Sherry Pierce

Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia

PURPOSE To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. CONCLUSION Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.

Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-α therapy

Table. SI Units and Abbreviation Chronic myelogenous leukemia is characterized by the presence of the Philadelphia chromosome (Ph) in the leukemic cells, a balanced translocation between chromosomes 9 and 22 (t[9; 22][q34; q11]) [1]. The molecular aberrations associated with the Ph abnormality have been described [2]. The relation between these molecular events and the development of chronic myelogenous leukemia has been documented in some animal models [3, 4]. These findings suggested that suppressing the Ph-positive clones might change the natural course of chronic myelogenous leukemia and its prognosis. Hydroxyurea and busulfan are the two agents most commonly used as the standard treatment in patients with chronic myelogenous leukemia. These drugs provide effective disease control in the chronic phase, inducing complete hematologic remissions in greater than 70% of patients, depending on the dose schedules used. They are attractive treatment options in community practice because they are administered orally, are relatively inexpensive, and have few chronic side effects. Busulfan may induce organ fibrosis (marrow, pulmonary), Addison-like disease, and unpredictable prolonged myelosuppression (in about 10% of patients) that may be fatal. A recent randomized trial [5] of hydroxyurea compared with busulfan therapy showed that hydroxyurea conferred a survival advantage (median survival, 58 compared with 45 months; P = 0.008). Patients having allogeneic bone marrow transplantation also have better survival if therapy before transplantation does not include busulfan [6]. Conventional therapy has been associated with a median survival range of 3 to 5 years, but neither busulfan nor hydroxyurea produced a substantial, durable suppression of the Ph-positive cells in patients with chronic myelogenous leukemia [7]. Investigations of interferon- therapy in chronic myelogenous leukemia were initiated by our group in 1982. Since then, several trials [8-12] have confirmed its efficacy in this disease. Interferon- therapy produces hematologic responses in 60% to 80% of patients and cytogenetic responses (suppression of the Ph-positive cells) in 35% to 55% of patients. These responses were major (<35% Ph-positive cells) and durable in about 15% to 25% of patients [7]. In a study [10] of chronic myelogenous leukemia by the Italian Cooperative Study Group (ICSG-CML), patients were randomly assigned to interferon- or conventional chemotherapy. The 218 patients assigned to interferon- had longer survival (median > 72 months compared with 52 months; P = 0.003) and time to transformation (median > 72 months compared with 45 months; P < 0.001) and a higher incidence of a major cytogenetic response (19% compared with 1%; P < 0.01) when compared with conventional chemotherapy. We determined whether achieving a cytogenetic response with interferon- therapy was independently related to prolonged survival in patients with chronic myelogenous leukemia. Methods Study Group Adults with a diagnosis of Ph-positive, early chronic-phase, chronic myelogenous leukemia (diagnosis for less than 12 months) who received interferon- therapy as their primary treatment after referral to our institution from 1982 until 1990 were included in the analysis. Informed consent was obtained for treatment with the interferon- protocols according to institutional guidelines. The interferon- programs were sequential studies with human leukocyte interferon- (1982 to 1984; DM82-49), recombinant interferon- alone (1984 to 1987; DM84-38, DM86-86), recombinant interferon- and interferon- (1985; DM85-45), and recombinant interferon- plus hydroxyurea (1988 to 1990; DM88-99). The early analyses of the clinical results of DM82-49 and DM84-38 have been reported [8, 12]. Patients had pretreatment and follow-up evaluations of bone marrow aspirates, and had cytogenetic analysis every 3 months in the first 2 years and every 4 to 6 months thereafter. Therapy In the subsequent studies, the daily dose of interferon- was 5 106 U/m2. The interferon- dose was reduced by 25% for persistent grade 2 toxicity. For grade 3 to 4 toxicity, interferon- was interrupted until resolution of the toxicity, and the agent was resumed at 50% of the dose. Toxicity grading was according to the National Cancer Institute guidelines [13]. The dose was also reduced by 25% if the leukocyte count was lower than 2 109/L or if the platelet count was lower than 60 109/L. In the study combining interferon- and interferon- (DM85-45), the interferon- daily dose was 0.025 mg/m (2), and interferons- and were administered daily. Oral hydroxyurea was adjusted in a daily dose range of 0.5 g to 2 g to keep the leukocyte count less than 5 109/L with a platelet count greater than 60 109/L. Response Criteria Response criteria have been previously described [8]. A complete hematologic