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1.  Phase III Randomized Intergroup Trial of CHOP Plus Rituximab Compared With CHOP Chemotherapy Plus 131Iodine-Tositumomab for Previously Untreated Follicular Non-Hodgkin Lymphoma: SWOG S0016 
Journal of Clinical Oncology  2012;31(3):314-320.
Purpose
Advanced follicular lymphomas (FL) are considered incurable with conventional chemotherapy and there is no consensus on the best treatment approach. Southwest Oncology Group (SWOG) and Cancer and Leukemia Group B compared the safety and efficacy of two immunochemotherapy regimens for FL in a phase III randomized intergroup protocol (SWOG S0016) that enrolled 554 patients with previously untreated, advanced-stage FL between March 1, 2001, and September 15, 2008.
Patients and Methods
Patients were eligible for the study if they had advanced-stage (bulky stage II, III, or IV) evaluable FL of any grade (1, 2, or 3) and had not received previous therapy. In one arm of the study, patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy at 3-week intervals with six doses of rituximab (CHOP-R). In another arm of the study, patients received six cycles of CHOP followed by consolidation with tositumomab/iodine I-131 tositumomab radioimmunotherapy (RIT).
Results
After a median follow-up period of 4.9 years, the 2-year estimate of progression-free survival (PFS) was 76% on the CHOP-R arm and 80% on the CHOP-RIT arm (P = .11). The 2-year estimate of overall survival (OS) was 97% on the CHOP-R arm and 93% on the CHOP-RIT arm (P = .08).
Conclusion
There was no evidence of a significant improvement in PFS comparing CHOP-RIT with CHOP-R. However, PFS and OS were outstanding on both arms of the study. Future studies are needed to determine the potential benefits of combining CHOP-R induction chemotherapy with RIT consolidation and/or extended rituximab maintenance therapy.
doi:10.1200/JCO.2012.42.4101
PMCID: PMC3732010  PMID: 23233710
2.  Mantle Cell Lymphoma International Prognostic Index but Not Pretransplantation Induction Regimen Predicts Survival for Patients With Mantle-Cell Lymphoma Receiving High-Dose Therapy and Autologous Stem-Cell Transplantation 
Journal of Clinical Oncology  2011;29(22):3023-3029.
Purpose
High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of intensive induction regimens before transplantation is unknown.
Patients and Methods
To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers.
Results
The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio [HR], 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients ≤ 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT.
Conclusion
An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis.
doi:10.1200/JCO.2010.33.7055
PMCID: PMC3157964  PMID: 21730271
3.  The Effective Use of Plerixafor as a Real-Time Rescue Strategy for Patients Poorly Mobilizing Autologous CD34+ cells 
Journal of clinical apheresis  2012;27(2):81-87.
Plerixafor enhances CD34+ cell mobilization, however, its optimal use is unknown. We hypothesized that plerixafor could “rescue” patients in the midst of mobilization when factors indicated a poor CD34+ yield. Of 295 consecutive autologous peripheral blood mobilization attempts at our center, 39 (13%) utilized plerixafor as rescue strategy due to a CD34+ cell concentration <10/µL (median 5.95/µL, n=30), low CD34+ cell yield from prior apheresis day (median 1.06 × 106 CD34+ cells/kg, n=7), or other (n=2). Patients received a median of 1 plerixafor dose (range 1–4). Thirty-four (87%) collected ≥ 2 × 106 CD34+ cells /kg and 26 (67%) collected ≥ 4 × 106 CD34+ cells /kg. Median collections for lymphoma (n=24) and myeloma (n=15) patients were 4.1 × 106 and 8.3 × 106 CD34/kg, respectively. A single dose of plerixafor was associated with an increase in the mean peripheral blood CD34+ concentration of 17.2 cells/µL (p<0.001) and mean increased CD34+ cell yield following a single apheresis of 5.11 × 106/kg (p<0.03). A real-time rescue use of plerixafor is feasible and may allow targeted use of this agent.
doi:10.1002/jca.21206
PMCID: PMC4004340  PMID: 22298418
AMD-3100; peripheral-blood stem cell mobilization; salvage
4.  A Phase I Study of Pulse High-Dose Vorinostat (V) plus Rituximab (R), Ifosphamide, Carboplatin, and Etoposide (ICE) in Patients with Relapsed Lymphoma 
British journal of haematology  2013;161(2):183-191.
