James W. Lynch

Phase II Trial of Individualized Rituximab Dosing for Patients With CD20-Positive Lymphoproliferative Disorders

PURPOSE To determine the feasibility and efficacy of pharmacokinetic (PK) -based maintenance dosing of rituximab and possibly design a more rational maintenance schedule. PATIENTS AND METHODS Patients with CD20-positive lymphoproliferative disorders were treated with four weekly infusions of rituximab 375 mg/m(2). All patients without progressive disease were then monitored for 1 year and received a single infusion of 375 mg/m(2) when the level decreased below 25 microg/mL. RESULTS Twenty-nine of 31 patients were assessable with a variety of histologic subtypes. The overall response rate (ORR) for the entire group was 59% with 27% complete responses (CRs) and 32% partial responses. The median PFS for all patients was 19 months, with a median follow-up of 25 months. In 22 patients with low-grade non-Hodgkins lymphoma (LGNHL), the ORR was 63% with 36% CR and median progression-free survival (PFS) has not been reached. Of 29 assessable patients, 22 were available for PK-based maintenance. The median time to repeat bolus was 5 months (range, 1 to 9 months) for the first, 3.5 months (range, 2 to 5 months) for the second, and 3 months (range, 2 to 4 months) for the third infusion. Ninety-five percent of patients required three or fewer infusions to be maintained in the therapeutic range. CONCLUSION Individualized PK dosing for rituximab produced efficacy comparable to other published maintenance strategies. PK data from this trial suggest that a rational maintenance strategy in patients with LGNHL would be a single dose of 375 mg/m(2) of rituximab every 3 to 4 months.

Poor mobilization of peripheral blood stem cells is a risk factor for worse outcome in lymphoma patients undergoing autologous stem cell transplantation

The effect of poor blood stem cells mobilization on the outcome of autologous stem cell transplantation (ASCT) has not been well studied. Our aim is to evaluate poor mobilization as a prognostic factor in lymphoma patients undergoing ASCT. We analyzed 90 consecutive patients with Hodgkins (HD) and non-Hodgkins lymphoma (NHL) who underwent ASCT. Poor mobilization was defined as the inability to obtain ≥ 1 × 10 6 CD34+ cells/kg ideal body weight with two large volume aphereses. Patients were divided into 2 groups: group 1=poor mobilizers, and group 2=good mobilizers. The poor mobilizers received lower median transplant CD34+ cell dose (2 × 10 6 vs. 4.5 × 10 6 /kg for good mobilizers, P =0.001 ), were more heavily pretreated (P =0.01), and required higher number of aphereses for PBSC collection (P =0.0006). The median progression-free survival (PFS) in groups 1 and 2 was 10 and 41 months (P =0.04), while the median overall survival (OS) was 38 months and not reached (P =0.02), respectively. Univariate analysis showed that ≥ 3 pre-transplant treatments, CD34+ cell dose ≤ 2 × 10 6, elevated LDH before transplant, and poor mobilization were significant prognostic factors for poor PFS, while only the first three were significant for worse OS. Multivariate analysis using these same four factors revealed that number of pre-transplant treatments (HR=6.03, P =0.001), CD34+ cell dose (HR=0.1, P =0.0007) were the only independent predictive factors for worse overall outcome. In conclusion, our data show that poor mobilization could indicate poor outcome in lymphoma patients undergoing ASCT, however, it is more likely to be a reflection of the heavy pre-transplant therapy and lower CD34+ cell dose re-infused in this group of patients.

The impact of radiotherapy dose and other treatment-related and clinical factors on in-field control in stage I and II non-Hodgkin's lymphoma.