response required normalization of the peripheral blood counts and differential, including a leukocyte count less than 10 109/L; a platelet count less than 450 109/L; an absence of immature peripheral blasts, promyelocytes, or myelocytes; and disappearance of all signs and symptoms of the disease, including palpable splenomegaly [8]. Patients achieving a complete hematologic response were further categorized by their best cytogenetic response [lowest percentage of Ph-positive metaphases]: 1) as complete, if the lowest Ph-positive percentage was 0%; 2) as partial, if it was between 1% and 34%; and 3) as minor, if it was between 35% and 90%. A major cytogenetic response included complete and partial cytogenetic responses (that is, patients with the lowest Ph-positive metaphase percentage below 35%). Prognostic Models Prognostic models for survival of patients with chronic myelogenous leukemia, previously proposed by our group and by Sokal and colleagues [14-16], were evaluated by comparing response and survival experiences of patients divided into different risk groups. The overall prognostic model was derived from an analysis of clinical, hematologic, and bone marrow features of 303 patients with Ph-positive, chronic-phase chronic myelogenous leukemia who were referred to our institution between 1965 and 1982 [14]. The multivariate analysis [14] identified five independent poor prognostic factors: 1) age of 60 years or greater; 2) black race; 3) marrow basophils of 3% or greater; 4) blood basophils of 7% or greater; and 5) cytogenetic clonal evolution (acquired chromosomal abnormalities other than Ph). The clinical prognostic model was based on the analysis of the same population but was derived excluding the bone marrow findings. In addition to age, race, and peripheral basophilia, two other independent poor prognostic factors were selected: 1) platelet count of 700 109 or greater or of less than 150 109/L; and 2) increasing splenomegaly [14]. Both models divide patients into good, intermediate, and poor risk groups based on their hazard ratio (or risk for death per unit time compared with the average expected risk), derived from solving a mathematical equation (detailed in reference 14). The Sokal model is based on a similar analysis. The population analyzed included 813 patients with good risk (essentially chronic-phase) chronic myelogenous leukemia who were treated in multiple institutions in the United States, Italy, and Spain [16]. It identified independent poor prognostic factors, including 1) older age; 2) higher platelet counts; 3) higher peripheral blast percentage; and 4) splenomegaly. The Equation tocalculate the hazard ratio and the analysis have been previously described [16]. The synthesis model attempted to synthesize the existing models, choosing the consistently reproducible prognostic factors and dividing patients into prognostic groups by a simple enumeration of the number of poor prognostic factors present at diagnosis. Patients are categorized as having stage 1, 2, or 3 disease if they have none or 1 (stage 1), 2 (stage 2), or 3 or more (stage 3) of the following poor prognostic factors: 1) age of 60 years or greater; 2) peripheral blasts of 3% or greater or bone marrow blasts of 5% or greater; 3) peripheral basophils of 7% or greater, or marrow basophils of 3% or greater; 4) platelet count of 700 109/L or greater; and 5) splenomegaly of 10 cm or greater below the costal margin. Accelerated-phase chronic myelogenous leukemia, or stage 4 disease, is defined by the presence of any of the following: 1) peripheral blasts of 15% or greater; 2) peripheral basophils of 20% or greater; 3) peripheral blasts plus promyelocytes of 30% or greater; 4) a platelet count less than 100 109/L that was unrelated to therapy; or 5) cytogenetic clonal evolution. Confirmation of the validity of the model was carried out in 406 patients with Ph-positive chronic myelogenous leukemia who were referred to our institution from 1975 through 1986. The details of the model and a discussion of the other models are available in a previous report [15]. Statistical Methods Outcomes evaluated in this study were frequency of cytogenetic response and duration of survival. Survival analysis was based on Kaplan-Meier estimation [17], and groups were compared by log-rank test [18]. Except where noted, survival was dated from initiation of interferon- therapy. Patients who had allogeneic bone marrow transplantation while still in the chronic phase of the disease were counted as censored observations at the date of transplantation. Cytogenetic response did not occur, on average, until a patient had received 12 months of interferon- therapy. Two approaches were used to evaluate the association of a cytogenetic response with survival: 1) comparison of survival subsequent to a fixed time point according to cytogenetic response at that time (landmark method) [19] and 2) use of a proportional hazards regression model [20] for survival that included a time-varying term for cytogenetic response. In the first approach, the landmark used for analysis was 12 months after

