Kay Ristow

Bleomycin Pulmonary Toxicity Has a Negative Impact on the Outcome of Patients With Hodgkin's Lymphoma

PURPOSE Bleomycin pulmonary toxicity (BPT) has been well described in Hodgkins lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. The influence of this pulmonary complication, along with the omission of bleomycin from further chemotherapy, on overall survival (OS) and progression-free survival (PFS) in HL remains unclear. We reviewed our experience with BPT in HL to better delineate outcome and appropriate treatment in these patients. PATIENTS AND METHODS One hundred forty-one patients who were treated with bleomycin-containing chemotherapy for newly diagnosed HL between January 1986 and February 2003 were eligible for this retrospective review. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence of an infectious etiology. RESULTS BPT was observed in 18% of patients. Increasing age, doxorubicin, bleomycin, vinblastine, and dacarbazine as initial therapy, and granulocyte colony-stimulating factor use were associated with the development of BPT. Patients with BPT had a median 5-year OS rate of 63% v 90% (P = .001) in unaffected patients. The mortality rate from BPT was 4.2% in all patients and 24% in patients who developed the pulmonary syndrome. BPT incidence and mortality were highest in patients older than 40 years. The omission of bleomycin had no impact on obtaining a complete remission, PFS, or OS. CONCLUSION BPT results in a significant decrease in 5-year OS in patients who are treated for HL. Age > or = 40 years seems to add substantially to the risk. In patients who do not die from acute pulmonary toxicity, both OS and PFS seem equal, despite the omission of bleomycin.

Prognostic Analysis for Survival in Adult Solid Organ Transplant Recipients With Post-Transplantation Lymphoproliferative Disorders

PURPOSE The objective of this study was to determine prognostic factors for overall survival in patients with post-transplantation lymphoproliferative disorders (PTLDs). PATIENTS AND METHODS This study focused on the 107 adult solid organ transplantation patients who were diagnosed with PTLDs at Mayo Clinic (Rochester, MN) between December 1970 and May 2003. RESULTS The median age at the time of diagnosis was 48 years (range, 15 to 75 years). Extranodal disease including grafted organ involvement was present in 85 patients (80%). The graft organ was involved in 30 patients (28%). At the time of these analyses, 62 patients (58%) had died. The median survival for the entire cohort was 31.5 months (95% CI, 10.7 to 72.5 months). The median follow-up of living patients was 51.8 months (range, 5.6 to 202.6 months). In univariate analyses for overall survival from the time of PTLD diagnosis, the following poor prognostic factors were identified: poor performance status with Eastern Cooperative Oncology Group levels 3 and 4 (P < .0001), grafted organ involvement (P = .0005), the presence of one or more extranodal sites (P = .005), both nodal and extranodal disease (P = .002), high International Prognostic Index (P = .006), advanced stage (P = .001), and elevated lactate dehydrogenase (P = .03). A final multivariable model for survival was constructed using three factors: poor performance status (3 to 4), monomorphic disease, and graft organ involvement. CONCLUSION A prognostic model has been developed for PTLD patients using one centers 30 years of experience. We propose additional confirmation and validation of these prognostic factors in larger prospective studies.

ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 × 10(-5)). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management.

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.

Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: are they two different diseases?

Background. The objective of the authors’ study was to characterize the clinical and pathologic differences between patients who develop posttransplant lymphoproliferative disorders (PTLD) early or late after transplantation and to assess the overall survival in these two groups. Methods. One hundred seven adult solid organ transplant patients were identified at the Mayo Clinic between December 1970 and May 2003. Results. Forty-nine patients developed PTLD within the first year (early PTLD, 1–11.8 months) and 58 patients developed PTLD after 1 year (late PTLD, 14 months–17 years). Patients with early PTLD more commonly had the following characteristics: positive Epstein-Barr virus (EBV) in situ hybridization status (P<0.0001), CD20-positive status (P=0.002), and involvement of the grafted organ (P=0.02). Overall survival did not differ between the two groups (P=0.25). PTLD may occur in two different settings with different characteristics. Conclusions. Early PTLD is more commonly EBV in situ hybridization-positive and CD20-positive, and more commonly involves the grafted organ.

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.

