Amanda F. Cashen

Multicenter, Phase II Study of Decitabine for the First-Line Treatment of Older Patients With Acute Myeloid Leukemia

PURPOSE Older patients with acute myeloid leukemia (AML) have limited treatment options because of the lack of effectiveness and the toxicity of available therapies. We investigated the efficacy and toxicity of the hypomethylating agent decitabine as initial therapy in older patients with AML. PATIENTS AND METHODS In this multicenter, phase II study, patients older than 60 years who had AML (ie, > 20% bone marrow blasts) and no prior therapy for AML were treated with decitabine 20 mg/m(2) intravenously for 5 consecutive days of a 4-week cycle. Response was assessed by weekly CBC and bone marrow biopsy after cycle 2 and after each subsequent cycle. Patients continued to receive decitabine until disease progression or an unacceptable adverse event occurred. RESULTS Fifty-five patients (mean age, 74 years) were enrolled and were treated with a median of three cycles (range, one to 25 cycles) of decitabine. The expert-reviewed overall response rate was 25% (complete response rate, 24%). The response rate was consistent across subgroups, including in patients with poor-risk cytogenetics and in those with a history of myelodysplastic syndrome. The overall median survival was 7.7 months, and the 30-day mortality rate was 7%. The most common toxicities were myelosuppression, febrile neutropenia, and fatigue. CONCLUSION Decitabine given in a low-dose, 5-day regimen has activity as upfront therapy in older patients with AML, and it has acceptable toxicity and 30-day mortality.

Impact of Mobilization and Remobilization Strategies on Achieving Sufficient Stem Cell Yields for Autologous Transplantation

The purpose of this article was to examine historic institutional autologous stem cell mobilization practices and evaluate factors influencing mobilization failure and kinetics. In this retrospective study we analyzed clinical records of 1834 patients who underwent stem cell mobilization for autologous transplantation from November 1995 to October 2006 at the Washington University in St. Louis. Successful mobilization was defined as collection of > or =2 x 10(6) CD34(+) cells/kg. From 1834 consecutive patients, 1040 met our inclusion criteria (502 non-Hodgkins lymphoma [NHL], 137 Hodgkins lymphoma, and 401 multiple myeloma [MM]). A total of 976 patients received granulocyte colony-stimulating factor (G-CSF) and 64 received G-CSF plus chemotherapy (G/C) for the initial mobilization. Although the median CD34(+) cell yield was higher in G/C group than in G-CSF alone group, the failure rates were similar: 18.8% and 18.6%, respectively. Overall, 53% of patients collected > or =2 x 10(6) CD34(+) cells/kg during the first apheresis with either mobilization regimen. Regardless of mobilization regimen used, MM patients had the highest total CD34(+) cell yield and required less aphereses to collect > or =2 x 10(6) CD34(+) cells/kg. Mobilized, preapheresis, peripheral blood CD34(+) count correlated with first day apheresis yield (r = .877, P < .001) and 20 cells/microL was the minimum threshold needed for a successful day 1 collection. For the remobilization analysis we included patients from the whole database. A total of 269 of 1834 patients underwent remobilization using G/C, G-CSF, and/or GM-CSF, and G-CSF plus plerixafor. Only 23% of remobilized patients achieved > or =2 x 10(6) CD34(+) cells/kg and 29.7% failed to pool sufficient number of stem cells from both collections. Patients receiving G-CSF plus plerixafor had lowest failure rates, P = .03. NHL patients remobilized with G-CSF who waited > or =25 days before remobilization had lower CD34(+) cell yield than those who waited < or =16 days, P = .023. Current mobilization regimens are associated with a substantial failure rate irrespective of underlying disease. Patients who fail initial mobilization are more likely to fail remobilization. These findings suggest that there is a need for more effective first-line mobilization agents.

A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia

The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide, and cytarabine. In phase 1, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose-limiting toxicities. In phase 2, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission and complete remission with incomplete blood count recovery rate (CR + CRi) of 46%. Correlative studies demonstrated a 2-fold mobilization in leukemic blasts into the peripheral circulation. No evidence of symptomatic hyperleukocytosis or delayed count recovery was observed with the addition of plerixafor. We conclude that the addition of plerixafor to cytotoxic chemotherapy is feasible in AML, and results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis.

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

BACKGROUND The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma

Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge, with limited effective treatment options available after stem cell transplantation. In a multicenter phase 2 study, the efficacy of lenalidomide in rel/ref cHL patients was evaluated at a dose of 25 mg/d on days 1-21 of a 28-day cycle. Patients remained on lenalidomide until disease progression or an unacceptable adverse event (AE) occurred. Thirty-eight cHL patients were enrolled with a median of 4 (range, 2-9) prior therapies; 87% had undergone prior stem cell transplantation and 55% of patients did not respond to their last prior therapy. Of 36 evaluable patients, responses were 1 complete remission (CR), 6 partial remissions (PRs), and 5 patients with stable disease (SD) for ≥ 6 months resulting in an International Working Committee (IWC) objective overall response rate (ORR) of 19% and a cytostatic ORR of 33%. Decreased chemokine (CCL17 and CCL22) plasma levels at 2 weeks were associated with a subsequent response. The treatment was well tolerated, and the most common grade 3/4 AEs were neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Four patients discontinued lenalidomide because of rash, elevated transaminases/bilirubin, and cytopenias. We provide preliminary evidence of lenalidomides activity in patients with rel/ref cHL, and therefore exploration of lenalidomide in combination with other active agents is warranted. This trial is registered at www.ClinicalTrials.gov as NCT00540007.