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.

New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge

PURPOSE The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients. PATIENTS AND METHODS Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results. RESULTS In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score. CONCLUSION In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories.

Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin

PURPOSE We examined the outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) with or without gemtuzumab ozogamicin (GO) but without traditional cytotoxic chemotherapy. PATIENTS AND METHODS From February 2002 to March 2008, 82 patients with APL were treated with a combination of ATRA plus ATO. The first cohort of 65 patients received ATRA and ATO (beginning on day 10 of ATRA). High-risk patients (WBCs >or= 10 x 10(9)/L) received GO on the first day. From July 2007, the second cohort of 17 patients received ATRA and ATO concomitantly on day 1. They also received GO on day 1, if high risk, and if their WBC increased to more than 30 x 10(9)/L during induction. Monitoring for PML-RARA fusion gene was conducted after induction and throughout consolidation and follow-up. RESULTS Overall, 74 patients achieved complete remission (CR) and one achieved CR without full platelet recovery after the induction, for a response rate of 92%. Seven patients died at a median of 4 days (range, 1 to 24 days) after inclusion in the study from disease-related complications. The median follow-up is 99 weeks (range, 2 to 282 weeks). Among the responding patients, three experienced relapse at 39, 52, and 53 weeks. Three patients died after being in CR for 14, 21, and 71 weeks, all from a second malignancy. The estimated 3-year survival rate is 85%. CONCLUSION The combination of ATRA and ATO (with or without GO) as initial therapy for APL was effective and safe and can substitute chemotherapy-containing regimens.

Pegylated Interferon Alfa-2a Yields High Rates of Hematologic and Molecular Response in Patients With Advanced Essential Thrombocythemia and Polycythemia Vera

PURPOSE We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV). PATIENTS AND METHODS Seventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN-alpha-2a was 54 months in patients with PV and 33 months in patients with ET. Eighty-one percent of patients had received prior therapy. The first three patients received PEG-IFN-alpha-2a at 450 microg weekly. As a result of poor tolerance, this dose was decreased in a stepwise manner to a current starting dose of 90 microg weekly. Seventy-seven patients are evaluable and have been observed for a median of 21 months. RESULTS The overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). The JAK2(V617F) mutation was detected in 18 patients with ET and 38 patients with PV; sequential measurements by a pyrosequencing assay were available in 16 patients with ET and 35 patients with PV. The molecular response rate was 38% in ET and 54% in PV, being complete (undetectable JAK2(V617F)) in 6% and 14%, respectively. The JAK2(V617F) mutant allele burden continued to decrease with no clear evidence for a plateau. The tolerability of PEG-IFN-alpha-2a at 90 microg weekly was excellent. CONCLUSION PEG-IFN-alpha-2a resulted in remarkable clinical activity, high rates of molecular response, and acceptable toxicity in patients with advanced ET or PV. The ability of PEG-IFN-alpha-2a to induce complete molecular responses suggests selective targeting of the malignant clone.

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.