SUMMARY
Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2.5 μM concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 days in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients (median age 56 years, median 2 prior therapies, 14 chemoresistant [of 27 evaluable], 2 prior transplants) were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 days. Common dose limiting toxicities included infection (n=2), hypokalaemia (n=2), and transaminitis (n=2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4.5 μM (range 4.2–6.0 μM) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted.
doi:10.1111/bjh.12230
PMCID: PMC3618618  PMID: 23356514
lymphoma; vorinostat; clinical trial; 2 stage design; phase I
5.  Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma 
Journal of Clinical Oncology  2012;30(18):2183-2189.
Purpose
Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas.
Patients and Methods
In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility.
Results
The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea.
Conclusion
The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.
doi:10.1200/JCO.2011.38.0410
PMCID: PMC3646316  PMID: 22454421
6.  Histology and Time to Progression Predict Survival for Lymphoma Recurring after Reduced Intensity Conditioning and Allogeneic Hematopoietic Cell Transplantation 
Reduced-intensity-conditioning (RIC) prior to allogeneic hematopoietic cell transplantation (HCT) is increasingly employed as a potentially curative option for patients with advanced lymphoma; however relapse remains a major challenge. Unfortunately, little data exist on the outcomes, predictors of survival, and results of specific management strategies of such individuals. One-hundred-one consecutive relapses occurred and were evaluated in 280 lymphoma patients following RIC-HCT. Characteristics included: aggressive non-Hodgkin lymphoma (NHL) (n=42), indolent NHL (n=33) and Hodgkin’s Lymphoma (HL) (n=26). Median time to relapse was 90 (range 3 - 1275) days and graft-versus-host-disease at relapse was present in 56 (55%) patients. Interventions following relapse included no therapy (n=14), withdrawal of immunosuppression alone (n=11), chemoradiotherapy (n=60), and donor lymphocyte infusion/second HCT (n=16). Overall survival (OS) at 3 and 5 years following relapse was 33% (95%CI 23-44%) and 23% (95%CI 13-34%), respectively. Aggressive NHL (vs indolent disease, HR=2.29, p=.008) and relapse <1 month after HCT (vs >6 months HR=3.17 p=.004) were each associated with increased mortality. Estimated 3-year OS after relapse for aggressive, indolent and HL was 16% (95%CI 5-32%), 40% (95%CI 19-61%) and 47% (95%CI 29-64%), respectively. The 1-year survival for patients relapsing within 1 month of HCT was 24% as compared to 52%, 74%, and 77%, for those relapsing at 1-3 months, 3-6 months, and >6 months after HCT. We conclude that despite relapse of lymphoma after RIC-HCT, some patients can experience prolonged survival with better post-relapse outcomes occurring in patients with indolent NHL, HL or late relapse.
doi:10.1016/j.bbmt.2011.03.010
PMCID: PMC3176968  PMID: 21536145
7.  A preclinical model of CD38-pretargeted radioimmunotherapy for plasma cell malignancies 
Cancer research  2013;74(4):1179-1189.
The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma (MM) has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on plasma cell malignancies. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin-biotin pretargeted RIT (PRIT) directed against the CD38 antigen, were assessed as approaches to deliver radiation doses sufficient for MM cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24hr after PRIT, while ratios never exceeded 1:1 with conventional RIT. 90Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 µCi to 1200 µCi of anti-CD38 pretargeted 90Y-DOTA-biotin, including 100% complete remissions (no detectable tumor in treated mice compared to tumors that were 2982±2834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 µCi of anti-CD38 pretargeted 90Y-DOTA-biotin achieved long-term myeloma-free survival (>70 days) compared to none (0%) of the control animals.
