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Vitamin C (ascorbic acid, ascorbate), despite controversy, has re-emerged as a promising anti-cancer agent. Recent knowledge of intravenous ascorbate pharmacokinetics and discovery of unexpected mechanisms of ascorbate action have spawned many investigations. Two mechanisms of anti-cancer activity with ascorbate have gained prominence: hydrogen peroxide-induced oxidative stress and DNA demethylation mediated by ten-eleven translocation enzyme activation. Here, we highlight salient aspects of the evolution of ascorbate in cancer treatment, provide insights into the pharmacokinetics of ascorbate, describe mechanisms of its anti-cancer activity in relation to the pharmacokinetics, outline promising preclinical and clinical evidence, and recommend future directions., (Published by Elsevier Inc.)

Background: Patients with diffuse large B-cell lymphoma (DLBCL) with an International Prognostic Index (IPI) ≥3 are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy (R-chemo). Everolimus has single-agent activity in lymphoma. PILLAR-2 aimed to improve disease-free survival (DFS) with 1 year of adjuvant everolimus., Patients and Methods: Patients with high-risk (IPI ≥3) DLBCL and a positron emission tomography/computed tomography-confirmed CR to first-line R-chemo were randomized to 1 year of everolimus 10 mg/day or placebo. The primary end point was DFS; secondary end points were overall survival, lymphoma-specific survival, and safety., Results: Between August 2009 and December 2013, 742 patients were randomized to everolimus (n = 372) or placebo (n = 370). Median follow-up was 50.4 months (range 24.0-76.9). Overall, 47% of patients were ≥65 years, 50% were male, and 42% had an IPI of 4 or 5. 48% and 67% completed everolimus and placebo, respectively. Primary reasons for everolimus discontinuation versus placebo were adverse events (AEs; 30% versus 12%) and relapsed disease (6% versus 13%). Everolimus did not significantly improve DFS compared with placebo (hazard ratio 0.92; 95% CI 0.69-1.22; P = 0.276). Two-year DFS rate was 77.8% (95% CI 72.7-82.1) with everolimus and 77.0% (95% CI 72.1-81.1) with placebo. Common grade 3/4 AEs with everolimus were neutropenia, stomatitis, and decreased CD4 lymphocytes., Conclusions: Adjuvant everolimus did not improve DFS in patients already in PET/CT-confirmed CR. Future approaches should incorporate targeted agents such as everolimus with R-CHOP rather than as adjuvant therapy after CR has been obtained., Clinicaltrials.gov: NCT00790036.

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Objective: We conducted a single-center retrospective analysis to determine the impact of the anti-CD52 monoclonal antibody alemtuzumab including route of administration compared to non-alemtuzumab-containing regimens in T-prolymphocytic leukemia (T-PLL)., Patients and Methods: The study was a retrospective analysis of a consecutive cohort of adult patients diagnosed with T-PLL at Mayo Clinic Rochester from January 1, 1997, through September 30, 2014., Results: A total of 41 patients were diagnosed with T-PLL per the World Health Organization 2008 classification. The median age was 66 years, and 23 (56%) were male. After a median follow-up of 18 months (range, 0.4-66.1 months), 32 patients (78%) had died, with a median overall survival of 16.9 months. Approximately half the cohort was treated with alemtuzumab, almost exclusively after 2004. Median survival for patients receiving intravenous alemtuzumab-based therapy was 40.5 versus 10.3 months for all other therapies (P = .0004). A significant survival difference between intravenous versus subcutaneous alemtuzumab administration of 40.5 versus 13.7 months was noted (P = .0014). Only 4 (14%) of 28 patients aged < 70 years underwent hematopoietic stem cell transplantation, with a median survival after transplantation of 4 months., Conclusion: In this large series of T-PLL patients treated at a single tertiary-care center, we confirmed the prior observation of the superiority of intravenous alemtuzumab over other therapies. Hematopoietic stem cell transplantation was feasible in a minority of potentially eligible patients. Early transplant referral should be considered for all eligible patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This phase 2 trial was designed to evaluate ixazomib, an orally bioavailable proteasome inhibitor, in patients with myeloma who have limited prior exposure to bortezomib. Thirty-three patients with relapsed multiple myeloma were enrolled. Ixazomib was given at 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added for lack of a minor response (MR) by end of cycle 2 or lack of a partial response (PR) by end of cycle 4 or for disease progression at any time. Median age was 69 years; patients had a median of two prior therapies (range 1-7). A grade 3 or 4 adverse event considered at least possibly related to drug was seen in 19 (59%) and 6 (19%) patients, respectively. The most common adverse events were thrombocytopenia, fatigue, nausea and diarrhea. Dexamethasone was initiated in 22 (67%) patients, 17 for not reaching the desired response and 5 for progression. Response (⩾PR) to single agent was seen in five patients within four cycles of therapy including three patients with PR, one patient with complete response (CR) and one patient with stringent CR. Six additional patients with either an MR (2) or SD (4) achieved a PR after addition of dexamethasone, translating to an overall response rate of 34%.

