by chemotherapeutic agents. Co-culture of pre-B ALL or REH cells with BM-derived mesenchymal stem cells (MSC) under hypoxia resulted in further induction of HIF-1α protein and acquisition of the glycolytic phenotype, in part via stroma-induced AKT/mTOR signaling. mTOR blockade with everolimus reduced HIF-1α expression, diminished glucose uptake and glycolytic rate and partially restored the chemosensitivity of ALL cells under hypoxia/stroma co-cultures. Hence, mTOR inhibition or blockade of HIF-1α-mediated signaling may play an important role in chemosensitization of ALL cells under hypoxic conditions of the BM microenvironment.
HIF-1α; chemoresistance; ALL; hypoxia; microenvironment
Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor family of transcription factors with important regulatory roles in cellular growth, differentiation and apoptosis. Using proteomic analysis, we demonstrated expression of PPARγ protein in a series of 260 newly diagnosed primary AML samples. Forced expression of PPARγ enhanced the sensitivity of myeloid leukemic cells to PPARγ agonists CDDO- or 15d15DPGJ2-induced apoptosis, through preferential cleavage of caspase-8. No effects on cell cycle distribution or differentiation were noted, despite prominent induction of p21 in PPARγ-transfected cells. In turn, antagonizing PPARγ function by siRNA or pharmacological PPARγ inhibitor significantly diminished apoptosis induction by CDDO. Overexpression of co-activator protein DRIP205 resulted in enhanced differentiation induction by CDDO in AML cells through PPARγ activation. Studies with DRIP205 deletion constructs demonstrated that the NR boxes of DRIP205 are not required for this co-activation. In a Phase I clinical trial of CDDO (RTA-401) in leukemia, CDDO induced an increase in PPARγ mRNA expression in 6 of 9 patient samples; of those, induction of differentiation was documented in 4, and of p21 in 3 patients, all expressing DRIP205 protein. In summary, these findings suggest that cellular levels of PPARγ regulate induction of apoptosis via caspase-8 activation, while the co-activator DRIP205 is a determinant of induction of differentiation, in response to PPARγ agonists in leukemic cells.
PPARgamma; DRIP205; AML; CDDO; differentiation; apoptosis
To our knowledge, the feasibility of therapy with hypomethylating agents (HAs) in patients with renal insufficiency (RI) has not been examined.
Patients and Methods
We reviewed 41 patients with a diagnosis of acute myeloid leukemia (n = 17), myelodysplastic syndromes (n = 15), and chronic myelomonocytic leukemia (n = 9) who had RI and were receiving therapy with azacitidine or decitabine. The median number of administered cycles was 3. Most patients (39; 95%) received a standard dose of the drugs at the initiation of therapy. Nine patients (22%) required treatment interruptions or discontinuation, and 10 patients (24%) required dose reductions.
The overall response rate was 63%, and 4 patients (10%) achieved a complete response. Twenty patients (51%) experienced grade 3 or 4 myelosuppression-related toxicities. Hospitalization was required in 68% of the patients. Among 12 patients with an estimated glomerular filtration rate of 29 mL per minute or less, 6 required dose reductions attributable to myelosuppression (n = 3) or to worsening renal function (n = 3). The overall survival (OS) at 18 months was 12%, and the median OS was 8.6 months.
The use of HA in patients with RI is feasible, but is associated with a higher incidence of toxicity. Dose adjustments and the use of growth factor may be necessary for some patients.
Azacitidine; Decitabine; Myelodysplastic syndrome; Serum creatinine