18F-FDG PET/CT for Early Response Assessment in Diffuse Large B-Cell Lymphoma: Poor Predictive Value of International Harmonization Project Interpretation

PET using 18F-FDG has prognostic value when performed at the completion of initial chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL). 18F-FDG PET may also be predictive of outcome when performed during the treatment course of DLBCL, but robust prospective studies and standardization of 18F-FDG PET interpretation in this setting are lacking. Methods: In this prospective study, patients with advanced-stage DLBCL were treated with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, and 18F-FDG PET/CT was performed after cycle 2 or 3 and at the end of therapy. The 18F-FDG PET/CT scans were interpreted according to the International Harmonization Project for Response Criteria in Lymphoma, and the maximum standardized uptake value (SUV) of the most 18F-FDG–avid lesions was recorded. Results: Fifty patients were enrolled, and all underwent interim 18F-FDG PET/CT. At a median follow-up of 33.9 mo, the positive predictive value (PPV) of interim 18F-FDG PET/CT for relapse or progression was 42%, and the negative predictive value (NPV) was 77%. Interim 18F-FDG PET/CT was significantly associated with event-free survival (P = 0.017) and with progression-free survival (P = 0.04) but not with overall survival (P = 0.08). End-of-therapy 18F-FDG PET/CT had high PPV and NPV (71% and 80%, respectively) and was significantly associated with event-free survival, progression-free survival, and overall survival (P < 0.001). SUV measurements did not discriminate patients who relapsed or progressed from those who remained in remission. Conclusion: When performed after 2 cycles of immunochemotherapy and interpreted according to International Harmonization Project criteria, early response assessment with PET/CT has a high NPV but low PPV in patients with advanced-stage DLBCL. Prospective trials are required to validate different criteria for the interpretation of interim 18F-FDG PET/CT and establish the role of interim 18F-FDG PET/CT in the management of patients with DLBCL.

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation.

Individuals affected with neurofibromatosis 1 (NF1) harbor increased numbers of GFAP-immunoreactive cerebral astrocytes and develop astrocytomas that can lead to blindness and death. Mice heterozygous for a targeted Nf1 mutation (Nf1+/−) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neurofibromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is sufficient for abnormal astrocyte proliferation. Here, we report that Nf1+/− mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/− astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were co-cultured with C17 neuronal cells. This C17 neuronal cell-induced Nf1+/− increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-ras-dependent effect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These findings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be sufficient for the development of astrocytic growth abnormalities in patients with NF1.

Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF?

Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.

A Phase II Study of Plerixafor (AMD3100) plus G-CSF for Autologous Hematopoietic Progenitor Cell Mobilization in Patients with Hodgkin Lymphoma

Collection of an adequate number of hematopoietic stem cells can be difficult in patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation (ASCT). Plerixafor (AMD3100), an inhibitor of the interaction between stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4, is an effective hematopoietic stem cell mobilization agent in patients with multiple myeloma and non-Hodgkin lymphoma (NHL). This study was undertaken to investigate the efficacy and safety of hematopoietic stem cell mobilization with plerixafor in patients with HL. Twenty-two patients with HL who were candidates for ASCT underwent hematopoietic stem cell mobilization with a combination of granulocyle-colony stimulating factor (G-CSF), 10 microg/kg daily, and plerixafor, 240 microg/kg subcutaneous, 10-11 hours prior to apheresis. The primary endpoint was the proportion of patients who collected>or=5x10(6) CD34+ cells/kg. Outcomes were compared to a historical control population of HL patients mobilized with G-CSF alone. Pharmacokinetic (PK) analysis of plerixafor was performed in a subset of patients. Fifteen patients (68%) collected>or=5x10(6) CD34+ cells/kg, and 21 patients (95%) achieved the minimum collection of >or=2x10(6) CD34+ cells/kg, in a median 2 apheresis procedures. Both the proportion of patients collecting>or=5x10(6) CD34+ cells/kg and the median CD34+ cells collected in days 1-2 of apheresis were significantly improved over historical controls. The PK of plerixafor in this patient population was similar to that previously seen in healthy volunteers. The regimen was generally safe and well tolerated.

A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia

Older patients with acute myeloid leukemia (AML) have limited treatment options and a poor prognosis, thereby warranting novel therapeutic strategies. We evaluated the efficacy of lenalidomide as front-line therapy for older AML patients. In this phase 2 study, patients 60 years of age or older with untreated AML received high-dose (HD) lenalidomide at 50 mg daily for up to 2 28-day cycles. If patients achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) or did not progress after 2 cycles of HD lenalidomide, they received low-dose lenalidomide (10 mg daily) until disease progression, an unacceptable adverse event, or completion of 12 cycles. Thirty-three AML patients (median age, 71 years) were enrolled with intermediate (55%), unfavorable (39%), or unknown (6%) cytogenetic risk. Overall CR/CRi rate was 30%, and 53% in patients completing HD lenalidomide. The CR/CRi rate was significantly higher in patients presenting with a low (< 1000/μL) circulating blast count (50%, P = .01). The median time to CR/CRi was 30 days, and duration of CR/CRi was 10 months (range, 1- ≥ 17 months). The most common grades ≥ 3 toxicities were thrombocytopenia, anemia, infection, and neutropenia. HD lenalidomide has evidence of clinical activity as initial therapy for older AML patients, and further study of lenalidomide in AML and MDS is warranted. This study is registered at www.clinicaltrials.gov as #NCT00546897.