Lloyd E. Damon

Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma

PURPOSE We previously determined that intravenous administration of rituximab results in limited penetration of this agent into the leptomeningeal space. Systemic rituximab does not reduce the risk of CNS relapse or dissemination in patients with large cell lymphoma. We therefore conducted a phase I dose-escalation study of intrathecal rituximab monotherapy in patients with recurrent CNS non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS The protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients. RESULTS The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy. CONCLUSION These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.

Intensified and Shortened Cyclical Chemotherapy for Adult Acute Lymphoblastic Leukemia

PURPOSE To assess the efficacy and toxicity of a new treatment program of intensified and shortened cyclical chemotherapy (protocol 8707) in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Previously untreated adults < or = 60 years old with ALL were treated with a four-agent induction chemotherapy regimen. This was followed by cyclical postremission therapy with high-dose cytarabine/etoposide; high-dose methotrexate/6-mercaptopurine; and daunorubicin, vincristine, prednisone, and asparaginase. Maintenance chemotherapy with oral methotrexate and 6-mercaptopurine was continued for 30 months. CNS prophylaxis was given with intrathecal methotrexate in addition to the systemic chemotherapy indicated above. RESULTS Seventy-eight of 84 patients (93%) achieved complete remission. With a median follow-up of 5.6 years, 5-year event-free survival (EFS) of all remission patients is 52%. Patients with high-risk features including adverse cytogenetics, failure to achieve remission with the first cycle of chemotherapy, and B-precursor disease with WBC counts more than 100,000/microL all relapsed unless taken off study for transplantation. For patients without these high-risk features, 5-year EFS was 60%. Compared with our previous treatment regimen, results appear to be improved for patients with standard-risk B-precursor disease (5-year EFS, 66% v 34%; P =.01). CONCLUSION Intensified and shortened chemotherapy may improve the outcome for patients with ALL with B-precursor disease lacking high-risk features. Further trials of this regimen are warranted.

Immunochemotherapy and Autologous Stem-Cell Transplantation for Untreated Patients With Mantle-Cell Lymphoma: CALGB 59909

PURPOSE Mantle-cell lymphoma (MCL) is an aggressive B-cell non-Hodgkins lymphoma with a poor prognosis. We explored the feasibility, safety, and effectiveness of an aggressive immunochemotherapy treatment program that included autologous stem-cell transplantation (ASCT) for patients up to age 69 years with newly diagnosed MCL. PATIENTS AND METHODS The primary end point was 2-year progression-free survival (PFS). A successful trial would yield a 2-year PFS of at least 50% and an event rate (early progression plus nonrelapse mortality) less than 20% at day +100 following ASCT. Seventy-eight patients were treated with two or three cycles of rituximab combined with methotrexate and augmented CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This treatment was followed by intensification with high doses of cytarabine and etoposide combined with rituximab and filgrastim to mobilize autologous peripheral-blood stem cells. Patients then received high doses of carmustine, etoposide, and cyclophosphamide followed by ASCT and two doses of rituximab. Results There were two nonrelapse mortalities, neither during ASCT. With a median follow-up of 4.7 years, the 2-year PFS was 76% (95% CI, 64% to 85%), and the 5-year PFS was 56% (95% CI, 43% to 68%). The 5-year overall survival was 64% (95% CI, 50% to 75%). The event rate by day +100 of ASCT was 5.1%. CONCLUSION The Cancer and Leukemia Group B 59909 regimen is feasible, safe, and effective in patients with newly diagnosed MCL. The incorporation of rituximab with aggressive chemotherapy and ASCT may be responsible for the encouraging outcomes demonstrated in this study, which produced results comparable to similar treatment regimens.

Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML.

CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 7+3 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission + incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ≥1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892.

Phase II Study of High-Dose [131I]Metaiodobenzylguanidine Therapy for Patients With Metastatic Pheochromocytoma and Paraganglioma

