Luis F. Porrata

A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma

The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkins lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20–41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant.

Malignant primary cardiac tumors: review of a single institution experience.

Primary cardiac sarcomas are uncommon. The authors undertook to review the Mayo Clinics experience with primary cardiac sarcomas consisting of 34 patients seen over a 32‐year period.

A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma

Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3‐kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin lymphoma (HL). The goal of this trial was to learn the antitumor activity and toxicity of everolimus in patients with relapsed/refractory HL. Patients were eligible if they had measurable disease, a platelet count >75,000, and an absolute neutrophil count >1,000. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Response was assessed after two and six cycles and then every three cycles until progression. Patients could remain on drug until progression or toxicity. Nineteen patients were enrolled. Median age was 37 years (range, 27–68). Patients had received a median of six prior therapies (range, 3–14) and 84% had undergone prior autologous stem cell transplant. The ORR was 47% (95% CI: 24–71%) with eight patients achieving a PR and one patient achieving a CR. The median TTP was 7.2 months. Four responders remained progression free at 12 months. Patients received a median of seven cycles of therapy. Of the 19 patients, one remains on therapy at 36 months; the others went off study because of progressive disease (16), toxicity (1), and death from infection (1). Four patients experienced a Grade 3 or higher pulmonary toxicity. Everolimus has single‐agent activity in relapsed/refractory HL and provides proof‐of‐concept that targeting the mTOR pathway in HL is clinically relevant. Am. J. Hematol., 2010.

Lenalidomide Combined With R-CHOP Overcomes Negative Prognostic Impact of Non–Germinal Center B-Cell Phenotype in Newly Diagnosed Diffuse Large B-Cell Lymphoma: A Phase II Study

PURPOSE Lenalidomide has significant single-agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). We demonstrated that lenalidomide can be safely combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone); this new combination is known as R2CHOP. The goal of this phase II study was to evaluate the efficacy of this combination in newly diagnosed DLBCL. PATIENTS AND METHODS Eligible patients were adults with newly diagnosed untreated stages II to IV CD20(+) DLBCL. Patients received lenalidomide 25 mg orally per day on days 1 through 10 with standard-dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry and classified as germinal center B-cell (GCB) versus non-GCB in the R2CHOP patients and 87 control patients with DLBCL from the Lymphoma Database who were treated with conventional R-CHOP. RESULTS In all, 64 patients with DLBCL were enrolled, and 60 were evaluable for response. The overall response rate was 98% (59 of 60) with 80% (48 of 60) achieving complete response. Event-free survival and overall survival (OS) rates at 24 months were 59% (95% CI, 48% to 74%) and 78% (95% CI, 68% to 90%), respectively. In R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% versus 64% (P < .001) and 46% versus 78% (P < .001) in non-GCB DLBCL versus GCB DLBCL, respectively. In contrast, there was no difference in 24-month PFS or OS for R2CHOP patients on the basis of non-GCB and GCB subtype (60% v 59% [P = .83] and 83% v 75% [P = .61] at 2 years, respectively). CONCLUSION R2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide appears to mitigate a negative impact of non-GCB phenotype on patient outcome.

Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in classical Hodgkin’s lymphoma

