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1.  Prospective Study of FLT PET for Early Interim Response Assessment in Advanced Stage B-cell Lymphoma 
Current clinical and imaging tools remain suboptimal for early assessment of prognosis and treatment response in aggressive lymphomas. Positron emission tomography (PET) with 18F-fluorothymidine (FLT) can be used to measure tumor cell proliferation and treatment response. In a prospective study in patients with advanced stage B-cell lymphoma we investigated the prognostic and predictive value of FLT PET in comparison to standard imaging with FDG PET and clinical outcome.
Patients and Methods
65 patients were treated with an induction/consolidation regimen consisting of four cycles of R-CHOP-14 followed by 3 cycles of ICE. FLT PET was performed at baseline and at interim (iPET) after 1–2 cycles of therapy. FDG PET was performed at baseline, after cycle 4, and at the end of therapy. The relationship between PET findings, progression free survival (PFS) and overall survival (OS) was investigated.
With a median follow-up of 51 months, PFS and OS were 71% and 86% respectively. FLT iPET, analyzed visually, using a 5-point score, or semi-quantitatively, using SUV and ΔSUV, predicted both PFS and OS (p<0.01 for all parameters). Residual FLT SUVmax on iPET was associated with an inferior PFS (HR: 1.26, p=0.001) and OS (HR: 1.27, p=0.002). Using FDG PET, findings in the end of treatment scan were better predictors of PFS and OS than findings on interim scan. Baseline PET imaging parameters, including SUV, proliferative or metabolic tumor volume, did not correlate with outcome.
FLT PET after 1–2 cycles of chemotherapy predicts PFS and OS, and a negative FLT iPET may potentially help design risk-adapted therapies in patients with aggressive lymphomas. In contrast, the positive predictive value of FLT iPET remains too low to justify changes in patient management.
PMCID: PMC4854760  PMID: 26719374
FLT PET; B-cell cell lymphoma; FDG PET; outcome
2.  A Positive Prospective Trial of Antibiotic Therapy in Advanced Stage, Non-Bulky Indolent Lymphoma 
We have prospectively studied a three month course of clarithromycin (substituted by Prevpac®, lansoprazole/ amoxicillin/ clarithromycin, in the first two wks when stool H pylori+) for non-bulky, advanced stage indolent lymphoma. These patients are often candidates for expectant monitoring and it is during this period that a window of opportunity may exist to identify and treat associated infections.
All previously untreated patients with a new diagnosis of indolent lymphoma (FL and non-FL) meeting GELF criteria were treated with 12 weeks of clarithromycin. There were 32 evaluable patients, 4 of whom had stool H pylori.
At one month post-antibiotic therapy, we have observed lymphoma responses in 7 of 32 patients (21.9%). Two additional patients had objective response during followup (28.1% overall response). The median treatment free survival for antibiotic responders is 69.9 months and for non-responders, 30.6 months (p = 0.019).
Three response patterns have been noted, perhaps suggestive of an immune-mediated response -- prompt PET negative; flair with delayed PET negative response; and gradual continuous improvement. This prospective study appears promising, may be a step toward developing a lymphoma prevention strategy by reducing “antigen drive,” and deserves further clinical/biological study.
PMCID: PMC4718606  PMID: 26798624
Clarithromycin; indolent lymphoma; free survival; antibiotic; improvement; treatment
3.  Treatment Patterns and Comparative Effectiveness in Elderly Diffuse Large B-Cell Lymphoma Patients: A Surveillance, Epidemiology, and End Results-Medicare Analysis 
The Oncologist  2014;19(12):1249-1257.
A disproportionate number of incident diffuse large B-cell lymphoma (DLBCL) occurs in elderly patients. Evidence from this analysis suggests that chemoimmunotherapy effectiveness is similar for elderly patients in routine oncology practice and younger patients from clinical trial settings. Age alone should not discourage the use of guideline-recommended therapies for DLBCL.
The incidence of diffuse large B-cell lymphoma (DLBCL) occurs disproportionately in elderly patients. We evaluated real-world treatment patterns and outcomes in elderly DLBCL patients in the U.S.