Background: Lenalidomide is an immunomodulatory agent with antitumor activity in B-cell malignancies. This phase II trial aimed to demonstrate the safety and efficacy of lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular grade 3 lymphoma (FL-III), or transformed lymphoma (TL)., Methods: Patients received oral lenalidomide 25 mg on days 1-21 every 28 days as tolerated or until progression. The primary end point was overall response rate (ORR)., Results: Two hundred and seventeen patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% (29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for MCL, 42% (8/19) for FL-III, and 45% (15/33) for TL. Median progression-free survival for all 217 patients was 3.7 months [95% confidence interval (CI) 2.7-5.1]. For 77 responders, the median response duration lasted 10.6 months (95% CI 7.0-NR). Median response duration was not reached in 29 patients who achieved a CR and in responding patients with FL-III or MCL. The most common adverse event was myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively., Conclusion: Lenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma.

We report updated time-to-event variables of a phase III randomized study comparing yttrium 90-labeled ibritumomab with rituximab standard therapy in 143 rituximab-naive patients with relapsed or refractory low-grade, follicular, or transformed CD20+ non-Hodgkin's lymphoma (NHL). Most patients (79%) had follicular lymphoma. Patients were randomized to receive a single intravenous (I.V.) dose of 90Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m2 I.V. weekly for 4 doses (n = 70). The radioimmunotherapy group was pretreated with 2 rituximab doses (250 mg/m2) to improve biodistribution and one dose of Indium 111-labeled ibritumomab tiuxetan for imaging. The overall response rate was 80% versus 56% (P = 0.002) and complete response (CR)/CR unconfirmed (CRu) rates were 34% for 90Y ibritumomab tiuxetan versus 20% for rituximab. With a median follow-up of 44 months, the data are mature as all ongoing patients in both groups exceeded the median Kaplan-Meier estimated time to progression (TTP), duration of response (DR), and time to next therapy. Although this study was not powered to detect differences in time-to-event variables, the results from this randomized trial demonstrate trends toward longer median TTP (15 vs. 10.2 months; P = 0.07), DR (16.7 vs. 11.2 months; P = 0.44) and time to next therapy (21.1 vs. 13.8 months; P = 0.27) in follicular NHL patients treated with 90Y ibritumomab tiuxetan compared with the rituximab control arm. In patients achieving a CR/CRu, the median TTP was 24.7 months for patients treated with 90Y ibritumomab tiuxetan compared with 13.2 months for rituximab-treated patients (P = 0.41), and ongoing responses of > 5 years have been observed. These results confirm that 90Y ibritumomab tiuxetan produces high response rates and durable remissions in patients with previously treated low-grade, follicular, and transformed NHL.

Autologous stem cell transplant (SCT) improves survival in multiple myeloma (MM) and remains the standard of care for eligible patients. Nearly a third of patients with newly diagnosed MM fail initial therapy aimed at reducing tumor burden preceding SCT (primary refractory). It is unclear if an initial response is important for successful SCT. We evaluated our experience with SCT in 50 patients with primary refractory MM and compared it to 101 patients with chemosensitive disease receiving SCT. The study cohort had a median age of 56 years (range 29-72) consisting of 87 males (58%). A total of 46 patients (92%) in the refractory group and 100 (99%) in the chemosensitive group had a response to transplant (50% or greater reduction in the M-protein). In all, 10 refractory patients (20%) and 35 (35%) in the chemosensitive group achieved a CR (P=0.06). The 1-year estimated progression-free survival from the time of transplant for the refractory group was 70% compared to 83% for the chemosensitive group (P=0.65). The lack of response to initial induction therapy does not appear to preclude a good response to SCT. We recommend that patients with primary refractory MM be offered early SCT.