Background Lymphopenia and tumor-associated macrophages are negative prognostic factors for survival in classical Hodgkin’s lymphoma. We, therefore, studied whether the peripheral blood absolute lymphocyte count/absolute monocyte count ratio at diagnosis affects survival in classical Hodgkin’s lymphoma. Design and Methods We studied 476 consecutive patients with classical Hodgkin’s lymphoma followed at the Mayo Clinic from 1974 to 2010. Receiver operating characteristic curves and area under the curve were used to determine cut-off values for the absolute lymphocyte count/absolute monocyte count ratio at diagnosis, while proportional hazards models were used to compare survival based on the absolute lymphocyte count/absolute monocyte count ratio at diagnosis. Results The median follow-up period was 5.6 years (range, 0.1–33.7 years). An absolute lymphocyte count/absolute monocyte count ratio at diagnosis of 1.1 or more was the best cut-off value for survival with an area under the curve of 0.91 (95% confidence interval, 0.86 to 0.96), a sensitivity of 90% (95% confidence interval, 85% to 96%) and specificity of 79% (95% confidence interval, 73% to 88%). Absolute lymphocyte count/absolute monocyte count ratio at diagnosis was an independent prognostic factor for overall survival (hazard ratio, 0.18; 95% confidence interval, 0.08 to 0.38, P<0.0001); lymphoma-specific survival (hazard ratio, 0.10; 95% confidence interval, 0.04 to 0.25, P<0.0001); progression-free survival (hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.66, P<0.002) and time to progression (hazard ratio, 0.27; 95% confidence interval, 0.17 to 0.57, P<0.0006). Conclusions The ratio of absolute lymphocyte count/absolute monocyte count at diagnosis is an independent prognostic factor for survival and provides a single biomarker to predict clinical outcomes in patients with classical Hodgkin’s lymphoma.

Early lymphocyte recovery is a predictive factor for prolonged survival after autologous hematopoietic stem cell transplantation for acute myelogenous leukemia

Absolute lymphocyte count (ALC) recovery correlates with survival after autologous hematopoietic stem cell transplantation (AHSCT) for patients with multiple myeloma, non-Hodgkins lymphoma, and metastatic breast cancer. The role of ALC recovery in relationship to clinical outcome after AHSCT in patients with acute myelogenous leukemia is unknown. We analyzed 45 patients who underwent AHSCT at Mayo Clinic, Rochester, Minnesota between 1990 and 2000. The ALC threshold was selected at 500 cells/μl on day 15 post-AHSCT based on our previous studies. Thirty-two females and 13 males were included in the study with a median age of 45 years (range 12–75). The median follow-up was 14 months with a maximum of 129 months. The median overall and leukemia-free survival were significantly better for the 23 patients with ALC at day 15 ⩾500 cells/μl compared with 22 patients with ALC <500 cells/μl (not yet reached vs 10 months, P < 0.0009; 105 vs 9 months, P < 0.0008, respectively). In conclusion, ALC ⩾500 cells/μl on day 15 post-AHSCT is associated with better survival in acute myelogenous leukemia and requires further studies.

The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high-risk patients in diffuse large-B-cell lymphoma

Despite the use of modern immunochemotherapy regimens, almost 50% of patients with diffuse large-B-cell lymphoma will relapse. Current prognostic models, including the International Prognostic Index, incorporate patient and tumor characteristics. In contrast, recent observations show that variables related to host adaptive immunity and the tumor microenvironment are significant prognostic variables in non-Hodgkin lymphoma. Therefore, we retrospectively examined the absolute monocyte and lymphocyte counts as prognostic variables in a cohort of 366 diffuse large-B-cell lymphoma patients who were treated between 1993 and 2007 and followed at a single institution. The absolute monocyte and lymphocyte counts in univariate analysis predicted progression-free and overall survival when analyzed as continuous and dichotomized variables. On multivariate analysis performed with factors included in the IPI, the absolute monocyte and lymphocyte counts remained independent predictors of progression-free and overall survival. Therefore, the absolute monocyte and lymphocyte counts were combined to generate a prognostic score that identified patients with an especially poor overall survival. This prognostic score was independent of the IPI and added to its ability to identify high-risk patients.

Risk-adjusted manipulation of melphalan dose before stem cell transplantation in patients with amyloidosis is associated with a lower response rate.