doi:10.1158/0008-5472.CAN-13-1589
PMCID: PMC3970848  PMID: 24371230
Radioimmunotherapy; multiple myeloma; CD38; pretargeting; preclinical
8.  Treatment strategies for Hodgkin lymphoma recurring following autologous hematopoietic stem cell transplantation 
Hodgkin lymphoma (HL) represents one of the great success stories in hematology going from a uniformly fatal disease, to one that is curable in the vast majority of cases. Despite this success, some patients experience relapse. To address this unmet need a variety of agents, classes of drugs, and strategies have demonstrated activity in HL recurring after autologous hematopoietic stem cell transplantation. These include chemotherapeutics (gemcitabine-based combinations, bendamustine), histone deacetylase (HDAC) inhibitors (panobinostat), immunomodulatory agents (lenalidomide), mTOR inhiobitors (everolimus), monoclonal antibodies (rituximab), and antibody-drug conjugates (brentuximab vedotin) as well the potential of long-term disease control via allogeneic transplantation. Such advances reflect our increased understanding of the biology of HL and hold promise for continued improved outcomes for those suffering with this condition.
doi:10.5045/kjh.2012.47.1.8
PMCID: PMC3317478  PMID: 22479273
Hodgkin lymphoma; Antibody drug conjugates; allogeneic transplant; HDAC inhibitor; IMID; mTOR
9.  Efficacy and Safety of Gemcitabine (G), Carboplatin (C), Dexamethasone (D), and Rituximab (R) in Patients with Relapsed/Refractory Lymphoma: A Prospective Multi-center Phase II Study of by the Puget Sound Oncology Consortium (PSOC) 
Leukemia & lymphoma  2010;51(8):1523-1529.
We conducted a multi-center phase II trial of gemcitabine (G), carboplatin (C), dexamethasone (D), and rituximab (R) in order to examine its safety and efficacy as an outpatient salvage regimen for lymphoma. Fifty-one patients received 2–4 21-day cycles of G (1000mg/m2, days 1 and 8), C (AUC=5, day 1), D (40mg daily days 1–4), and R (375mg/m2, day 8 for CD20 positive disease) and were evaluable for response. Characteristics included: median age 58y (19–79y), stage III/IV 88%, elevated LDH 33%, median prior therapies 2, prior stem cell transplant 12%, chemoresistant 62%, median prior remission duration 2.5 months. The overall and complete response rates were 67% (95% confidence interval [CI], 54–80%) and 31% (95% CI 19–44%), respectively, with activity seen in a broad variety of histologies. Responses occurred in 16 of 17 (94%, 95% CI 83–100%) transplant eligible patients and 15 of 28 (54%, 95% CI 34–71%) with chemoresistant disease. The median CD34 yield in patients attempting peripheral blood stem cell (PBSC) collection following this regimen was 10.9 × 106 CD34+ cells/kg (range, 5.0 – 24.1 × 106). Hematologic toxicity was common but febrile neutropenia (2.5%) and grade 4 non-hematologic adverse events (n=2) were rare with no treatment-related deaths. GCD(R) is a safe and effective outpatient regimen for relapsed lymphoma and successfully mobilizes PBSC.
doi:10.3109/10428194.2010.491137
PMCID: PMC3018339  PMID: 20578815
10.  Anti-CD45 Radioimmunotherapy with 90Y but Not 177Lu Is Effective Treatment in a Syngeneic Murine Leukemia Model 
PLoS ONE  2014;9(12):e113601.
Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11) targeted hematologic tissues, as at 24 hours 48.8±21.2 and 156±14.6% injected dose per gram of tissue (% ID/g) of 90Y-DOTA-30F11 and 54.2±9.5 and 199±11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM) and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model.
doi:10.1371/journal.pone.0113601
PMCID: PMC4252056  PMID: 25460570
11.  A Comparative Analysis of Prognostic Factor Models for Follicular Lymphoma based on a Phase III Trial of CHOP-Rituximab vs CHOP + 131Iodine-Tositumomab 
Purpose
There is currently no consensus on optimal front-line therapy for patients with follicular lymphomas (FL). We analyzed a Phase III randomized intergroup trial comparing 6 cycles of CHOP-R with six cycles of CHOP followed by iodine I-131 tositumomab radioimmunotherapy (RIT) to assess whether any subsets benefitted more from one treatment or the other, and to compare three prognostic models.
Experimental Design
We conducted univariate and multivariate Cox regression analyses of 532 patients enrolled on this trial and compared the prognostic value of the FLIPI, FLIPI2, and LDH + β2M models.