Patients with early-stage myeloma are typically observed without therapy until symptomatic disease occurs. However, they are at high risk of progression to symptomatic myeloma, with a median time to progression of approximately 1-2 years. We report the final results of a phase II trial of thalidomide as initial therapy for early-stage multiple myeloma in an attempt to delay progression to symptomatic disease. In total, 31 patients with smoldering or indolent multiple myeloma were studied at the Mayo Clinic. Two patients were deemed ineligible because they were found to have received prior therapy for myeloma, and were excluded from analyses except for toxicity. Thalidomide was initiated at a starting dose of 200 mg/day. Patients were followed-up monthly for the first 6 months and every 3 months thereafter. Of the 29 eligible patients, 10 (34%) had a partial response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49% decrease in M protein) were included, the response rate was 66%. Three patients had progressive disease while on therapy. Kaplan-Meier estimates of progression-free survival are 80% at 1 year and 63% at 2 years. Major grade 3-4 toxicities included two patients with somnolence and one patient each with neuropathy, deep-vein thrombosis, hearing loss, weakness, sinus bradycardia, and edema. Thalidomide has significant activity in early-stage myeloma and has the potential to delay progression to symptomatic disease. This approach must be further tested in randomized trials.

Thalidomide is a glutamic acid derivative initially introduced as a sedative hypnotic nearly forty years ago. It was withdrawn following numerous reports linking it to a characteristic pattern of congenital abnormalities in babies born to mothers who used the drug for morning sickness. It has gradually been re-introduced into clinical practice over the past two decades, albeit under strict regulation, since it was found to be useful in the management of erythema nodosum leprosum and HIV wasting syndrome. Recognition of its anti-angiogenic effect led to its evaluation in the treatment of various malignancies, where angiogenesis has been shown to play an important role. Numerous clinical trials done over the past four years have confirmed the significant anti-myeloma activity of this drug. It has also shown promise in preliminary trials in the treatment of a variety of different malignant diseases. The mechanisms of its antineoplastic effects continue to be the focus of ongoing research. It has become clear that even though its anti angiogenic effects play a significant role in the anti-tumor activity, there are other properties of this drug which are responsible as well. It also possesses anti-TNF alpha activity, which has led to its evaluation in several inflammatory states. In this concise review, we briefly describe the historical background and pharmacological aspects of this drug. We have concisely reviewed the current knowledge regarding mechanisms of its anti-neoplastic activity and the results of various clinical trials in oncology.

Infusion related adverse events (AE) with day 1 rituximab in patients with B-cell non-Hodgkin's lymphoma (NHL) are common. The purpose of this study was to evaluate the AE occurring in patients with malignant B-cell lymphocytosis who received rituximab. Patients with a > or = 3 x 10(9)/L absolute lymphocyte count (ALC) receiving rituximab from 1998 to 1999 or participating in a phase I study of rituximab and interleukin-12 were reviewed. The AE occurring on the day of rituximab, the treatment provided (including hospitalization), and the subsequent ALC responses were recorded. Twenty-seven patients were identified; 14 had NHL, one Waldenstrom's macroglobulinemia, and 12 patients had chronic lymphocytic leukemia. The baseline median ALC was 9.58 x 10(9)/L (mean, 49.31; range, 3.56-380.95). All patients received rituximab as an outpatient. There were only two AE > or = grade 3. One patient was hospitalized for 1 day for i.v. fluids to treat an increase in creatinine that occurred with tumor lysis. A second patient developed a pulmonary syndrome five days after day 1 rituximab and required mechanical ventilation, but had no long-term lung toxicity. This study demonstrates that patients with high numbers of circulating blood B-lymphocytes can usually safely receive rituximab as outpatients. Patients who experience a rapid drop in ALC should be monitored closely for tumor lysis and the pulmonary syndrome.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a monoclonal antibody that targets the CD20 antigen present in most B-cell non-Hodgkin's lymphomas. Previous studies have shown overall response rates (ORR) of approximately 50% in relapsed patients. Ibritumomab is the murine parent anti-CD20 antibody that is linked through a MX-DTPA chelator to yttrium 90 (90Y) to form the radioimmunoconjugate 90Y-ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA). A phase I study of 90Y-ibritumomab tiuxetan determined that 0.4 mCi/kg was the maximum tolerated dose, and responses were reported in 67% of all patients and in 82% of patients with low-grade non-Hodgkin's lymphoma. A separate trial randomized eligible patients to either rituximab or 90Y-ibritumomab tiuxetan. An interim analysis of the first 90 patients showed an ORR of 80% with 90Y-ibritumomab tiuxetan versus 44% with rituximab (P < .05). A subsequent trial for patients with rituximab-refractory disease showed a 46% ORR. These studies show that 90Y-ibritumomab tiuxetan is an active agent in relapsed non-Hodgkin's lymphoma and appears to have a higher ORR compared with unconjugated rituximab.

