Association of immunophenotype with expression of topoisomerase II α and ß in adult acute myeloid leukemia.

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIß. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIß by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIß (P < 0.0001). In contrast to topo IIα, topo IIß was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P < 0.0001) and CD54 (P < 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0-3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1-4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIß and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIß expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy.

Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report.

PURPOSE: Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3-internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD-negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD-negative status in older patients with AML. PATIENTS AND METHODS: Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Group (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD-negative genotype. RESULTS: Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD-negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. CONCLUSION: NPM1-positive/FLT3-ITD-negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.

Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy.

The aim of this study was to describe the fate of patients with newly diagnosed acute myeloid leukemia (AML) who did not achieve an initial remission while being treated on a contemporary cooperative group trial. We analyzed the outcome of patients entered into S0106, a recently reported cooperative group trial for patients with newly diagnosed AML. A total of 589 eligible patients was treated, of whom 150 (25%) did not achieve a remission while on study and were available for further analysis. The 4-year survival rate for the entire cohort of 150 patients was 23%. Among the 64 patients who received an allogeneic hematopoietic cell transplant, the 4-year survival rate was 48% compared with 4% for the 86 patients who did not undergo transplantation. Among those transplanted, we could not detect a difference in outcome according to remission status, donor source, type of preparative regimen, or cytogenetic risk category. More than 20% of patients with newly diagnosed AML who fail induction therapy can still be cured, particularly if they are able to receive an allogeneic hematopoietic cell transplant. These results suggest that early HLA typing and donor identification are important components of the initial therapy of AML.

Specific features identify patients with relapsed or refractory mantle cell lymphoma benefitting from autologous hematopoietic cell transplantation.

Outcomes with autologous hematopoietic cell transplantation (auto HCT) for relapsed and/or refractory mantle cell lymphoma (MCL) are typically poor. We hypothesized that certain factors could predict which patients experience a favorable outcome with this approach. We thus developed a predictive score from a cohort of 67 such patients using 3 factors independently associated with progression-free survival (PFS): (1) simplified Mantle Cell Lymphoma International Prognostic Index score before auto HCT (hazard ratio [HR], 2.9; P = .002); (2) B symptoms at diagnosis (HR, 2.7; P = .005); and (3) remission quotient, calculated by dividing the time, in months, from diagnosis to auto HCT by the number of prior treatments (HR, 1.4; P = .02). The estimated 5-year PFS for favorable-risk patients (n = 23) and unfavorable-risk patients (n = 44) were 58% (95% confidence interval [CI], 34% to 75%) and 15% (95% CI, 6% to 28%), respectively. These factors also independently predicted overall survival. In summary, we have defined 3 simple factors that can identify patients with relapsed/refractory MCL who derive a durable benefit from salvage auto HCT.

A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia.

This randomized phase 3 clinical trial evaluated the potential benefit of the addition of gemtuzumab ozogamicin (GO) to standard induction and postconsolidation therapy in patients with acute myeloid leukemia. Patients were randomly assigned to receive daunorubicin (45 mg/m(2) per day on days 1, 2, and 3), cytarabine (100 mg/m(2) per day by continuous infusion on days 1-7), and GO (6 mg/m(2) on day 4; DA+GO) vs standard induction therapy with daunorubicin (60 mg/m(2) per day on days 1, 2, and 3) and cytarabine alone (DA). Patients who achieved complete remission (CR) received 3 courses of high-dose cytarabine. Those remaining in CR after consolidation were randomly assigned to receive either no additional therapy or 3 doses of GO (5 mg/m(2) every 28 days). From August 2004 until August 2009, 637 patients were registered for induction. The CR rate was 69% for DA+GO and 70% for DA (P = .59). Among those who achieved a CR, the 5-year relapse-free survival rate was 43% in the DA+GO group and 42% in the DA group (P = .40). The 5-year overall survival rate was 46% in the DA+GO group and 50% in the DA group (P = .85). One hundred seventy-four patients in CR after consolidation underwent the postconsolidation randomization. Disease-free survival was not improved with postconsolidation GO (HR, 1.48; P = .97). In this study, the addition of GO to induction or postconsolidation therapy failed to show improvement in CR rate, disease-free survival, or overall survival.

New Treatment Approaches for Older Adults with Multiple Myeloma.