Outcome of philadelphia chromosome-positive adult acute lymphoblastic leukemia

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) represents the most common cytogenetic abnormality in adult ALL. It is found in 15% to 30% of patients, and its incidence increases with age. As in children, prognosis in Ph-positive adult ALL is poor. No therapeutic approach has had substantial impact on its unfavorable course. We analyzed the characteristics and outcome of newly diagnosed adults with Ph-positive ALL treated at the M. D. Anderson Cancer Center between 1980 and 1997. The diagnosis of patients was based on typical morphological and immunophenotypic criteria of marrow aspirate and biopsy specimens. Cytogenetic and molecular studies were also performed. A total of 67 patients were included in this study. From 1980 until 1991, 38 patients with Ph-positive ALL were treated with vincristine, Adriamycin, and dexamethasone (VAD), or with acute myeloid leukemia (AML)-like induction protocols. Since 1992 a total of 29 patients received induction therapy with an intensified treatment protocol, called “hyper-CVAD”. The outcome of patients treated with standard and intensified treatment regimens was compared and results of our institution contrasted with data obtained from other centers. Ph-positive ALL was present in 67 of 498 patients with newly diagnosed ALL (13%). Patients with Ph-positive ALL had a higher median age (44 versus 34, P=0.007), higher median white blood cell (WBC) counts at presentation (25 versus 8, P=0.0002), and higher peripheral median percentage of blast counts (63 versus 40, P=0.023). FAB subtype L2 (70% versus 49%, P=0.001) and CALLA-positive pre-B immunophenotype (75% versus 37%, P<0.001) predominated among Ph-positive ALL. Myeloid marker coexpression was more frequent in Ph-positive ALL when compared with Ph-negative ALL (52% vs. 27% for CD13, P<0.001, and 44% vs. 27% for CD33, P=0.005). Among patients treated with hyper-CVAD, the complete remission (CR) rate was 90% versus 55% (P=0.002) with pre-hyper-CVAD regimens (VAD and AML-like induction protocols), the median CR duration was 43 weeks versus 32 weeks (P >0.5), median disease-free survival (DFS) was 42 weeks versus 29 weeks (P=0.008), and median survival was 66 weeks versus 45 weeks (P >0.5). Patients with hyper-diploid Ph-positive ALL on hyper-CVAD therapy achieved significantly longer CR duration and DFS than hypo- and pseudodiploid cases (59 weeks versus 42 and 31 weeks, P=0.02 and 0.04, respectively). In contrast, patients treated with regimens prior to hyper-CVAD had significantly shorter CR duration (21 weeks versus 33 and 29 weeks, P=0.03) and DFS with hyperdiploid karyotypes when compared to pseudodiploid and hypodiploid cases (16 weeks versus 30 and 13 weeks, P=0.008). In conclusion, our results demonstrate improved response rate and DFS with current intensive regimens (hyper-CVAD) in patients with Ph-positive ALL, but no advantage in overall survival.

A prognostic score for patients with lower risk myelodysplastic syndrome.

Current prognostic models for myelodysplastic syndromes (MDS) do not allow the identification of patients with lower risk disease and poor prognosis that may benefit from early therapeutic intervention. We evaluated the characteristics of 856 patients with low or intermediate-1 disease by the International Prognostic Scoring System. Mean follow-up was 19.6 months (range 1–262). Of these patients, 87 (10%) transformed to acute myelogenous leukemia, and 429 (50%) had died. By multivariate analysis, characteristics associated with worse survival (P<0.01) were low platelets, anemia, older age, higher percent of marrow blasts and poor-risk cytogenetics. Although not included in the model, higher ferritin (P=0.007) and β2-microglobulin (P<0.001) levels were associated with worse prognosis. This allowed the development of a scoring system in which patients could be grouped in three categories: category 1 (n=182, 21%) with a median survival of 80.3 months (95% CI 68-NA); category 2 (n=408, 48%) with a median survival of 26.6 months (95% CI 22–32) and category 3 (n=265, 31%) with a median survival of 14.2 months (95% CI 13–18). In summary, this analysis indicates that it is possible to identify patients with lower risk MDS and poor prognosis who may benefit from early intervention.