Dosimetry studies in patients with non-Hodgkin's lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of 90Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received (111)In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of 90Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of (111)In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n=56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2-7.8 Gy), 2.6 Gy to lungs (range 0.72-4.4 Gy), and 0.38 Gy to kidneys (range 0.07-0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8-67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T(1/2), blood AUC, plasma T(1/2), and plasma AUC. It is concluded that 90Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T(1/2), reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population.

Phenylacetate (PA) and phenylbutyrate (PB) are aromatic fatty acids that are presently undergoing evaluation as potential antineoplastic agents. In vitro, PA and PB cause differentiation or growth inhibition of malignant cells. Clinical trials of these drugs as single agents indicate that they are not myelosuppressive; therefore, combinations with other chemotherapy agents may be possible. The goals of this study were to determine whether PA and PB (a) are cytotoxic to malignant B cells from patients with non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia and (b) exhibit additive or synergistic induction of apoptosis when administered to myeloma cell lines in combination with conventional drugs. In the clinical specimens, cytotoxicity was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and percent apoptosis was measured using 7-aminoactinomycin D and flow cytometry. Viability was decreased by > 50% in 7% (1/15) of non-Hodgkin's lymphoma samples treated with 5 mM PA, 27% treated with 1 mM PB, and 60% treated with 2 mM PB. Likewise, viability was decreased by > 50% in 44% (4/9) of chronic lymphocytic leukemia samples treated with 5 mM PA, 67% treated with 1 mM PB, and 100% treated with 2 mM PB. Studies in the myeloma cell lines demonstrated that PB treatment induced activation of caspases 3, 7, and 9 accompanied by cleavage of their substrates and internucleosomal DNA degradation. Combinations of PA or PB with conventional drugs (cytarabine, topotecan, doxorubicin, etoposide, chlorambucil, melphalan, fludarabine, carboplatin, and cisplatin) were examined for synergism (combination index < 1 in median effect analysis) in inducing apoptosis of both the MY5 and 8226 human myeloma cell lines. At concentrations that killed > 50% of cells, most combinations were additive; however, PB was synergistic with cytarabine, etoposide, and topotecan, with the combination index < 1 at each of the 50, 75, and 95% apoptosis levels. These observations indicate that PA and PB can induce apoptosis in malignant B cells and enhance the cytotoxicity of agents used in the treatment of these malignancies.

Purpose: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy., Patients and Methods: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20(+) B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass > or = 5 cm., Results: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/microL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (> or = 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody)., Conclusion: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.

L-asparaginase (L-asp) has become an important component of combination chemotherapy for acute lymphoblastic leukemia (ALL). However, L-asp can produce depletions in many of the clotting factors with an associated risk for thrombosis and hemorrhage. Three consecutive patients seen at the Mayo Clinic with L-asp related thrombosis are described and an in-depth review of the literature is provided. Two of the 3 patients developed central nervous system (CNS) complications with evidence of thrombosis and hemorrhagic infarction. Two of the patients also developed extensive upper extremity thrombosis. The results of comprehensive hemostatic surveys showed marked abnormalities in all 3 patients. Many of the thrombotic complications related to L-asp involve the CNS, as illustrated in 2 of our patients. These patients should be treated aggressively since full recovery is possible. The precise cause of thrombosis is yet to be determined but is likely multifactorial. The optimal treatment and prevention of thrombosis in this group of patients remains poorly defined.

A specific predictor during routine follow-up to ascertain risk for relapse after standard chemotherapy in non-Hodgkin's lymphoma (NHL) has not been identified. Thus, we studied absolute lymphocyte count (ALC) as a marker of poststandard chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine and prednisone (R-CHOP)) NHL relapse in patients with diffuse large B-cell lymphoma (DLBCL). ALC was obtained at the time of confirmed relapse and at last follow-up. From 2000 until 2006, 149 consecutive DLBCL patients, originally diagnosed, treated with R-CHOP and followed up at Mayo Clinic, Rochester, were included in this study. Patients at last follow-up without relapse (N=112) had a higher ALC compared with those with relapsed lymphoma ((N=37) median ALC × 109/l of 1.43 (range: 0.33–4.0) versus 0.67 (range: 0.18–1.98), P<0.0001, respectively). ALC at the time of confirmed relapse was a strong predictor for relapse with an area under the curve =0.91 (P<0.0001). An ALC <0.96 × 109/l at the time of confirmed relapse had a positive predictive value of 72% and a positive likelihood ratio of 7.4 to predict relapse after R-CHOP in DLBCL. Patients with an ALC0.96 × 109/l (N=103) had a cumulative incidence of relapse of 6 versus 79% with an ALC <0.96 × 109/l (N=46) (P<0.0001). This study suggests that lymphopenia measured by ALC can be used as a marker to assess risk of DLBCL relapse during routine follow-up after standard chemotherapy. [ABSTRACT FROM AUTHOR]