The incidence of multiple myeloma (MM) increases with age, and with the aging of the population, the number of adults with MM is expected to double in the next 20 years. Novel agents, including the immunomodulatory agents thalidomide and lenalidomide, and the proteosome inhibitor bortezomib have dramatically changed the treatment of multiple myeloma in the past decade. The purpose of this review was to examine the recent clinical therapeutic trials in older adults with MM. A number of trials have evaluated the addition of novel agents to the traditional backbone of melphalan and prednisone. The combination of thalidomide with melphalan and prednisone has been evaluated in 7 randomized trials. The combination improves response rates and, in meta-analyses, survival, but at the expense of increased toxicity. Other combination regimens which include lenalidomide or bortezomib likewise are associated with higher response rates, but at the expense of greater toxicity. High dose dexamethasone is excessively toxic in older adults and should be avoided. The roles for high-dose therapy with autologous stem cell transplant or intermediate-dose melphalan with autologous stem cell transplant in older adults with MM in the era of modern therapy remain to be defined. In summary, there are a number of new therapeutic options for older adults with MM, allowing an individualized treatment strategy based on the patient's comorbidities and goals of care.

Acute lymphoblastic leukemia.

The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL.

Prognostic implications of the IDH1 synonymous SNP rs11554137 in pediatric and adult AML: a report from the Children's Oncology Group and SWOG.

IDH1 SNP rs11554137 was recently reported in association with poor prognosis in normal karyotype adult acute myeloid leukemia (AML). We aimed to determine the prevalence, clinical associations, and prognostic significance of SNP rs11554137 in unselected pediatric and adult AML patients. Diagnostic marrow specimens from 527 AML patients treated on the pediatric trial Children's Oncology Group-AAML03P1 (N = 253) or adult SWOG trials (N = 274) were analyzed for the presence of the SNP. SNP rs11554137 was present in 11% of all patients. SNP status had no prognostic impact on survival in pediatric patients. In adult AML, overall survival for SNP-positive patients was 10% versus 18% for SNP-negative patients (P = .44). Among the 142 adults who achieved complete remission, 5-year relapse-free survival was significantly worse for SNP-positive patients (0% vs 25%, P = .0014). However, among adults with normal cytogenetics, FLT3/ITD was present in 90% of SNP-positive patients versus 59% of SNP-negative patients (P = .0053). In multivariate analysis, adjusting for the effects of age, cytogenetics, and FLT3/ITD, the independent prognostic effect of SNP positivity was not statistically significant (hazard ratio = 1.72, P = .18). The clinical profile of SNP-positive patients suggests that SNP rs11554137 may have biologic effects that bear further investigation. The clinical trials in this study are registered at http://www.clinicaltrials.gov as #NCT000707174 and #NCT00899171.

Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia.

This phase I/II study was conducted to determine the maximum tolerated dose, toxicity, and efficacy of clofarabine in combination with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming (GCLAC), in the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML). Dose escalation of clofarabine occurred without dose-limiting toxicity, so most patients were treated at the maximum dose, 25 mg/m(2) per day with cytarabine 2 g/m(2) per day, each for 5 d, and G-CSF 5 µg/kg, beginning the day before chemotherapy and continuing daily until neutrophil recovery. The complete remission (CR) rate among the 46 evaluable patients was 46% (95% confidence interval [CI] 31-61%) and the CR + CR but with a platelet count <100 × 10(9)/l rate was 61% (95% CI 45-75%). Multivariate analysis showed that responses to GCLAC were independent of age, cytogenetic risk category, and number of prior salvage regimens. GCLAC is highly active in relapsed and refractory AML and warrants prospective comparison to other regimens, as well as study in untreated patients.

Histology and time to progression predict survival for lymphoma recurring after reduced-intensity conditioning and allogeneic hematopoietic cell transplantation.

Reduced-intensity conditioning (RIC) before allogeneic hematopoietic cell transplantation (HCT) is increasingly used as a potentially curative option for patients with advanced lymphoma; however, relapse remains a major challenge. Unfortunately, little data are available on outcomes, predictors of survival, and results of specific management strategies in these patients. In the present study, a total of 101 consecutive relapses occurred and were evaluated in 280 patients with lymphoma who underwent RIC HCT. Diseases included aggressive non-Hodgkin lymphoma (NHL) (n = 42), indolent NHL (n = 33), and Hodgkin lymphoma (HL) (n = 26). Median time to relapse was 90 days (range, 3-1275 days), and graft-versus-host disease at relapse was present in 56 patients (55%). Interventions after relapse included no therapy (n = 14), withdrawal of immunosuppression alone (n = 11), chemoradiotherapy (n = 60), and donor lymphocyte infusion/second HCT (n = 16). Overall survival (OS) was 33% (95% confidence interval [CI], 23%-44%) at 3 years after relapse and 23% (95% CI, 13%-34%) at 5 years after relapse. Both aggressive NHL (vs indolent disease; hazard ratio, 2.29; P = .008) and relapse within 1 month post-HCT (vs >6 months; hazard ratio, 3.17; P = .004) were associated with increased mortality. Estimated 3-year OS was 16% (95% CI, 5%-32%) after relapse for aggressive NHL, 40% (95% CI, 19%-61%) after relapse for indolent NHL, and 47% (95% CI, 29%-64%) after relapse for HL. The 1-year survival was 24% for patients relapsing within 1 month post-HCT, compared with 52% for those relapsing at 1-3 months, 74% for those relapsing at 3-6 months, and 77% for those relapsing at more than 6 months. We conclude that despite relapse of lymphoma after RIC HCT, some patients may experience prolonged survival, with better postrelapse outcomes occurring in patients with indolent NHL, HL, or late relapse.