PURPOSE To evaluate the safety and efficacy of high-dose [(131)I]metaiodobenzylguanidine ([(131)I]MIBG) in the treatment of malignant pheochromocytoma (PHEO) and paraganglioma (PGL). METHODS Fifty patients with metastatic PHEO or PGL, age 10 to 64 years, were treated with [(131)I]MIBG doses ranging from 492 to 1,160 mCi (median, 12 mCi/kg). Cumulative [(131)I]MIBG administered ranged from 492 to 3,191 mCi. Autologous hematopoietic stem cells were collected and cryopreserved before treatment with [(131)I]MIBG greater than 12 mCi/kg or with a total dose greater than 500 mCi. Sixty-nine [(131)I]MIBG infusions were given, which included infusions to 35 patients treated once and infusions to 15 patients who received two or three treatments. Response was evaluated by [(123)I]MIBG scans, computed tomography/magnetic resonance imaging, urinary catecholamines/metanephrines, and chromogranin A. RESULTS The overall complete response (CR) plus partial response (PR) rate in 49 evaluable patients was 22%. Additionally, 35% of patients achieved a CR or PR in at least one measure of response without progressive disease, and 8% of patients maintained stable disease for greater than 12 months. Thirty-five percent of patients experienced progressive disease within 1 year after therapy. The estimated 5-year overall survival rate was 64%. Toxicities included grades 3 to 4 neutropenia (87%) and thrombocytopenia (83%). Grades 3 to 4 nonhematologic toxicity included acute respiratory distress syndrome (n = 2), bronchiolitis obliterans organizing pneumonia (n = 2), pulmonary embolism (n = 1), fever with neutropenia (n = 7), acute hypertension (n = 10), infection (n = 2), myelodysplastic syndrome (n = 2), and hypogonadism (n = 4). CONCLUSION Although serious toxicity may occur, the survival and response rates achieved with high-dose [(131)I]MIBG suggest its utility in the management of selected patients with metastatic PHEO and PGL.

High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

PURPOSE Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). PATIENTS AND METHODS Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). RESULTS The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). CONCLUSION High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

Protein Biomarker Identification in the CSF of Patients With CNS Lymphoma

PURPOSE Elucidation of the CSF proteome may yield insights into the pathogenesis of CNS disease. We tested the hypothesis that individual CSF proteins distinguish CNS lymphoma from benign focal brain lesions. METHODS We used a liquid chromatography/mass spectrometry-based method to differentially quantify and identify several hundred CSF proteins in CNS lymphoma and control patients. We used enzyme-linked immunosorbent assay (ELISA) to confirm one of these markers in an additional validation set of 101 cases. RESULTS Approximately 80 CSF proteins were identified and found to be present at significantly different concentrations, both higher and lower, in training and test studies, which were highly concordant. To further validate these observations, we defined in detail the expression of one of these candidate biomarkers, antithrombin III (ATIII). ATIII RNA transcripts were identified within CNS lymphomas, and ATIII protein was localized selectively to tumor neovasculature. Determination of ATIII concentration by ELISA was significantly more accurate (> 75% sensitivity; > 98% specificity) than cytology in the identification of cancer. Measurement of CSF ATIII levels was found to potentially enhance the ability to diagnose and predict outcome. CONCLUSION Our findings demonstrate for the first time that proteomic analysis of CSF yields individual biomarkers with greater sensitivity in the identification of cancer than does CSF cytology. We propose that the discovery of CSF protein biomarkers will facilitate early and noninvasive diagnosis in patients with lesions not amenable to brain biopsy, as well as provide improved surrogates of prognosis and treatment response in CNS lymphoma and brain metastasis.

Prevention and management of asparaginase/pegasparaginase- associated toxicities in adults and older adolescents: recommendations of an expert panel

Abstract The rapidly increasing use of pegasparaginase (pegASNase) in adults, after a half century of use of asparaginase (ASNase) in children, has prompted a need for guidelines in the management and prevention of toxicities of asparagine depletion in adults. Accordingly, an initial set of recommendations are provided herein. Major advantages of pegASNase are its 2–3-week duration of action, in contrast to less than 3 days with native ASNase, and the flexibility of intravenous or intramuscular administration of pegASNase and associated patient and physician convenience. The most frequent toxicities of both types of ASNase are hepatic and pancreatic, with pancreatitis being the most serious. Other toxicities are hypersensitivity reactions, thrombosis, nausea/vomiting, and fatigue. Whether or not the replacement of one dose of pegASNase for 6–9 doses of native ASNase can be achieved in adults with similar efficacy and acceptable toxicities to those achieved in children remains to be established.

Ki67 and PIM1 expression predict outcome in mantle cell lymphoma treated with high dose therapy, stem cell transplantation and rituximab: a Cancer and Leukemia Group B 59909 correlative science study

The proliferation index in mantle cell lymphoma (MCL) has not been validated in the context of aggressive therapy regimens in the rituximab era. We assessed Ki67 and PIM1 (a cell cycle-related gene upregulated in blastoid MCL) expression by immunohistochemistry in a phase II study Cancer and Leukemia Group B 59909 of aggressive chemotherapy and rituximab followed by autologous stem cell transplantation plus rituximab in untreated MCL patients <70 years of age. As a continuous variable or using a cutoff of 35%, higher image analysis (IA Ki67, n = 52) was associated with shorter progression free survival (PFS) (P ≤ 0.030) and event free survival (EFS) (P ≤ 0.017). PIM1 expression (n = 50) was associated with PFS (P = 0.033) and EFS (P = 0.043). Bivariate Cox models showed IA Ki67 and PIM1 were independent of clinical factors. High Ki67 (>35%) is an important independent prognostic marker in aggressively treated MCL in the rituximab era. PIM1 expression predicts poor outcome and, given its potential role as a therapeutic target, deserves further study.