Results
Outcomes were excellent, but not statistically different between the two study arms (5 year PFS of 60% with CHOP-R and 66% with CHOP-RIT [p =0.11]; 5-yr OS of 92% with CHOP-R and 86% with CHOP-RIT [p=0.08]; overall response rate of 84% for both arms). The only factor found to potentially predict the impact of treatment was serum β2 microglobulin (β2M); among patients with normal β2M, CHOP-RIT patients had better PFS compared to CHOP-R patients, whereas among patients with high serum β2M, PFS by arm was similar (interaction p-value=.02).
Conclusions
All three prognostic models (FLIPI, FLIPI2, LDH + β2M) predicted both PFS and OS well, though the LDH + β2M model is easiest to apply and identified an especially poor risk subset. In an exploratory analysis using the latter model, there was a statistically significant trend suggesting that low risk patients had superior observed PFS if treated with CHOP-RIT, whereas high risk patients had a better PFS with CHOP-R.
doi:10.1158/1078-0432.CCR-13-1120
PMCID: PMC3872052  PMID: 24130072
Follicular Lymphoma; Prognostic Factors; Subset Analysis; β2 microglobulin; Front-Line Therapy
12.  High-Dose Therapy and Autologous Stem Cell Transplantation for Chemoresistant Hodgkin Lymphoma: The Seattle Experience 
Cancer  2008;113(6):1344-1350.
Background
High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), but this therapy is commonly denied to patients with resistant disease. We explored the utility of HDT and ASCT for chemoresistant HL since there are few established therapies for these patients.
Patients and Methods
Sixty-four chemoresistant HL patients underwent HDT followed by ASCT at our center. Baseline characteristics included: median age = 35 years (range, 14–59 yrs), stage III/IV = 49 (77%), nodular sclerosis histology = 51 (80%), and prior radiation = 32 (50%). Twenty-six patients (41%) received total body irradiation (TBI)-based regimens and 38 (59%) underwent non-TBI conditioning.
Results
The estimated 5-year overall survival (OS) and progression-free survival (PFS) were 31% and 17%, respectively, (median follow-up = 4.2 years). Multivariable analysis only identified year of transplant as independently associated with improved OS (p=.008) and PFS (p=.04), with patients transplanted in later years having better outcome. The probabilities of 3-year PFS for patients transplanted between 1986–1989, 1990–July 1993, August 1993–1999, and 2000–2005 were 9%, 21%, 33%, and 31%, respectively.
Conclusions
These data suggest that HDT and ASCT may result in prolonged remissions and survival for a subset of chemoresistant HL pts, with improved outcomes in patients transplanted more recently.
doi:10.1002/cncr.23715
PMCID: PMC2700660  PMID: 18623377
13.  PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma 
The New England journal of medicine  2014;370(11):1008-1018.
Background
Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas.
Methods
In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety.
Results
The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).
Conclusions
In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.)
doi:10.1056/NEJMoa1314583
PMCID: PMC4039496  PMID: 24450858
14.  Specific features identify patients with relapsed/refractory mantle cell lymphoma benefitting from autologous hematopoietic cell transplantation 
Outcomes with autologous hematopoietic cell transplantation (auto HCT) for relapsed/refractory mantle cell lymphoma (MCL) are typically poor. We hypothesized that certain factors could predict which patients experience a favorable outcome with this approach. We thus developed a predictive score from a cohort of 67 such patients using 3 factors independently associated with progression-free survival (PFS): (1) simplified MIPI score prior to auto HCT (HR 2.9, p = 0.002); (2) B symptoms at diagnosis (HR 2.7, p = 0.005); and (3) remission quotient, calculated by dividing the time in months from diagnosis to auto HCT by the number of prior treatments (HR 1.4, p = 0.02). The estimated 5-year PFS for favorable (n = 23) and unfavorable (n = 44) risk patients were 58% (95% CI, 34–75%) and 15% (95% CI, 6–28%), respectively. These factors also independently predicted overall survival. In summary, we have defined 3 simple factors that can identify patients with relapsed/refractory MCL who derive a durable benefit from salvage auto HCT.
doi:10.1016/j.bbmt.2013.07.005
PMCID: PMC3788600  PMID: 23871782
15.  CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies 
Journal of clinical pharmacology  2013;53(8):866-877.
Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells. This study evaluated the CYP3A-mediated drug-drug interaction potential of brentuximab vedotin and the excretion of MMAE. Two 21-day cycles of brentuximab vedotin (1.2 or 1.8 mg/kg intravenously) were administered to 56 patients with CD30-positive hematologic malignancies. Each patient also received either a sensitive CYP3A substrate (midazolam), an effective inducer (rifampin), or a strong inhibitor (ketoconazole). Brentuximab vedotin did not affect midazolam exposures. ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, MMAE exposures were lower with rifampin and higher with ketoconazole. The short-term safety profile of brentuximab vedotin in this study was generally consistent with historic clinical observations. The most common adverse events were nausea, fatigue, diarrhea, headache, pyrexia, and neutropenia. Over a 1-week period, ~23.5% of intact MMAE was recovered after administration of brentuximab vedotin; all other species were below the limit of quantitation. The primary excretion route is via feces (median 72% of the recovered MMAE). These results suggest that brentuximab vedotin (1.8 mg/kg) and MMAE are neither inhibitors nor inducers of CYP3A; however, MMAE is a substrate of CYP3A.
doi:10.1002/jcph.116
PMCID: PMC3777854  PMID: 23754575
Clinical Pharmacology; Clinical Trials; Biotechnology; Oncology; Pharmacokinetics and Drug Metabolism
16.  131I-Tositumomab Myeloablative Radioimmunotherapy for Non-Hodgkin Lymphoma: Radiation Dose to Testes 
Nuclear medicine communications  2012;33(12):1225-1231.
Purpose
To investigate radiation dose to testes delivered by radiolabeled anti-CD20 antibody and its effects on male sex hormone levels.
METHODS
Testicular uptake and retention of 131I tositumomab were measured and testicular absorbed doses were calculated for 67 male patients (54 ± 11 years old) with non-Hodgkin lymphoma who underwent myeloablative radioimmunotherapy (RIT) using 131I-tositumomab. Time-activity curves for the major organs, testes, and whole body were generated from planar imaging. In a subset of patients, male sex hormones were measured before and one year after the therapy.
RESULTS
Absorbed dose to testes showed considerable variability (range = 4.4 to 70.2 Gy). Pre-therapy levels of total testosterone were below the lower limit of the reference range, and post-therapy evaluation demonstrated further reduction (4.6 ± 1.8 nmol/L (pre-RIT) vs. 3.8 ± 2.9 nmol/L (post-RIT), p < 0.05). Patients receiving higher radiation doses to the testes (≥ 25 Gy) showed a greater reduction (4.7 ± 1.6 nmol/L (pre RIT) vs. 3.3 ± 2.7 nmol/L (post-RIT), p < 0.05) than did patients receiving lower doses (< 25 Gy), who showed no significant change in total testosterone levels.
CONCLUSION
The testicular radiation absorbed dose varied highly among individual patients. Patients receiving higher doses to testes were more likely to show post-RIT suppression of testosterone levels.
doi:10.1097/MNM.0b013e328358d34b
PMCID: PMC3703155  PMID: 22955187
131I-tositumomab; follicular lymphoma; radioimmunotherapy; radiation dosimetry; male sex hormones
17.  Allogeneic hematopoietic cell transplantation in mantle cell lymphoma 
Mantle cell lymphoma (MCL) is a high-risk non-Hodgkin lymphoma that is considered incurable with standard chemotherapy. While autologous hematopoietic cell transplantation (autoHCT) can provide lengthy disease-free survival in select patients, cure generally is not an expected outcome with this approach. Allogeneic hematopoietic cell transplantation (alloHCT), which can exploit the potential benefits of graft-versus-lymphoma (GVL) effect, has been shown in multiple studies to yield a small but reproducible portion of patients with long-term remission more suggestive of cure. Historically, alloHCT for MCL was administered after myeloablative conditioning, but this approach was limited by early non-relapse mortality. Development of reduced-intensity (RI)-alloHCT has abrogated some of the early post-transplant risks, allowing this potentially effective therapy to be offered to a larger number of affected individuals. The trends in published data reflect a preference toward using RI-alloHCT for MCL, often because patients in whom alloHCT is being considered have relapsed disease following myeloablative autoHCT. Further efforts to spare the effects of graft-versus-host disease (GVHD) while still evoking GVL remain a focus of investigation in this area. In this review, we will discuss the application of alloHCT in the management of MCL, the factors associated with outcome, the different methods in which it can be performed, and the strategies that can be employed in post-alloHCT relapse.