A phase I/II study of chemotherapy followed by donor lymphocyte infusion plus interleukin-2 for relapsed acute leukemia after allogeneic hematopoietic cell transplantation.

The efficacy of donor lymphocyte infusion (DLI) for treatment of relapsed acute leukemia after allogeneic hematopoietic cell transplantation is limited. We hypothesized that interleukin-2 (IL-2) combined with DLI after chemotherapy might augment graft-versus-leukemia effects. To identify a safe and effective IL-2 regimen, a phase I/II study of DLI plus IL-2 therapy was performed for such patients. After chemotherapy, 17 patients received DLI (1 × 10(8) CD3/kg for patients with related donors, and 0.1 × 10(8) CD3/kg for those with unrelated donors) and an escalating dose of induction IL-2 (1.0, 2.0, or 3.0 × 10(6) IU/m(2)/day representing levels I [n = 7], Ia [n = 9], and II [n = 1]) for 5 days followed by maintenance (1.0 × 10(6) IU/m(2)/day) for 10 days as a continuous intravenous infusion. Unacceptable IL-2-related toxicities developed in 1 patient at level I, 2 at level Ia, and 1 at level II. Grades III-IV acute graft-versus-host disease (aGVHD) developed in 5 patients, and extensive chronic GVHD (cGVHD) developed in 8. Eight patients had a complete remission after chemotherapy prior to DLI, and 2 additional patients had a complete remission after DLI plus IL-2 therapy. In conclusion, the maximal tolerated induction dose of IL-2 combined with DLI appears to be 1.0 × 10(6) IU/m(2)/day. IL-2 administration after DLI might increase the incidence of cGVHD.

Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium.

We conducted a multi-center phase II trial of gemcitabine (G), carboplatin (C), dexamethasone (D), and rituximab (R) in order to examine its safety and efficacy as an outpatient salvage regimen for lymphoma. Fifty-one patients received 2-4 21-day cycles of G (1000 mg/m(2), days 1 and 8), C (AUC = 5, day 1), D (40 mg, daily days 1-4), and R (375 mg/m(2), day 8 for CD20-positive disease) and were evaluable for response. Characteristics included: median age 58 years (19-79 years), stage III/IV 88%, elevated LDH 33%, median prior therapies 2, prior stem cell transplant 12%, chemoresistant 62%, median prior remission duration 2.5 months. The overall and complete response rates were 67% (95% confidence interval [CI] 54-80%) and 31% (95% CI 19-44%), respectively, with activity seen in a broad variety of histologies. Responses occurred in 16 of 17 (94%, 95% CI 83-100%) transplant-eligible patients and 15 of 28 (54%, 95% CI 34-71%) with chemoresistant disease. The median CD34 yield in patients attempting peripheral blood stem cell (PBSC) collection following this regimen was 10.9 x 10(6) CD34+ cells/kg (range 5.0-24.1 x 10(6)). Hematologic toxicity was common, but febrile neutropenia (2.5%) and grade 4 non-hematologic adverse events (n = 2) were rare, with no treatment-related deaths. GCD(R) is a safe and effective outpatient regimen for relapsed lymphoma, and successfully mobilizes PBSCs.

Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia.