Materials and Methods.
A retrospective cohort analysis of 9,333 DLBCL patients from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was conducted. Patients were diagnosed between January 1, 2000, and December 31, 2007; were aged >66 years, and were continuously enrolled in Medicare Part A and B in the year prior to diagnosis. Within 3 months of diagnosis, 4,565 (49%) received rituximab plus chemotherapy (R+chemo), 2,181 (23%) received chemotherapy only, and 467 (5%) received rituximab monotherapy (R-mono). Cox proportional hazards regression assessed overall survival between R+chemo versus chemotherapy only and R-mono versus no treatment.
Overall, 23% of patients received no treatment, and the proportion was higher among those aged >80 years (33%). Patients receiving R+chemo were younger and more likely white compared with those receiving chemotherapy only. Patients receiving R-mono were older and more likely female compared with those not treated. In multivariate analysis, patients receiving chemotherapy only had a twofold increased mortality risk versus R+chemo, and this was confirmed in a subanalysis of patients aged >80 years. A 91% higher mortality risk was noted with receipt of fewer than six cycles versus six cycles of chemotherapy or chemoimmunotherapy. Patients receiving R-mono had a 69% decreased mortality risk compared with patients who were not treated.
This real-world analysis of elderly DLBCL patients confirmed that 23% do not receive treatment. Overall survival is higher for patients receiving R+chemo and R-mono relative to chemotherapy only and no treatment, respectively. Suboptimal durations of therapy with curative intent (fewer than six cycles) were associated with poorer outcomes.
PMCID: PMC4257739  PMID: 25342313
Diffuse large B-cell lymphoma; Elderly patients; Chemotherapy; Treatment; Survival
4.  Phase 2 Study of Weekly Bortezomib in Mantle Cell and Follicular Lymphoma 
British journal of haematology  2009;146(6):652-655.
Twice-weekly bortezomib has proven activity in mantle cell (MCL) and indolent lymphomas. This study explored a weekly schedule of bortezomib in follicular lymphoma (FL) and MCL. Although weekly bortezomib was better tolerated, the overall response rate (ORR) was inferior (18% vs. 50%, p = 0.02) with no complete remissions (CR) (compared with 18% CR for the twice-weekly schedule). Progression-free survival (PFS) was not different. The weekly schedule of bortezomib was less toxic, but yielded fewer and lower quality responses than twice-weekly bortezomib. Given the similar PFS, the weekly schedule may still be appropriate for some patients.
PMCID: PMC4035037  PMID: 19624539
Bortezomib; Follicular Lymphoma; Mantle cell Lymphoma; Non-Hodgkin Lymphoma; Proteasome inhibitor
5.  High-Dose Chemo-Radiotherapy for Relapsed or Refractory Hodgkin Lymphoma and the Significance of Pre-transplant Functional Imaging 
British journal of haematology  2010;148(6):890-897.
We previously reported that three risk factors (RF): initial remission duration <1 year, active B symptoms, and extranodal disease predict outcome in relapsed or refractory Hodgkin lymphoma (HL). Our goal was to improve event-free survival (EFS) for patients with multiple RF and to determine if response to salvage therapy impacted outcome. We conducted a phase II intent-to-treat study of tailored salvage treatment: patients with 0 or 1 RF received standard-dose ifosfamide, carboplatin, and etoposide (ICE); patients with 2 RF received augmented ICE; patients with 3 RF received high-dose ICE with stem cell support. This was followed by evaluation with both computed tomography and functional imaging (FI); those with chemosensitive disease underwent high-dose chemoradiotherapy and autologous stem cell transplantation (ASCT). There was no treatment-related mortality. Compared to historical controls this therapy eliminated the difference in EFS between the 3 prognostic groups. Pre-ASCT FI predicted outcome; 4-year EFS rates was 33% vs. 77% for patients transplanted with positive vs negative FI respectively, p=0.00004, hazard ratio 4.61. Risk-adapted augmentation of salvage treatment in patients with HL is feasible and improves EFS in poorer-risk patients. Our data suggest that normalization of FI pre-ASCT predicts outcome, and should be the goal of salvage treatment.