doi:10.1016/j.beha.2012.04.002
PMCID: PMC3374153  PMID: 22687452
mantle cell lymphoma; allogeneic transplantation
18.  Pretargeted Radioimmunotherapy using Genetically Engineered Antibody-Streptavidin Fusion Proteins for Treatment of Non-Hodgkin Lymphoma 
Purpose
Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, “endogenous” biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that down-modulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem.
Experimental Design
The single-chain variable region gene of the murine 1F5 anti-CD20 antibody was fused to the wild-type (WT) SAv gene and to mutant SAv genes, Y43A-SAv and S45A-SAv. FPs were expressed, purified and compared in studies using athymic mice bearing Ramos lymphoma xenografts.
Results
Biodistribution studies demonstrated delivery of more radioactivity to tumors of mice pretargeted with mutant SAv FPs followed by 111In-DOTA-bis-biotin (6.2 ± 1.7 % of the injected dose per gram [%ID/gm] of tumor 24 hours after Y43A-SAv FP and 5.6 ± 2.2 %ID/g with S45A-SAv FP) than in mice on normal diets pretargeted with WT-SAv FP (2.5 ± 1.6 %ID/g; p = 0.01). These superior biodistributions translated into superior anti-tumor efficacy in mice treated with mutant FPs and 90Y-DOTA-bis-biotin (tumor volumes after 11 days: 237 ± 66 mm3 with Y43A-SAv, 543 ± 320 mm3 with S45A-SAv, 1129 ± 322 mm3 with WT-SAv and 1435 ± 212 mm3 with control FP [p < 0.0001]).
Conclusions
Genetically engineered mutant-SAv FPs and bis-biotin reagents provide an attractive alternative to current SAv-biotin PRIT methods in settings where endogenous biotin levels are high.
doi:10.1158/1078-0432.CCR-11-1204
PMCID: PMC3229652  PMID: 21976541
radioimmunotherapy; CD20; lymphoma
19.  Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome and Concurrent Lymphoid Malignancy 
Bone Marrow Transplantation  2011;47(6):804-809.
Allogeneic hematopoietic cell transplantation (HCT) can be curative for both myelodysplastic syndromes (MDS) and lymphoid malignancies. Little is known about the efficacy of allogeneic HCT in patients in whom both myeloid and lymphoid disorders are present at the time of HCT. We analyzed outcomes in 21 patients with MDS and concurrent lymphoid malignancy when undergoing allogeneic HCT. Seventeen patients had received extensive prior cytotoxic chemotherapy, including autologous HCT in seven, for non-Hodgkin lymphoma (NHL, n=7), Hodgkin lymphoma (HL, n=2), chronic lymphocytic leukemia (CLL, n=5), NHL plus HL (n=1), multiple myeloma (n=1), or T-cell acute lymphocytic leukemia (ALL) (n=1), and had, presumably, developed MDS as a consequence of therapy. Four previously untreated patients had CLL. Nineteen patients were conditioned with high-dose (n=14) or reduced-intensity regimens (n=5), and transplanted from HLA-matched or one antigen/allele mismatched related (n=10) or unrelated (n=9) donors; two patients received HLA-haploidentical related transplants following conditioning with a modified conditioning regimen. Currently, 2 of 4 previously untreated, and 2 of 17 previously treated patients are surviving in remission of both MDS and lymphoid malignancies. However, the high non-relapse mortality among previously treated patients, even with reduced-intensity conditioning regimens, indicates that new transplant strategies need to be developed.
doi:10.1038/bmt.2011.180
PMCID: PMC3237793  PMID: 21909142
concurrent MDS and lymphoid malignancy; conditioning regimens; secondary MDS; relapse
20.  Blood-Based Detection of Radiation Exposure in Humans Based on Novel Phospho-Smc1 ELISA 
Radiation Research  2010;175(3):266-281.