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study. [ABSTRACT FROM AUTHOR]

Summary:Given the survival advantage, high-dose therapy (HDT) remains the standard of care for patients with multiple myeloma eligible for the procedure. For those undergoing HDT, initial therapy aimed at reducing tumor burden is given prior to stem cell harvest. Various regimens, mostly variations of VAD (vincristine, doxorubicin, dexamethasone), are used for induction therapy. We retrospectively evaluated if single agent dexamethasone would be an effective induction therapy, given that it is the most active drug in these combinations. A total of 35 patients who received induction therapy with dexamethasone alone were compared to a similar group of 72 patients who received VAD as the initial therapy. We found a 63%response rate with dexamethasone compared to 74%with VAD (P=0.25). Including minimal responses, the overall response rate for Dex and VAD was 74 and 86%, respectively (P=0.13). The overall and complete response rates to transplant, respectively, were 97 and 26%for the dexamethasone group and 100 and 39%for the VAD group; P=0.33 and 0.18. No significant differences were observed in the progression-free and overall survival at 1 year post transplant. Single agent dexamethasone appears to be an effective alternative to VAD for induction therapy prior to HDT in myeloma.Bone Marrow Transplantation (2004) 34, 485-490. doi:10.1038/sj.bmt.1704633 Published online 2 August 2004 [ABSTRACT FROM AUTHOR]

Background: Microsatellite instability (MSI) and allelic imbalance involving chromosome arms 5q, 8p, 17p, and 18q are genetic alterations commonly found in colorectal cancer. We investigated whether the presence or absence of these genetic alterations would allow stratification of patients with Astler-Coller stage B2 or C colorectal cancer into favorable and unfavorable prognostic groups.Methods: Tumors from 508 patients were evaluated for MSI and allelic imbalance by use of 11 microsatellite markers located on chromosome arms 5q, 8p, 15q, 17p, and 18q. Genetic alterations involving each of these markers were examined for associations with survival and disease recurrence. All P values are two-sided.Results: In univariate analyses, high MSI (MSI-H), i.e., MSI at 30% or more of the loci examined, was associated with improved survival (P =.02) and time to recurrence (P =.01). The group of patients whose tumors exhibited allelic imbalance at chromosome 8p had decreased survival (P =.02) and time to recurrence (P =.004). No statistically significant associations with survival or time to recurrence were observed for markers on chromosome arms 5q, 15q, 17p, or 18q. In multivariate analyses, MSI-H was an independent predictor of improved survival (hazard ratio [HR] = 0.51; 95% confidence interval [CI] = 0.31-0.82; P =.006) and time to recurrence (HR = 0.42; 95% CI = 0.24-0.74; P =.003), and 8p allelic imbalance was an independent predictor of decreased survival (HR = 1.89; 95% CI = 1.25-2.83; P =. 002) and time to recurrence (HR = 2.07; 95% CI = 1.32-3.25; P =.002).Conclusions: Patients whose tumors exhibited MSI-H had a favorable prognosis, whereas those with 8p allelic imbalance had a poor prognosis; both alterations served as independent prognostic factors. To our knowledge, this is the first report of an association between 8p allelic imbalance and survival in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Background Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma with poor overall prognosis, requiring the development of new therapies. Lenalidomide is an immunomodulatory agent demonstrating antitumor and antiproliferative effects in MCL. We report results from a long-term subset analysis of 57 patients with relapsed/refractory MCL from the NHL-003 phase II multicenter study of single-agent lenalidomide in patients with aggressive lymphoma Design Lenalidomide was administered orally 25 mg daily on days 1–21 every 28 days until progressive disease (PD) or intolerability. The primary end point was overall response rate (ORR). Results Fifty-seven patients with relapsed/refractory, advanced-stage MCL had a median of three prior therapies. The ORR was 35% [complete response (CR)/CR unconfirmed (CRu) 12%], with a median duration of response (DOR) of 16.3 months (not yet reached in patients with CR/CRu) by blinded independent central review. The median time to first response was 1.9 months. Median progression-free survival was 8.8 months, and overall survival had not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), and anemia (13%). Conclusions These results show the activity of lenalidomide in heavily pretreated, relapsed/refractory MCL. Responders had a durable response with manageable side-effects. Clinical trial number posted on www.clinicaltrials.gov NCT00413036. [ABSTRACT FROM AUTHOR]