PMCID: PMC3920913  PMID: 20085577
Hodgkin Lymphoma; HSCT; high-dose chemoradiotherapy
6.  Phase II Study of Bendamustine in Relapsed and Refractory Hodgkin Lymphoma 
Journal of Clinical Oncology  2012;31(4):456-460.
Limited data exist regarding the activity of bendamustine in Hodgkin lymphoma (HL). This phase II study evaluated the efficacy of bendamustine in relapsed and refractory HL.
Patients and Methods
Patients with relapsed and refractory HL who were ineligible for autologous stem-cell transplantation (ASCT), or for whom this treatment failed, received bendamustine 120 mg/m2 as a 30-minute infusion on days 1 and 2 every 28 days with growth factor support. The primary end point was overall response rate (ORR). A secondary end point was referral rate to allogeneic stem-cell transplantation (alloSCT) for patients deemed eligible for alloSCT at the time of enrollment.
Of the 36 patients enrolled, 34 were evaluable for response. Patients had received a median of four prior treatments, and 75% had relapsed after ASCT. The ORR by intent-to-treat analysis was 53%, including 12 complete responses (33%) and seven partial responses (19%). The response rate among evaluable patients was 56%. Responses were seen in patients with prior refractory disease, prior ASCT, and prior alloSCT; however, no responses were seen in patients who relapsed within 3 months of ASCT. The median response duration was 5 months. Five patients (20% of those eligible) proceeded to alloSCT after treatment with bendamustine. Grade ≥ 3 adverse events were infrequent and most commonly included thrombocytopenia (20%), anemia (14%), and infection (14%).
This study confirms the efficacy of bendamustine in heavily pretreated patients with HL. These results support current and future studies evaluating bendamustine combinations in relapsed and refractory HL.
PMCID: PMC3862960  PMID: 23248254
7.  Risk-Adapted Dose-Dense Immunochemotherapy Determined by Interim FDG-PET in Advanced-Stage Diffuse Large B-Cell Lymphoma 
Journal of Clinical Oncology  2010;28(11):1896-1903.
In studies of diffuse large B-cell lymphoma, positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) performed after two to four cycles of chemotherapy has demonstrated prognostic significance. However, some patients treated with immunochemotherapy experience a favorable long-term outcome despite a positive interim FDG-PET scan. To clarify the significance of interim FDG-PET scans, we prospectively studied interim FDG-positive disease within a risk-adapted sequential immunochemotherapy program.
Patients and Methods
From March 2002 to November 2006, 98 patients at Memorial Sloan-Kettering Cancer Center received induction therapy with four cycles of accelerated R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by an interim FDG-PET scan. If the FDG-PET scan was negative, patients received three cycles of ICE (ifosfamide, carboplatin, and etoposide) consolidation therapy. If residual FDG-positive disease was seen, patients underwent biopsy; if the biopsy was negative, they also received three cycles of ICE. Patients with a positive biopsy received ICE followed by autologous stem-cell transplantation.
At a median follow-up of 44 months, overall and progression-free survival were 90% and 79%, respectively. Ninety-seven patients underwent interim FDG-PET scans; 59 had a negative scan, 51 of whom are progression free. Thirty-eight patients with FDG-PET–positive disease underwent repeat biopsy; 33 were negative, and 26 remain progression free after ICE consolidation therapy. Progression-free survival of interim FDG-PET–positive/biopsy-negative patients was identical to that in patients with a negative interim FDG-PET scan (P = .27).
Interim or post-treatment FDG-PET evaluation did not predict outcome with this dose-dense, sequential immunochemotherapy program. Outside of a clinical trial, we recommend biopsy confirmation of an abnormal interim FDG-PET scan before changing therapy.
PMCID: PMC3651601  PMID: 20212248
8.  Distress in Older Patients With Cancer 
Journal of Clinical Oncology  2009;27(26):4346-4351.