PURPOSE/OBJECTIVE To assess local (in-field) disease control, identify potential prognostic factors, and elucidate the optimal radiotherapy dose in various clinical settings of Stage I and II non-Hodgkins lymphoma (non-CNS). MATERIALS & METHODS A total of 285 consecutive patients with Stage I and II non-Hodgkins lymphoma were treated with curative intent, including 159 with radiotherapy (RT) alone and 126 with combined-modality therapy (CMT). Of these, 72 patients had low-grade lymphomas (LGL), 92 had intermediate or high-grade lymphomas (I/HGL), and 21 had unclassified lymphomas. Clinical and treatment variables with potential prognostic significance for in-field disease control, freedom from relapse (FFR), and absolute survival (AS) were evaluated by univariate and multivariate analyses. RESULTS The 5-, 10-, and 20-year actuarial AS rates were 73%, 46%, and 33% for patients with LGL and 64%, 44%, and 18% for patients with I/HGL, respectively. The 5-, 10-, and 20-year actuarial FFR rates were 62%, 59%, and 49% for patients with LGL and 66%, 57%, and 57% for patients with I/HGL, respectively. Significant prognostic factors identified by the multivariate analysis were age, tumor size, and histology for AS; tumor size and treatment for FFR; and only tumor size for in-field disease control. There were 95 total failures, with only 12 occurring infield. Most failures (65%) were in contiguous unirradiated sites. All 4 in-field failures in patients with LGL occurred after RT doses < 30 Gy, although none occurred in 10 patients with small-volume LGL of the orbit treated with doses < 30 Gy. The 8 in-field failures in patients with I/HGL were distributed evenly throughout the RT dose range; 5 occurred in patients treated with CMT, all with tumors > 6 cm, and 4 with less than a complete response (CR) to chemotherapy. CONCLUSION Our analysis suggests that the overwhelming problem in the treatment of non-Hodgkins lymphoma is not in-field failure but, rather, failure in contiguous unirradiated sites. A dose of 20-25 Gy may be sufficient for small-volume LGL of the orbit. A dose of 30 Gy is sufficient for LGL in general, as well as for patients with nonbulky (< or = 6 cm) I/HGL treated with CMT who have a CR. However, patients with I/HGL treated with CMT for tumors > 6 cm and/or without a CR may benefit from doses > or = 40 Gy.

Effective Dose Reduction to Cardiac Structures Using Protons Compared With 3DCRT and IMRT in Mediastinal Hodgkin Lymphoma

PURPOSE We investigated the dosimetric impact of proton therapy (PT) on various cardiac subunits in patients with Hodgkin lymphoma (HL). METHODS AND MATERIALS From June 2009 through December 2010, 13 patients were enrolled on an institutional review board-approved protocol for consolidative involved-node radiotherapy (INRT) for HL. Three separate treatment plans were developed prospectively by using three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and PT. Cardiac subunits were retrospectively contoured on the 11 patients with intravenous-contrast simulation scans, and the doses were calculated for all treatment plans. A Wilcoxon paired test was performed to evaluate the statistical significance (p < 0.05) of 3DCRT and IMRT compared with PT. RESULTS The mean heart doses were 21 Gy, 12 Gy, and 8 Gy (relative biologic effectiveness [RBE]) with 3DCRT, IMRT, and PT, respectively. Compared with 3DCRT and IMRT, PT reduced the mean doses to the left and right atria; the left and right ventricles; the aortic, mitral, and tricuspid valves; and the left anterior descending, left circumflex, and right circumflex coronary arteries. CONCLUSIONS Compared with 3DCRT and IMRT, PT reduced the radiation doses to all major cardiac subunits. Limiting the doses to these structures should translate into lower rates of cardiac toxicities.

Non‐Hodgkin's lymphoma of the head and neck: A 30‐year experience at the university of Florida

Outcome in previously untreated patients with non‐Hodgkins lymphoma of the head and neck needed to be assessed.

Stevens-Johnson syndrome resulting from whole-brain radiation and phenytoin

Phenytoin, one of the most widely prescribed anticonvulsants, and steroids are routinely utilized for seizure prophylaxis in patients with various intracranial tumors. We report a case of severe Stevens-Johnson syndrome (SJS), documented by biopsy, which occurred in a patient, with metastatic squamous cell carcinoma receiving phenytoin, whole-brain radiation therapy (WBRT), and a tapering steroid dose. The pathogenesis and implications are then briefly discussed.

Involved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study.

PURPOSE This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. METHODS AND MATERIALS Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. RESULTS The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. CONCLUSIONS Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes were similar to those of conventional photon therapy.