The structural maintenance of chromosome 1 (Smc1) protein is a member of the highly conserved cohesin complex and is involved in sister chromatid cohesion. In response to ionizing radiation, Smc1 is phosphorylated at two sites, Ser-957 and Ser-966, and these phosphorylation events are dependent on the ATM protein kinase. In this study, we describe the generation of two novel ELISAs for quantifying phospho-Smc1Ser-957 and phospho-Smc1Ser-966. Using these novel assays, we quantify the kinetic and biodosimetric responses of human cells of hematological origin, including immortalized cells, as well as both quiescent and cycling primary human PBMC. Additionally, we demonstrate a robust in vivo response for phospho-Smc1Ser-957 and phospho-Smc1Ser-966 in lymphocytes of human patients after therapeutic exposure to ionizing radiation, including total-body irradiation, partial-body irradiation, and internal exposure to 131I. These assays are useful for quantifying the DNA damage response in experimental systems and potentially for the identification of individuals exposed to radiation after a radiological incident.
doi:10.1667/RR2402.1
PMCID: PMC3123689  PMID: 21388270
21.  Impact of Pretransplantation Minimal Residual Disease, As Detected by Multiparametric Flow Cytometry, on Outcome of Myeloablative Hematopoietic Cell Transplantation for Acute Myeloid Leukemia 
Journal of Clinical Oncology  2011;29(9):1190-1197.
Purpose
Allogeneic hematopoietic cell transplantation (HCT) benefits many patients with acute myeloid leukemia (AML) in first remission. Hitherto, little attention has been given to the prognostic impact of pretransplantation minimal residual disease (MRD).
Patients and Methods
We retrospectively studied 99 consecutive patients receiving myeloablative HCT for AML in first morphologic remission. Ten-color multiparametric flow cytometry (MFC) was performed on bone marrow aspirates before HCT. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRD positive.
Results
Before HCT, 88 patients met morphologic criteria for complete remission (CR), whereas 11 had CR with incomplete blood count recovery (CRi). Twenty-four had MRD before HCT as determined by MFC. Two-year estimates of overall survival were 30.2% (range, 13.1% to 49.3%) and 76.6% (range, 64.4% to 85.1%) for MRD-positive and MRD-negative patients; 2-year estimates of relapse were 64.9% (range, 42.0% to 80.6%) and 17.6% (range, 9.5% to 27.9%). After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (hazard ratio [HR], 4.05; 95% CI, 1.90 to 8.62; P < .001) and relapse (HR, 8.49; 95% CI, 3.67 to 19.65; P < .001) relative to MRD-negative HCT.
Conclusion
These data suggest that pre-HCT MRD is associated with increased risk of relapse and death after myeloablative HCT for AML in first morphologic CR, even after controlling for other risk factors.
doi:10.1200/JCO.2010.31.8121
PMCID: PMC3083874  PMID: 21282535
22.  Relapsed Mantle Cell Lymphoma Presenting as “Sister Mary Joseph Nodule” 
Case Reports in Medicine  2010;2010:708348.
The finding of umbilical metastasis has historically been called a “Sister Mary Joseph Nodule”. A few case reports of lymphoma presenting in this manner have been documented. We report a case of relapsed mantle cell lymphoma (MCL) presenting as a Sister Mary Joseph's nodule. Although the few reports of lymphoma exhibiting umbilical metastasis suggest that patients may still expect a reasonable response to chemotherapy, this patient experienced multiple relapses, despite aggressive chemotherapy regimens. This clinical course is characteristic of the mantle cell form of non-hodgkin's lymphoma and illustrates a need to seek out more effective therapies.
doi:10.1155/2010/708348
PMCID: PMC2852603  PMID: 20396390
23.  Pretargeted Radioimmunotherapy Using Anti-CD45 Monoclonal Antibodies to Deliver Radiation to Murine Hematolymphoid Tissues and Human Myeloid Leukemia 
Cancer research  2009;69(1):185-192.