To determine the predictors of distress in older patients with cancer.
Patients and Methods
Patients age ≥ 65 years with a solid tumor or lymphoma completed a questionnaire that addressed these geriatric assessment domains: functional status, comorbidity, psychological state, nutritional status, and social support. Patients self-rated their level of distress on a scale of zero to 10 using a validated screening tool called the Distress Thermometer. The relationship between distress and geriatric assessment scores was examined.
The geriatric assessment questionnaire was completed by 245 patients (mean age, 76 years; standard deviation [SD], 7 years; range, 65 to 95 years) with cancer (36% stage IV; 71% female). Of these, 87% also completed the Distress Thermometer, with 41% (n = 87) reporting a distress score of ≥ 4 on a scale of zero to 10 (mean score, 3; SD, 3; range, zero to 10). Bivariate analyses demonstrated an association between higher distress (≥ 4) and poorer physical function, increased comorbid medical conditions, poor eyesight, inability to complete the questionnaire alone, and requiring more time to complete the questionnaire. In a multivariate regression model based on the significant bivariate findings, poorer physical function (increased need for assistance with instrumental activities of daily living [P = .015] and lower physical function score on the Medical Outcomes Survey [P = .018]) correlated significantly with a higher distress score.
Significant distress was identified in 41% of older patients with cancer. Poorer physical function was the best predictor of distress. Further studies are needed to determine whether interventions that improve or assist with physical functioning can help to decrease distress in older adults with cancer.
PMCID: PMC2799049  PMID: 19652074
9.  Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies 
Journal of Clinical Oncology  2009;27(26):4357-4364.
To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma.
Patients and Methods
Pralatrexate, initially given at a dose of 135 mg/m2 on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m2 weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/μL, and a platelet count greater than 50,000/μL for the first dose of any cycle.
The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m2 weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months.
Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.
PMCID: PMC3651599  PMID: 19652067
10.  Placebo-Controlled Phase III Trial of Patient-Specific Immunotherapy With Mitumprotimut-T and Granulocyte-Macrophage Colony-Stimulating Factor After Rituximab in Patients With Follicular Lymphoma 
Journal of Clinical Oncology  2009;27(18):3036-3043.
To evaluate patient-specific immunotherapy with mitumprotimut-T (idiotype keyhole limpet hemocyanin [Id-KLH]) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD20+ follicular lymphoma.
Patients and Methods
Patients with treatment-naive or relapsed/refractory disease achieving a complete response (CR), partial response (PR), or stable disease (SD) with four weekly rituximab infusions were randomly assigned to mitumprotimut-T/GM-CSF or placebo/GM-CSF, with doses given monthly for six doses, every 2 months for six doses, and then every 3 months until disease progression (PD). Randomization was stratified by prior therapy (treatment-naive or relapsed/refractory) and response to rituximab (CR/PR or SD). The primary end point was time to progression (TTP) from randomization.
A total of 349 patients were randomly assigned; median age was 54 years, 79% were treatment naive, and 86% had stage III/IV disease. Median TTP was 9.0 months for mitumprotimut-T/GM-CSF and 12.6 months for placebo/GM-CSF (hazard ratio [HR] = 1.384; P = .019). TTP was comparable between the two arms in treatment-naive patients (HR = 1.196; P = .258) and shorter with mitumprotimut-T/GM-CSF in relapsed/refractory disease (HR = 2.265; P = .004). After adjusting for Follicular Lymphoma International Prognostic Index (FLIPI) scores, the difference in TTP between the two arms was no longer significant. Overall objective response rate, rate of response improvement, and duration of response were comparable between the two arms. Toxicity was similar in the two arms; 76% of adverse events were mild or moderate, and 94% of patients had injection site reactions.
TTP was shorter with mitumprotimut-T/GM-CSF compared with placebo/GM-CSF. This difference was possibly due to the imbalance in FLIPI scores.
PMCID: PMC3646306  PMID: 19414675

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