Summary:High-dose chemotherapy and autologous stem cell transplantation are used increasingly to treat patients with light-chain-related amyloidosis (AL). Treatment-related mortality is approximately 15%. To enable more patients to undergo stem cell transplantation, a risk-adapted strategy has been developed to treat with lower chemotherapy doses those patients who are at excessive risk. It is unclear whether reducing the chemotherapy dose in patients at excessive risk of treatment toxicity reduces the overall response. We retrospectively reviewed 171 AL patients who underwent conditioning chemotherapy with stem cell transplantation. The patients comprised two groups: those receiving standard high-dose melphalan and those receiving intermediate-dose melphalan. Responses were categorized as hematologic response, which used criteria for myeloma response. The two groups showed statistically significant differences; the overall response rates were 75% in the high-dose group and 53% in the intermediate-dose group although treatment-related mortality was the same in both groups. Reducing the melphalan dose appeared to render more AL patients eligible for stem cell transplantation but sacrificed an element of response. Methods are needed to reduce treatment-related toxicity so that more patients can receive full-dose conditioning chemotherapy.

Early Lymphocyte Recovery Predicts Superior Survival after Autologous Stem Cell Transplantation in Non-Hodgkin Lymphoma: A Prospective Study

Day 15 absolute lymphocyte count (ALC-15) after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT) has been reported to be a significant predictor for survival in multiple hematologic malignancies. Limitations of previous reports included their retrospective nature and the lack of ALC-15 lymphocyte subset analyses. To address these limitations, from February 2002 until February 2007, 50 non-Hodgkin lymphoma (NHL) patients were enrolled in a prospective study. The primary endpoint of the study was to confirm prospectively the ALC-15 survival role after APHSCT in NHL. The secondary endpoint was to identify the ALC-15 lymphocyte subset affecting survival after APHSCT. With a median follow-up of 22.2 months (range: 6-63.7 months), patients with an ALC-15 > or =500 cells/microL (n = 35) experienced superior overall survival (OS) and progression-free survival (PFS) compared with those who did not; median OS: not reached versus 5.4 months, 3-year OS rates of 80% (95% confidence interval [CI]: 55%-95%) versus 37% (95% CI: 15%-65%), P < .0001; and median PFS: not reached versus 3.3 months, 3-year PFS rates of 63% (95% CI: 40%-85%) versus 13% (95% CI: 4%-40%), P < .0001, respectively. Univariately, CD16+/56+/CD3- natural killer (NK) cells were the only ALC-15 lymphocyte subset identified as a predictor for survival. Patients with an NK cell count > or =80 cells/microL (n = 38) experienced superior OS and PFS compared with those who did not (median OS: not reached versus 5 months, 3-year OS rates of 76% [95% CI: 57%-92%] versus 36% [95% CI: 11%-62%], P < .0001; and median PFS: not reached versus 3 months, 3-year PFS rates of 57% [95% CI: 38%-85%] versus 9% [95% CI: 1%-41%], P < .0001, respectively). Multivariate analysis showed that NK cells are an independent predictor for survival. This is the first study confirming the ALC-15 survival role prospectively and identifying NK cells as the key ALC-15 lymphocyte subset affecting survival after APHSCT.

Absolute lymphocyte count predicts overall survival in follicular lymphomas

The peripheral blood absolute lymphocyte count (ALC) recovery after autologous stem cell transplantation has been shown to be an independent prognostic factor for survival for different haematologic malignancies. The role of ALC at diagnosis for follicular (grades 1 and 2) lymphomas (FL) on survival is not well described. The primary objective of this study was to assess the role of ALC on overall survival (OS) in FL patients. Of 1104 FL patients, 228 patients were originally diagnosed, followed, and had all treatment at the Mayo Clinic from 1984 and 1999, were evaluated. The median follow‐up was 89 months (range: 8·35–248). ALC as a continuous variable was identified as a predictor for OS [Hazard ratio (HR) = 0·74, P < 0·04]. ALC ≥ 1·0 × 109/l (n = 164) predicted a longer OS versus ALC < 1·0 × 109/l (n = 64; 175 vs. 73 months respectively, P < 0·0001). When compared with the Follicular Lymphoma International Prognostic Index (FLIPI), ALC was an independent prognostic factor for OS by multivariate analysis (HR = 0·677, P < 0·0001). These data suggest a critical role of FL patients’ immune status at diagnosis on survival.