Adhesion of acute myeloid leukemia (AML) blasts in the bone marrow microenvironment confers protection from chemotherapy-induced apoptosis. One mechanism for retention of blasts within the bone marrow is adhesion via very late antigen-4 (VLA-4), the alpha(4)beta(1) integrin heterodimer that binds to its main ligands, fibronectin, and vascular cell adhesion molecule-1 (VCAM-1). To examine the relationship of functional expression of VLA-4 to prognosis in AML, we studied marrow samples from 175 adult AML patients who underwent induction chemotherapy with anthracycline and cytarabine on Southwest Oncology Group trials. The studies included flow cytometry and functional in vitro assays for ligand binding and maximal beta(1) activation. VLA-4 expression varied widely, with mean expression 60.6% for alpha(4), and was not significantly associated with response to chemotherapy, relapse-free, or overall survival (OS). However, increased binding of soluble VCAM-1 via VLA-4 was significantly associated with longer OS, corrected for age (P = .033). Estimated 5-year OS was 31% (95% confidence interval, 14%-48%) in 30 patients with soluble VCAM-1 binding greater than or equal to 40%, compared with 10% (confidence interval, 3%-17%) in 72 patients with lower binding. Adhesion and migratory properties of AML blasts thus appear to influence chemosensitivity and therefore may be therapeutic targets.

High-dose therapy and autologous stem cell transplantation for chemoresistant Hodgkin lymphoma: the Seattle experience.

BACKGROUND: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), but this therapy is commonly denied to patients with resistant disease. We explored the utility of HDT and ASCT for chemoresistant HL because there are few established therapies for these patients. METHODS: Sixty-four chemoresistant HL patients underwent HDT followed by ASCT at our center. Baseline characteristics included median age = 35 years (range, 14-59 years), stage III/IV = 49 (77%), nodular sclerosis histology = 51 (80%), and prior radiation = 32 (50%). Twenty-six patients (41%) received total body irradiation (TBI)-based regimens, and 38 (59%) underwent non-TBI conditioning. RESULTS: The estimated 5-year overall survival (OS) and progression-free survival (PFS) were 31% and 17%, respectively (median follow-up = 4.2 years). Multivariate analysis only identified year of transplant as independently associated with improved OS (P = .008) and PFS (P = .04), with patients receiving transplants in later years having better outcome. The probabilities of 3-year PFS for patients receiving transplants during 1986 to 1989, 1990 to July 1993, August 1993 to 1999, and 2000 to 2005 were 9%, 21%, 33%, and 31%, respectively. CONCLUSIONS: These data suggest that HDT and ASCT may result in prolonged remissions and survival for a subset of chemoresistant HL patients, with improved outcomes in patients receiving transplants more recently.

External beam irradiation and the combination of cisplatin and carmustine followed by carmustine alone for the treatment of high-grade glioma: a phase 2 Southwest Oncology Group trial.

BACKGROUND: The poor prognosis reported for patients with high-grade glial neoplasms indicates a need for the development of multimodality therapeutic approaches. The addition of chemotherapy has contributed variably to increased survival. The objective of the current study (Southwest Oncology Group [SWOG] 9016) was to determine whether concurrent radiotherapy and chemotherapy with the combination of carmustine and cisplatin could be given safely in a cooperative group setting. Additional objectives included the estimation of response rate, the rate of disease stabilization, and the probability of 1-year survival. METHODS: SWOG 9016 study included 59 eligible patients with grade III or IV astrocytoma who received radiotherapy concurrently with carmustine/cisplatin chemotherapy. Patients were required to have either measurable or evaluable disease. The therapeutic endpoints were comprised of complete response (CR), partial response (PR), or progressive disease (PD). RESULTS: Six patients achieved a CR (CR rate of 10%; 95% confidence interval [95% CI], 4-21%), 4 achieved a PR (PR rate of 7%; 95% CI, 2-16%), and 2 patients (3%) experienced an unconfirmed response. Twenty-four patients (41%; 95% CI, 28-54%) had stable disease and 10 patients (17%) demonstrated PD. The overall disease stabilization rate (CR + PR + stable disease, excluding unconfirmed response) was 58% (95% CI, 44-70%). CONCLUSIONS: Despite the presence of a cohort of long-term survivors, the results of the current study do not appear to support the additional study or routine use of concurrent cisplatin and carmustine.

Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma.

We analysed the outcomes of autologous stem cell transplantation (ASCT) following high-dose therapy with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive patients with mantle cell lymphoma (MCL). Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (+/-R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (+/-R) followed by ASCT in CR1/PR1 and 20 received ASCT following disease progression. Estimates of overall and progression-free survival (PFS) at 3 years among patients transplanted in CR1/PR1 were 93% and 63% compared with 46% and 36% for patients transplanted with relapsed/refractory disease, respectively. The hazard of mortality among patients transplanted with relapsed/refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P = 0.006). Patients in the CHOP (+/-R) group had a higher risk of failure for PFS compared with patients in the HyperCVAD (+/-R) group, though the difference did not reach statistical significance (hazard ratio 3.67, P = 0.11). These results suggest that ASCT in CR1/PR1 leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed/refractory disease, and a HyperCVAD (+/-R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1.