Subsequent Chemotherapy Regimens Are Well Tolerated After Radioimmunotherapy With Yttrium-90 Ibritumomab Tiuxetan for Non-Hodgkin’s Lymphoma

PURPOSE Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceutical, San Diego, CA) is an effective therapy for patients with relapsed B-cell non-Hodgkins lymphoma. The predominant toxicity of 90Y ibritumomab tiuxetan has been myelosuppression, and concern has been expressed about the tolerability of further treatment after this therapy. The goal of this analysis was to evaluate the therapy given to patients who relapsed after 90Y ibritumomab tiuxetan. PATIENTS AND METHODS A retrospective analysis was performed on 58 patients treated at a single institution on five separate protocols that used 90Y ibritumomab tiuxetan 0.4 mCi/kg. All patients had experienced disease progression after 90Y ibritumomab tiuxetan treatment and received subsequent therapy. The toxicity seen in this cohort of patients with subsequent treatment regimens was analyzed and compared with that of control groups who did not receive 90Y ibritumomab tiuxetan. RESULTS The median number of subsequent therapies was two (range, one to seven). Sixteen (28%) of the 58 patients received growth factor support with subsequent chemotherapy, and two patients were treated with reduced doses because of persistent pancytopenia. Eight patients subsequently had an autologous stem-cell transplantation with stem cells collected after 90Y ibritumomab tiuxetan therapy. Excluding patients hospitalized at the time of transplantation, 13 patients were hospitalized for neutropenic fever, thrombocytopenia, or both. When compared to patients who did not receive 90Y ibritumomab tiuxetan, there was no significant difference in toxicity. CONCLUSION We conclude that chemotherapy or autologous stem-cell transplantation after prior therapy with 90Y ibritumomab tiuxetan is feasible and reasonably well tolerated. The toxicity with subsequent therapy seems similar to that in patients not treated with 90Y ibritumomab tiuxetan.

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.

The clinical spectrum of Castleman's disease.

Castlemans disease (CD) is a rare, poorly understood lymphoproliferative disease. The spectrum of symptoms and course of disease are broad, but there is no large study describing the natural history of this disease. Basic clinic and laboratory data from the records of 113 patients with CD evaluated at the Mayo Clinic and University of Nebraska were abstracted. The impact of these variables on overall survival (OS) from time of diagnosis was evaluated. Sixty patients had multicentric disease. Of the patients with multicentric CD, 32% had criteria sufficient for a diagnosis of POEMS syndrome. For all patients, 2, 5, and 10‐year OS was 92%, 76%, 59%, respectively. Most of the factors identified as risk factors for death on univariate analysis cosegregated with diagnostic criteria for POEMS syndrome, which supported the concept of four categories of CD, which are (along with their 5‐year OS): (1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%). We have demonstrated that CD represents a spectrum of disease that can be differentiated by simple prognostic factors that provide a framework for further study. Am. J. Hematol. 2012.

Prognostic factors in patients with post-transplant lymphoproliferative disorders (PTLD) in the rituximab era.

To assess the effect of rituximab therapy and other prognostic factors on overall survival in patients with post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation, 30 consecutive patients diagnosed with PTLD between 1999 and 2002 were analyzed. Fifteen (50%) patients received rituximab (375 mg/m2 once a week). Fifteen (50%) patients had other interventions including observation, immunosuppression reduction, surgery, chemotherapy, radiation or a combination of these. Patients receiving rituximab vs. non-rituximab differed in the following variables: age at diagnosis of PTLD (P = 0.009), days to PTLD (P = 0.0005), Epstein-Barr virus (EBV) in situ hybridization status (P = 0.02) and CD20-positive status (P = 0.006). At the time of last follow-up, 10 (33%) patients in the rituximab group and 5 (17%) in the non-rituximab group were alive. On univariate analysis for overall survival of all 30 patients, the significant factors were: treatment with rituximab (P = 0.03), response to treatment (P = 0.005), CD20 positive (P = 0.0004), low international prognostic index (IPI; P = 0.02) and good performance status (P = 0.009). Multivariate analysis of all patients was significant for CD20-positive status (P = 0.0007) and low performance status (P = 0.006). On multivariate analysis for overall survival in patients with CD20-positive PTLD, low IPI (P = 0.004) and rituximab therapy (P = 0.03) were significant. Low IPI and rituximab therapy led to an improved overall survival in patients with CD20-positive PTLD.