Radioimmunotherapy (RIT) for treatment of hematological malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of therapy using a pretargeted anti-human (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled-DOTA-biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT. In vivo imaging studies confirmed that the PRIT approach provided high-contrast tumor images with minimal blood-pool activity, whereas directly-labeled anti-hCD45 Ab produced distinct tumor images but the blood pool retained a large amount of labeled Ab for a prolonged time. Therapy experiments demonstrated that 90Y-DOTA-biotin significantly prolonged survival of mice treated with pretargeted anti-hCD45 Ab-SA compared to mice treated with conventional RIT using 90Y-labeled anti-hCD45 Ab at 200 μCi. Since human CD45 antigens are confined to xenograft tumor cells in this model, and all murine tissues are devoid of hCD45 and will not bind anti-hCD45 Ab, we also compared one-step and PRIT using an anti-murine (m)CD45 Ab where the target antigen is present on normal hematopoietic tissues. After 24 hours, 27.3 ± 2.8% of the injected dose of activity was delivered per gram (% ID/g) of lymph node using 131I-A20-Ab compared with 40.0 ± 5.4% ID/g for pretargeted 111In-DOTA-biotin. These data suggest that pretargeted methods for delivering RIT may be superior to conventional RIT when targeting CD45 for the treatment of leukemia and may allow for the intensification of therapy, while minimizing toxicities.
doi:10.1158/0008-5472.CAN-08-2513
PMCID: PMC2613544  PMID: 19118002
Radioimmunotherapy; CD45; leukemia
24.  Effect of Remission Status and Induction Chemotherapy Regimen on Outcome of Autologous Stem Cell Transplantation for Mantle Cell Lymphoma 
Leukemia & lymphoma  2008;49(6):1062-1073.
We analyzed the outcomes of autologous stem cell transplantation (ASCT) following high-dose therapy with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive patients with mantle cell lymphoma (MCL). Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (±R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (±R) followed by ASCT in CR1/PR1, and 20 received ASCT following disease progression. Estimates of overall and progression-free survival (PFS) at three years among patients transplanted in CR1/PR1 were 93% and 63% compared with 46% and 36% for patients transplanted with relapsed/refractory disease, respectively. The hazard of mortality among patients transplanted with relapsed/refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P=.006). Patients in the CHOP (±R) group had a higher risk of failure for PFS compared to patients in the HyperCVAD (±R) group, though the difference did not reach statistical significance (hazard ratio 3.67, P=.11). These results suggest that ASCT in CR1/PR1 leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed/refractory disease, and a HyperCVAD (±R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1.
doi:10.1080/10428190801923725
PMCID: PMC2769072  PMID: 18452065
Mantle cell lymphoma; Autologous stem cell transplantation; HyperCVAD; CHOP; Non-Hodgkin lymphoma
25.  Radioimmunotherapy based conditioning regimens for stem cell transplantation 
Seminars in hematology  2008;45(2):118-125.
Radioimmunotherapy (RIT) combines the mechanism of action and targeting capability of monoclonal antibodies with the tumoricidal effect of radiation and has shown promising results in the treatment of various hematologic malignancies. Based on RIT’s efficacy and safety profile, many investigators have evaluated its use in transplant conditioning regimens with the goal of improving long-term disease control with limited toxicity. In lymphoma, two basic transplant approaches targeting CD20 have emerged: 1. Myeloablative doses of RIT with or without chemotherapy, and 2. Standard non-myeloablative doses of RIT combined with high-dose chemotherapy. Myeloablative RIT has been shown to be feasible and efficacious using escalated doses of I-131-Tositumomab (Bexxar), Y-90-ibritumomab tiuxetan (Zevalin), and I-131-rituximab with or without chemotherapy followed by autologous stem cell transplant (ASCT). The second approach predominantly has used standard doses of Y-90-ibritumomab tiuxetan or I-131 Tositumomab plus BEAM chemotherapy followed ASCT. RIT targeting CD-45, CD-33 and CD-66 prior to allogeneic transplantation has also been evaluated for the treatment of acute leukemia. Overall RIT-based transplant conditioning for lymphoma and leukemia has been shown to be safe, effective, and feasible with ongoing randomized trials currently underway to definitively establish its place in the treatment of hematologic malignancies.
doi:10.1053/j.seminhematol.2008.02.002
PMCID: PMC2460561  PMID: 18381107
Radioimmunotherapy; stem cell transplantation; CD20; CD45; I-131; Y-90

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