Dose-intense ifosfamide/doxorubicin/cisplatin based chemotherapy for osteosarcoma in adults

The efficacy of neoadjuvant and adjuvant chemotherapy has been clearly established in the treatment of osteosarcoma; however, the most active regimen remains to be identified. This prospective study evaluated the efficacy and toxicity of a dose-intense ifosfamide, doxorubicin, and cisplatin-based neoadjuvant regimen in adults with osteosarcoma. We prospectively treated 20 patients with osteogenic sarcoma with two cycles of ifosfamide/doxorubicin followed by two cycles of doxorubicin/cisplatin every 2 weeks. Surgical specimens were analyzed for percent tumor necrosis. Patients who demonstrated a “good response” (GR) to chemotherapy received the same combination postoperatively at a lower dose rate. Patients who demonstrated a “poor response” (PR) received four cycles of high-dose methotrexate alternating with two cycles of ifosfamide/etoposide and two cycles of cisplatin/etoposide after the surgery. Neoadjuvant chemotherapy was well tolerated with moderate hematologic toxicity. Twelve of 19 evaluable patients (63%) were treated according to the GR arm and 7 according to the PR arm. At median follow-up of 5.5 years, disease-free survival (DFS) and overall survival (OS) are 68% and 74%, respectively. Patients treated on the GR arm had DFS and OS of 75% and 83%, respectively, whereas patients on the PR arm had DFS and OS of 57%. Intensive neoadjuvant chemotherapy is effective and moderately well tolerated in patients with de novo osteosarcoma. The outcome data suggest that lack of a near complete response to preoperative chemotherapy reflects inherent biologic resistance to chemotherapy and hence a poor prognosis.

Is comprehensive lymphatic irradiation for low-grade non-Hodgkin's lymphoma curative therapy? long-term experience at a single institution

PURPOSE This study reports 21 patients with Stage I-III low-grade non-Hodgkins lymphoma who were treated with comprehensive lymphatic irradiation (CLI) at the University of Florida between 1966 and 1992. METHODS AND MATERIALS Sites clinically involved with disease were treated with 30 Gy, whereas clinically uninvolved sites were treated with 25 Gy. Median follow-up for the group was 14 years (24.5 years for Stage III patients). RESULTS Overall absolute survival rates at 5, 10, and 15 years were 84%, 68%, and 34%. Cause-specific survival rates at 5, 10, and 15 years were 84%, 68%, and 56%. Freedom-from-relapse rates at 5, 10, and 15 years were 75%, 58%, and 58%, with no relapses noted after 10 years. Bulky disease (>6 cm) was a significant indicator of poor prognosis for cause-specific survival (p = .01). CONCLUSION These data support findings from other institutions suggesting a role for CLI as potentially curative therapy with acceptable toxicity and a short treatment time for patients with Stages I and II and limited Stage III disease.

The role of prognostic factors in treatment selection for early-stage Hodgkin's disease.

PurposeTo identify poor prognostic factors in early-stage Hodgkins disease that predict a high rate of relapse after radiotherapy alone. Materials and MethodsA total of 153 patients with stages I and II supradiaphragmatic Hodgkins disease, treated between 1964 and 1986 with either radiotherapy alone (120 patients) or combined modality therapy (33 patients), were studied retrospectively to determine factors affecting freedom from relapse and absolute survival. Median follow-up was 13 years. Clinical factors were assessed by the stepwise use of a stratified log-rank test and included maximum tumor dimension in any site (≤6 cm or >6 cm), age (≤40 or >40), presence or absence of B symptoms, pathologic and clinical stages (I or II), number of sites involved (≤4 or >4), gender, histologic subtype, and large mediastinal mass (none, small [≤6 cm], large [>6 cm]). ResultsThe only factors independently predicting a high rate of relapse were tumor dimension (>6 cm) and number of sites (>4 sites). At 10 years, in patients with and without the two poor prognostic factors treated with radiotherapy alone, the freedom from relapse rates were 53% and 84% (p < .0001) and the absolute survival rates were 72% and 85% (p = .004), respectively. Combined modality therapy significantly improved freedom from relapse, but not absolute survival, in patients with one or both poor prognostic factors. ConclusionsTwo poor prognostic factors were identified that were highly significant in predicting a high risk of relapse after radiotherapy alone. The addition of three cycles of chemotherapy to standard radiotherapy significantly reduced the relapse rate in high-risk patients.