Jianqin Shan

Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome.

Elderly patients (age ≥ 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML‐type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I–II studies, low‐intensity regimens, or ‘targeted’ therapies. However, baseline expectations for outcomes of elderly AML with ‘standard’ AML‐type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8‐week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated.

Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia

Adult Burkitt‐type lymphoma (BL) and acute lymphoblastic leukemia (B‐ALL) are rare entities composing 1% to 5% of non‐Hodgkin lymphomas NHL) or ALL. Prognosis of BL and B‐ALL has been poor with conventional NHL or ALL regimens, but has improved with dose‐intensive regimens.

Long‐term follow‐up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper‐CVAD), a dose‐intensive regimen, in adult acute lymphocytic leukemia

Modern intensive chemotherapy regimens have improved the prognosis for patients with adult acute lymphocytic leukemia (ALL). With these regimens, the complete response rates are now reported to be > 80%, and the long‐term survival rates range from 30% to 45%. The current analysis updated the long‐term results with the original hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper‐CVAD) program, with a median follow‐up time of 63 months.

Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System.

Recent studies have highlighted issues with the International Prognostic Scoring System (IPSS) model in relation to the exclusion of many subgroups that now represent a large proportion of patients with myelodysplastic syndrome (MDS) (eg, secondary MDS, chronic myelomonocytic leukemia [CMML] with leukocytosis, prior therapy) and its lack of applicability to most patients on investigational programs, because many would have received prior therapies and would have had MDS for a significant length of time.

DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes

PURPOSE The current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS. PATIENTS AND METHODS We screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome. RESULTS In an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses. CONCLUSION DNA methylation predicts overall and progression-free survival in MDS.

Nilotinib As Front-Line Treatment for Patients With Chronic Myeloid Leukemia in Early Chronic Phase

PURPOSE Although most patients with chronic myeloid leukemia (CML) in chronic phase respond well to front-line therapy with imatinib, some patients do not achieve the desirable end point, and others may eventually lose response or are intolerant. PATIENTS AND METHODS Patients with newly diagnosed CML in chronic phase were treated with nilotinib 400 mg twice daily on an empty stomach as initial therapy. RESULTS Among 51 patients in chronic phase observed for at least 3 months, 50 (98%) achieved a complete cytogenetic remission (CCyR), and 39 (76%) achieved a major molecular response (MMR). Responses occurred rapidly, with 96% of patients achieving CCyR by 3 months and 98% achieving CCyR by 6 months. The projected event-free survival at 24 months is 90%, and all patients are alive after a median follow-up time of 17 months. Grade >or= 3 neutropenia occurred in 12% of patients, and thrombocytopenia in occurred 11%. Nonhematologic toxicity was usually grade 1 to 2 and manageable. The actual median dose at 12 months was 800 mg (range, 200 to 800 mg). CONCLUSION Nilotinib is an effective option for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR, with most patients reaching these responses early during their therapy.

Results of Dasatinib Therapy in Patients With Early Chronic-Phase Chronic Myeloid Leukemia

PURPOSE Dasatinib is effective therapy for chronic myeloid leukemia (CML) after imatinib failure. In this study, we investigate the efficacy of dasatinib as initial therapy for patients with CML in early chronic phase. PATIENTS AND METHODS Patients with newly diagnosed CML in early chronic phase were randomly assigned to receive dasatinib 100 mg once daily or 50 mg twice daily as initial therapy. RESULTS Among 50 patients observed for at least 3 months, 49 patients (98%) achieved a complete cytogenetic response (CCyR), and 41 patients (82%) achieved a major molecular response (MMR). Responses occurred rapidly, with 94% of patients achieving CCyR by 6 months. There was no difference in response rate by treatment arm. The projected event-free survival rate at 24 months is 88%, and all patients are alive after a median follow-up time of 24 months. Grade >or= 3 neutropenia and thrombocytopenia occurred in 21% and 10% of patients, respectively. Nonhematologic toxicity was usually grade 1 to 2. There was no significant difference in toxicity between the two arms, and the actual median dose at 12 months was 100 mg (range, 20 to 100 mg). CONCLUSION Dasatinib is an effective agent for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR.

Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia

Patients ≥ 70 years of age with acute myeloid leukemia (AML) have a poor prognosis. Recent studies suggested that intensive AML-type therapy is tolerated and may benefit most. We analyzed 446 patients ≥ 70 years of age with AML (≥ 20% blasts) treated with cytarabine-based intensive chemotherapy between 1990 and 2008 to identify risk groups for high induction (8-week) mortality. Excluding patients with favorable karyotypes, the overall complete response rate was 45%, 4-week mortality was 26%, and 8-week mortality was 36%. The median survival was 4.6 months, and the 1-year survival rate was 28%. Survival was similar among patients treated before 2000 and since 2000. A multivariate analysis of prognostic factors for 8-week mortality identified the following to be independently adverse: age ≥ 80 years, complex karyotypes, (≥ 3 abnormalities), poor performance (2-4 Eastern Cooperative Oncology Group), and elevated creatinine > 1.3 mg/dL. Patients with none (28%), 1 (40%), 2 (23%), or ≥ 3 factors (9%) had estimated 8-week mortality rates of 16%, 31%, 55%, and 71% respectively. The 8-week mortality model also predicted for differences in complete response and survival rates. In summary, the prognosis of most patients (72%) ≥ 70 years of age with AML is poor with intensive chemotherapy (8-week mortality ≥ 30%; median survival < 6 months).

Complete cytogenetic and molecular responses to interferon-α-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis

Little is known regarding long‐term prognosis among patients with Philadelphia chromosome (Ph)‐positive chronic myelogenous leukemia (CML) who achieve a complete cytogenetic response (0% Ph‐positive cells) after treatment with interferon‐α.

Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia.

General and site‐specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti‐CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML.