bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost of 90Y-Ibritumomab Tiuxetan Radioimmunotherapy Versus Cost of Standard Regimens for the Treatment of Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma in Switzerland.
Authors: Frei Andreas , Delmore Geoffrey , Hitz Felicitas , Schwenkglenks Matthias , Szucs Thomas
Published: October 2019

Current standard second-line regimens for the treatment of non-Hodgkin’s lymphoma (NHL) are administered over a period of 3–6 months, generating substantial treatment costs. In Switzerland, Yttrium-90 (90Y)-ibritumomab tiuxetan was introduced in 2004 as the first-in-class radioimmunotherapy for the treatment of relapsed or refractory indolent NHL. It is delivered in an outpatient setting over a period of 8 days. In Switzerland, just as in the United States, assessment of the biodistribution of the antibody is required one week prior to the actual treatment (this step is not required in the European Union). This analysis compared the costs of 90Y-ibritumomab tiuxetan with 8 cycles of rituximab (R), 6 or 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), and 6 or 8 cycles of R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone), respectively. Direct medical treatment costs and costs of absence from work (indirect costs) were included. For each treatment option, the number of cycles per treatment and the total medical resources used to care for the patient throughout the treatment were assessed for a theoretical standard patient, defined as 60 years old with therapy refractory, grade 1–2, stage III-IV NHL. The resources used were valued with unit costs or prices gained from the Swiss national fee schedule for medical services, lists of administered prices for laboratory tests and pharmaceuticals, and purchasing prices for all other relevant items. Total lost productivity due to absence from work was estimated by multiplying the days absent from work with average income per day. Results are summarized in Table 1. Direct treatment costs for 90Y-ibritumomab tiuxetan were lower than 8 x R, 8 x R-CHOP, and 8 x R-CVP but higher than 6 x R-CHOP or 6 x R-CVP. When indirect costs were taken into account, total 90Y-ibritumomab tiuxetan cost was lower than for all other regimens except 6 x R-CVP. The only sensitivity analysis that changed the ranking of the treatment options was omitting the biodistribution study and thus adopting the EU regimen for 90Y-ibritumomab tiuxetan. This reduced the costs of radioimmunotherapy to CHF 27,766. In conclusion, 90Y-ibritumomab tiuxetan is not more expensive than other established treatments for relapsed or refractory indolent NHL. Table 1. Per-patient costs by treatment in Switzerland.

Costs (CHF) Treatment option Direct Indirect Total 6 x R-CVP 34,045 3,794 37,839 90Y-ibritumomab tiuxetan 38,619 1,265 39,884 6 x R-CHOP 36,711 5,691 42,403 8 x R 42,625 2,024 44,649 8 x R-CVP 44,878 5,059 49,937 8 x R-CHOP 48,250 7,589 55,839
Multiple Myeloma in Manitoba: A Population Based Study.
Authors: Szwajcer David , Seftel Mathew D. , Dupont Erin , Rubinger Morel , Schacter Brent A.
Published: October 2019

Background: We reviewed outcomes for all Manitoba myeloma patients 1993–2006 treated conventionally or with high dose therapy followed by stem cell transplantation.

Methods: A retrospective cohort study was undertaken where all individuals with a diagnosis of MM (ICD-O-3) were identified within the CancerCare Manitoba (CCMB) Registry and the Manitoba Blood and Bone Marrow Transplant (MBMT) Registry. Complete incidence, mortality and demographic data are available for all patients in the CCMB registry and complete staging, transplant characteristics and outcome data are available for individuals in the MBMT registry. A multivariate model was used to explore predictors of outcome for the entire cohort. Kaplan-Meier survival analysis was performed to compare those who have and who have not undergone transplantation, as well as to compare those who have undergone autologous (autoSCT) versus allogeneic stem cell transplantation (alloSCT).

Results: 771 pts were diagnosed with MM. Incidence rates of MM over the last decade have remained stable. Age and sex adjusted rates (per 105) were 6.6 and 4.5 for males and females respectively. Median age of the cohort was 69, whereas the median age of those who have undergone transplantation is 54. 78 pts underwent autoSCT and 11 underwent alloSCT, with the majority of transplants performed after 2001. As a fraction of total transplants performed per year, MM transplant rates have remained stable since 2002 at 29%. Six pts have undergone sequential transplants for relapse or progression. Median overall survival for those undergoing transplantation is 5.2 years compared to 3 years for those not transplanted (p<0.01). On multivariate analysis, for the entire cohort, undergoing transplantation was associated with a hazard ratio for death of 0.39 (CI 0.25–0.6), while being 70 or above was associated with a hazard ratio for death of 1.45 (CI 1.12–1.87). For those who have undergone transplantation median overall survival was not affected by transplant type, age at transplant (< or ≥ 60), or disease status prior to transplantation (log-rank test p>0.05).

Conclusions: In this population based analysis, utilization of stem cell transplantation provides a survival benefit to patients with MM. For those eligible for autoSCT, disease status prior to transplantation does not affect outcome.
Fas-Dependent Apoptosis in Early MDS Erythroid Precursors Involves Endoplasmic Reticulum.
Authors: Gyan Emmanuel , Frisan Emilie , Beyne-Rauzy Odile , Pierre-Eugene Cecile , Deschemin Jean-Christophe , Randriamampita Clotilde , Dubart-Kupperschmitt Anne , Garrido Carmen , Dreyfus Francois , Guesnu Martine , Lacombe Catherine , Mayeux Patrick , Solary Eric , Fontenay Michaela
Published: October 2019

The anemia that characterizes most early myelodysplastic syndromes (MDS) was proposed to involve a deregulation in cell death pathways leading to excessive apoptosis of bone marrow erythroid precursors. Pathways leading to this excess in MDS erythroid precursors have been partially depicted in ex vivo liquid cultures of patients CD34+ bone marrow cells induced to differentiate into red cells in the presence of various cytokines. For example, we have identified the Fas-dependent activation of caspase-8 as a key initiating event. In order to further understand the mechanisms of MDS erythroid precursor death, we explored the role of the endoplasmic reticulum (ER) in this process. We first observed that Fas-dependent activation of caspase-8 in these cells induced the cleavage of BAP-31, an ER protein that is associated to Bcl-2 at the ER surface and was demonstrated to be a caspase-8 substrate. We also detected a proteolysis of caspase-4, which was proposed to play a role in ER-mediated apoptosis. To further explore the role of the ER, we constructed a lentivirus expressing a Bcl-2 mutant targeted to the ER membrane. The specific expression of Bcl-2 at the ER level prevented BAP-31 and caspase-4 cleavage induced by Fas engagement at the surface of MDS erythroid precursors and inhibited Fas-dependent apoptosis. Interestingly, ER-targeted Bcl-2 also inhibited mitochondrial membrane permeabilization (MMP) and cytochrome c release in MDS erythroid precursors undergoing spontaneous or Fas-induced apoptosis. These data argued for a role of the ER in MDS erythroid precursor apoptosis, upstream of the mitochondria. MDS erythroid precursors also demonstrated elevated ER Ca2+ stores when compared to normal erythroid precursors cultured in the same conditions. Ca2+ chelation with BAPTA or treatment with pharmacologic Ca2+ inhibitors such as nicardipine prevented the spontaneous apoptosis of MDS erythroid precursors. Altogether, these data suggest that the ER is involved in the spontaneous apoptosis of MDS erythroid precursors, downstream of Fas and upstream of the mitochondria, through mechanisms that can be inhibited by Bcl-2 and that involve Ca2+ stores.
The In Vivo Inactivation of MASTL Kinase Results in Thrombocytopenia.
Authors: Johnson Helen J. , Gandhi Manish J. , Shafizadeh Ebrahim , Langer Nathaniel B. , Pierce Eric L. , Paw Barry , Gilligan Diana M. , Drachman Jonathan
Published: October 2019

Previously in our lab, a missense mutation in the MASTL (FLJ14813) gene on human chromosome 10 was linked to an autosomal dominantly inherited thrombocytopenia in a single pedigree. The mutation results in an amino acid change from glutamic acid at position 167 to aspartic acid and correlates with the inheritance of the disorder in all the affected individuals. The patients present with mild thrombocytopenia with an average platelet count of 60,000 platelets per microliter of blood. Northern blot analysis indicates that MASTL mRNA is restricted in its expression to hematopoietic and cancer cell lines. Functional studies presented here demonstrate a direct relationship between the transient knockdown of the Microtubule Associated Serine/Threonine Like (MASTL) kinase expression and the reduction of circulating thrombocytes in zebrafish (Danio rerio) while erythrocytes development normally. This transient knockdown of MASTL in zebrafish correlates with a decrease in the expression of the thrombopoietin receptor, c-mpl, and the CD41 platelet adhesion GpIIb protein but has no effect on essential housekeeping zebrafish gene, EF1α. The transient expression of a fluorescent protein fused to MASTL and E167D MASTL kinase demonstrates that MASTL localizes to the nucleus of cells as determined by confocal microscopy and TO-PRO-3 counterstain.
Oncogenic Transformation of NIH 3T3 Fibroblasts by BCR-ABL Oncoprotein Requires the IL-3 Receptor.
Authors: Tao Wenjing , Lin Hui , Sun Tong , Samanta Ajoy K. , Arlinghaus Ralph B.
Published: October 2019

Bcr-Abl is a leukemia-inducing protein, which causes oncogenic transformation of myeloid progenitors in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) and lymphoid progenitors in Ph+ acute lymphoid leukemia (ALL). Oncogenic transformation of hematopoietic cells by the Bcr-Abl oncoprotein directly involves the activation Jak2 tyrosine kinase and the Stat5 transcription factor. Both proteins are normally linked to the IL-3/GM-CSF receptors for growth and survival. Since fibroblastic cells are not targets of BCR-ABL induced oncogenesis, we determined whether forced expression of the IL-3 receptor would allow oncogenic transformation of NIH 3T3 fibroblasts known to be resistant to transformation by BCR-ABL. NIH 3T3 cells transduced with the human IL-3 receptor a and b chains were highly susceptible to oncogenic transformation by expression of BCR-ABL. Forced expression of both receptor chains but not either one alone allowed efficient foci formation of NIH 3T3 cells expressing BCR-ABL, and these cells formed colonies in soft agar whereas BCR-ABL positive NIH 3T3 cells lacking IL-3 receptor expression did not. The Bcr-Abl kinase inhibitor imatinib mesylate (1 mM) and the Jak kinase inhibitor AG490 (10 mM) strongly inhibited agar colony formation. A small molecule inhibitor of Jak2 kinase, 1,2,3,4,5,6-hexabromocyclohexane reported to be specific for Jak2 (Sandberg et al. J. Med. Chem, 2005)-significantly reduced the phosphorylation of Gab2 at the YxxM motif, which is needed for activation of the PI-3 kinase and Akt, two proteins that are part of the Bcr-Abl/Jak2 Network (Samanta et al. Cancer Res, 2006). These findings indicate that Bcr-Abl oncoprotein requires the IL-3 receptor/Jak2/Stat5 pathways for oncogenic transformation of NIH 3T3 fibroblasts, and may explain partially why Bcr-Abl oncogenesis is restricted to hematopoietic malignancies. Furthermore, this cell system in fibroblastic and other cell lineages will provide a model to probe the detailed steps that require IL-3 receptor and Jak2 for Bcr-Abl induced leukemia.
Environmental Factors Determine Lineage Fate in a Human Model of MLL-AF9 Leukemia.
Authors: Wei Junping , Mark Wunderlich , Fox Catherine , DiMartino Jorge F. , Mulloy James C.
Published: October 2019

The MLL gene is fused to over 30 different fusion partners by reciprocal translocations in human acute leukemias. Some fusion partners are associated almost exclusively with myeloid or lymphoid leukemias while others are found in both. The degree to which the fusion partner contributes to the lineage of the resulting leukemia remains a matter of controversy. Using a novel model system, we demonstrate that myeloid vs lymphoid differentiation of hematopoietic progenitors transformed by MLL-AF9 can be predictably driven by cytokine combinations in vitro and in vivo. The t(9;11)(p22;q23) MLL-AF9 fusion gene is commonly associated with M5 myeloid leukemia but approximately 5% of MLL-AF9 leukemia is B-lymphoid. Expression of MLL-AF9 in human CD34+ cells enables efficient modeling of acute myeloid, B-lymphoid and biphenotypic leukemia. The lineage of the resulting leukemia can be readily manipulated in vitro (by altering the growth factors) or in vivo (using B-lymphoid-biased NOD/SCID mice or myeloid-biased NOD/SCID that are transgenic for human SCF, GM-CSF and IL-3). The cytokines IL-3, IL-7 and FLT3L appear to exert the major effects on lineage fate determination in vitro. Through limiting dilution and clonality analyses, we find a complex relationship between different leukemia stem cell compartments, with some LSC demonstrating multipotentiality and others showing strict lineage commitment. Data indicate that these differences are primarily due to microenvironment effects, with the identity of the initial cell that is targeted by MLL-AF9 possibly playing a role. These results would argue against a deterministic role for the fusion partner in MLL leukemia. This human-based system should prove useful in addressing the mechanism of lineage promiscuity of MLL leukemias. It also affords us the unique ability to determine the susceptibility of the different LSC to standard chemotherapeutic compounds, in addition to identifying novel therapeutic strategies that may be effective in treating MLL leukemia.
The Identification and Genomic Analysis of microRNAs in Human Erythrocytes in Sickle Cell Diseases.
Authors: Chen Shao-Yin , Wang Yulei , Telen Marilyn I. , Chi Jen-Tsan A.
Published: October 2019

Erythrocytes are circulating blood cells responsible for efficient gas exchange in human body. Since mature erythrocytes are terminally differentiated cells without nuclei and organelles, it is commonly thought that they do not contain nucleic acids. In this study, we re-examined this issue and found that human mature erythrocytes, while lacking ribosomal and large-sized RNAs, possess abundant small-sized RNAs. Using a combination of microarray analysis, real-time RT-PCR and Northern blots we found that mature erythrocytes contained abundant and diverse microRNAs which were distinct from microRNAs observed in reticulocytes/leukocytes and contributed to the majority of the microRNA expression in whole blood. When we used microarrays to analyze erythrocytes from normal (HbAA) and homozygous sickle (HbSS) individulas, we noted dramatic a difference in their microRNA expression pattern. To investigate how this difference is associated with erythrocyte disease phenotypes, we found that the poor expression of miR-320 was responsible for the defective downregulation of its target gene CD71 in HbSS cells during terminal differentiation. Collectively, we have discovered significant microRNA expression in human mature erythrocytes, which enables the microarray analysis of erythrocyte property to provide insights into the human erythrocyte diseases.
Elevated Urinary Leukotriene E4 Levels Are Associated with Hospitalization for Pain in Children with Sickle Cell Disease.
Authors: Jennings Jeanine E. , Ramkumar Thiruvamoor , Mao Jingnan , Boyd Jessica , Castro Mario , Strunk Robert C. , DeBaun Michael R.
Published: October 2019

Introduction: Sickle cell disease (SCD) is associated with an inflammatory state. Luekotrienes are inflammatory mediators derived from arachidonic acid and produced by white blood cells in response to inflammatory stimuli. We tested two hypotheses among children with SCD:

Baseline leukotriene levels are elevated in SCD when compared to controls children without SCD, Baseline leukotriene levels are associated with an increased incidence rate of hospitalization for pain.

Methods: During routine clinical visits, baseline urinary leukotriene E4 (LTE4) levels were measured in children with SCD (cases) and age, and ethnic, matched children without SCD (controls). Medical records of the cases were reviewed to assess the frequency of hospitalization for pain within three years of entering the study.

Results: LTE4 levels were obtained in 71 cases and 22 controls. LTE4 levels were higher in the cases compared to controls (median LTE4: 100 vs.57 pg/mg creatinine); P < 0.001. After adjustment for age and diagnosis of asthma, a greater incidence rate of hospitalization for pain was observed among children with SCD in the highest tertile group when compared to the lowest tertile group (114 vs. 52 episodes per 100 patient-years, P=0.038).

Conclusion: LTE4 levels are elevated in children with SCD when compared to controls without SCD and are associated with an increased rate of hospitalizations for pain.
Complement Activation and Resistance within the Cerebrospinal Fluid Following Intraventricular Administration of Anti-CD20 in the Treatment of Recurrent CNS Lymphoma.
Authors: Kadoch Cigall , Shuman Marc A. , Rubenstein James L.
Published: October 2019

We recently conducted the first phase I dose escalation study of intraventricular rituximab (anti-CD20 antibody) in patients with recurrent central nervous system (CNS) non-Hodgkin’s lymphoma (NHL). The goals of this study have been to define the safety and pharmacokinetics of intraventricular rituximab monotherapy and to gain insight into the molecular basis of rituximab efficacy and resistance in the treatment of high-grade lymphomas. We observed a rapid lymphocytotoxic effect of intraventricular rituximab administration in six out of ten subjects treated, resulting in four complete responses at the completion of five weeks of therapy. Cytologic responses were evident within one hour of rituximab treatment and were not likely related to the action of corticosteroids as these were held stable, tapered or withheld in the week before intrathecal therapy. Three potential mechanisms have been proposed to explain the basis for rituximab efficacy in the treatment of NHL:

direct induction of apoptosis; complement-dependent cytotoxicity (CDC); antibody dependent cellular cytotoxicity (ADCC).

Given the rapid rate of response detected in the leptomeningeal compartment and the relative paucity of Fc-receptor bearing natural killer cells detected in the CSF, we tested the hypothesis that complement activation is responsible for the rapid rituximab-mediated tumor cell lysis which we observed. Pretreatment gene expression profile analysis of meningeal lymphoma cells isolated from CSF demonstrated that RNA levels of expression of CD46, CD55, and CD59 were similar in both responding and non-responding patients. However microarray analysis suggested a possible correlation between low levels of complement receptor 2 (CD21) and immediate rituximab resistance. We focused on the potential generation of C3a anaphylatoxin in the CSF after rituximab administration as C3 is the central component in the classical and alternative complement pathways. Quantitative measurement of C3a concentration in CSF by ELISA demonstrated rapid activation of the complement cascade within one hour of intrathecal anti-CD20 antibody administration. C3a concentrations increased between three-to-eight-fold up to peak concentrations greater than 300 ng/ml. These findings were confirmed by immunoblot analysis of C3a in CSF. Acquired rituximab resistance was associated with marked decreases in the magnitude of complement activation in two patients who initially had exhibited complete responses to intraventricular rituximab monotherapy. These results suggest a mechanistic basis for the rapid lymphocytoxic effects observed and provide a possible explanation for the development of acquired rituximab resistance.
Efficacy and Safety of YM155 in Relapsed/Refractory Non-Hodgkin’s Lymphoma Patients Enrolled in a Phase I Study.
Authors: Papadopoulos Kyriakos , Mita Alain , Antonio Scott , Lewis Lionel D. , Reddy N.J. , Till Elizabeth , Mahany J.J. , Keating Anne , Seiz Amanda , Bartels Pamela , Tolcher Anthony
Published: October 2019

Background: YM155 is a member of a novel class of compounds called survivin suppressants that target survivin. Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin over-expression has been reported in a variety of tumor cells including lymphoma. A Phase I dose escalation study of YM155 was conducted to evaluate safety, tolerability and antitumor activity in patients with solid tumors or non-Hodgkin’s lymphoma (NHL).

Methods: Patients with solid tumors or NHL with no other treatments options were eligible for this Phase I study and received YM155 in escalating doses ranging from 1.8 – 6 mg/m2/day as a 168 hour (7 day) continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until either disease progression or toxicity. 41 patients were enrolled into the study including 5 patients with NHL (2 diffuse large B-cell lymphoma [DLBCL], 1 each small lymphocytic B-cell, follicular [FL] and anaplastic large cell lymphoma). This report focuses solely on the patients with NHL. All 5 NHL patients had at least 2 prior treatment regimens (range: 2 – 7) including stem cell transplant in two patients (DLBCL, FL) and one patient who received 2 investigational therapies. Three patients were considered refractory to the treatment regimen given just prior to study entry (DLBCL, anaplastic large cell, FL).

Results: All 5 NHL patients were male with a mean age of 56 (range: 46 – 64). They were all dosed at the maximum tolerated dose (MTD) of 4.8 mg/m2/day. The most common adverse events reported, regardless of relationship to YM155, were URI (3/5) and arthralgia, fever, hypomagnesemia, mucositis peripheral edema and rash (2/5). The majority of adverse events were Grade 1 or 2 with 3 events reported as Grade 4: Klebsiella bacteremia, neutropenia and hypokalemia. Three patients (60%) (2 DLBCL and FL) had partial response (PR) to YM155 as assessed by independent review using both RECIST and 1999 Cheson criteria. One responder (DLBCL) had a PR after 2 cycles, completed a total of 5 cycles and proceeded to stem cell transplant. This patient has no evidence of disease at 3 years. A second responder (DLBCL) had a PR after 12 cycles and received a total of 26 cycles (∼ 1.5yrs) before disease progression. The third responder (FL) had a PR after 14 cycles, has maintained a prolonged PR for ∼ 2 years and continues to receive YM155 in a long-term extension study.

Conclusion: Based upon the objective responses, the tolerability and safety profile observed in this Phase I study in 5 NHL patients, a Phase II study in refractory DLBCL has been initiated.
Survival in Follicular Lymphoma: The Stanford Experience, 1960–2003.
Authors: Tan Daryl , Rosenberg Saul A. , Levy Ronald , Lavori Philip , Tibshirani Robert , Hoppe Richard T. , Warnke Roger , Advani Ranjana , Natkunam Yasodha , Yuen Alan , Horning Sandra J.
Published: October 2019

Background: Recent data from retrospective and prospective studies indicate an improvement in the overall survival (OS) of follicular lymphoma (FL) patients (pt). We sought to evaluate survival data in FL pt managed at our institution and to analyze their presenting features, management and disease course.

Methods: Previously untreated FL (grades 1 and 2) pt referred from 1960–2003 and followed at Stanford were identified from the Lymphoma Database for this retrospective study. Data were reviewed for quality and consistency of coding for histology (pathology reviewed at Stanford) and treatment courses. Four eras were defined by date of diagnosis 1 (1960–75, n=180); 2 (1976–86, n=426); 3 (1987–96, n=471); and 4 (1997–2003, n=257). Patient (age, gender) and disease (stage, histology) characteristics, management (time from diagnosis to referral, time to first treatment, courses/types of treatment), and outcomes (progression-free survival [PFS], OS, transformation) were evaluated, overall and with respect to era.

Results: The OS for the 1334 FL pt in the dataset was 12.6 years (yr). Age (median = 49 yr), gender (54% male) and stage (83% III-IV) did not differ across the eras. Median OS improved from 11.2 yr [95% CI 10.2,12.1] in eras 1 and 2 (1960–86) to 18.4 yr [95% CI 14.5,22.4] in eras 3 and 4 (1986–2003), p<0.001. Greatest gains were observed in pt less than 60 yr old and in advanced stage disease. OS was not different in eras 3 and 4 (p=0.56) but median follow-up is just 5 yr in era 4. Although treatment varied over the eras, PFS was no longer for the later eras (3 and 4) compared to early eras (1 and 2), p=0.73. Initial therapy was more likely to be deferred in the later eras: 16%, 44%, 59%, 60% for eras 1, 2, 3 and 4, respectively. Rituximab use, as expected, varied over the eras: 1 (1% pt), 2 (8% pt), 3 (23% pt), 4 (42% pt). The incidence of transformation was similar over the eras and OS after transformation was significantly longer if patients were chemotherapy-naive at transformation (p<0.001).

Conclusions: OS of patients with FL managed at Stanford University significantly improved in the 1986–2003 eras, particularly among younger and advanced stage patients. This improvement was not associated with longer PFS after the first course of treatment or differences in the incidence of histologic transformation. Application of a time-variant Cox regression model is in progress to better understand the contributions of treatment, particularly rituximab, as well as other factors in these patients.
Improved Survival of Intravascular Large B-Cell Lymphoma (IVLBCL) by Rituximab Containing Combination Chemotherapies.
Authors: Shimada Kazuyuki , Matsue Kosei , Yamamoto Kazuhito , Ichikawa Naoaki , Okamoto Masataka , Niitsu Nozomi , Kosugi Hiroshi , Tsukamoto Norifumi , Murase Takuhei , Miwa Hiroshi , Asaoku Hideki , Kikuchi Ako , Matsumoto Morio , Saburi Yoshio , Masaki Yasufumi , Kashimura Makoto , Yamaguchi Motoko , Nakamura Shigeo , Naoe Tomoki , Tomohiro Kinoshita
Published: October 2019

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL) with poor prognosis. Recently, the addition of rituximab to CHOP regimen has significantly improved the outcome of DLBCL. However, the efficacy of rituximab in IVLBCL remains unclear.

Objective and Patients: To evaluate the usefulness of rituximab in IVLBCL, 70 patients who were diagnosed as IVLBCL between 1999 and 2007 from the 16 participating centers were retrospectively analyzed. Patient characteristics were as follows: median age, 68 yrs (range, 34 to 88 yrs); sex, M/F 56%/44%; LDH > UNL, 99%; stage III/IV, 100%; extranodal site > 1, 81%; PS > 1, 84%; IPI: H-I/H, 97%. Sixty four of 70 patients received anthracycline containing chemotherapies. In 64 patients, 43 (67%) and 21 (33%) patients received rituximab containing chemotherapies (R-chemo) and chemotherapies without rituximab (chemo), respectively. There was no significant difference between the two groups in terms of various clinical variables.

Results: The complete response rate (%CR) was significantly higher in the R-chemo group than in the chemo group (90% vs. 55%, P = 0.0003). With a median follow up time of 24 months (range, 2 to 88 months) in living patients, 2-year progression-free and overall survival (OS) rates were significantly higher in the R-chemo group than in the chemo group (63% vs. 32%, 71% vs. 39%, P = 0.015 and 0.01, respectively). In univariate analysis, age, LDH, the number of extranodal site, PS and platelet count were not significant prognostic factor, while the use of rituximab was favorably associated with OS (HR, 0.33; 95% CI, 0.13 to 0.88; P = 0.015). Grade 3 hypoxia due to the infusion of rituximab was observed in one of 43 patients (2%). Grade 3 or 4 non-hematologic adverse events were observed in the 3 of 43 (7%) patients and 3 of 21 (14%) patients, respectively. Treatment related death was observed in 3 patients. Two in the R-chemo group died of HBV reactivation and tuberculosis, and one in the chemo group died of sepsis. Eight of 43 and 12 of 21 patients in the each group died at the time point of the study, respectively, and the most major cause of death was primary disease (6 and 11 patients, respectively).

Conclusion: Our data strongly suggested that the addition of rituximab to chemotherapies significantly improved the %CR and survival in IVLBCL without significant increase in toxicities. Thus, prospective clinical trials of rituximab-containing chemotherapies for IVLBCL are warranted.
Primary Diffuse Large B-Cell Lymphoma of the Colon: Surgery for Local Disease Control Does Not Improve Outcome.
Authors: Katipamula Rajini , Ristow Kay , Colgan Joseph P. , Habermann Thomas M. , Johnston Patrick B. , Inwards David J. , Markovic Svetomir N. , Micallef Ivana N. , Porrata Luis F. , White William L. , Witzig Thomas E. , Ansell Stephen M.
Published: October 2019

Purpose: Primary colorectal large B-cell lymphoma is rare and accounts for less than 1% of all malignancies in the colon. Standard treatment for limited stage diffuse large B-cell lymphomas (DLBCL) includes systemic therapy combined with involved field radiation therapy. However, radiation therapy may often not be feasible in patients with primary colon lymphoma. For primary DLBCL of the colon particularly the cecum, surgical resection prior to the administration of systemic chemotherapy has been considered to improve local control. The goal of this study was therefore to determine whether surgical resection improves the outcome of patients with primary DLBCL of the colon.

Methods: Clinical information and outcomes on all the patients with primary DLBCL of the colon seen at Mayo Clinic, Rochester, between January 1980 and June 2005 were retrospectively reviewed.

Results: There were 28 patients identified with primary colon DLBCL. Pre-existing conditions like colon polyps, Crohn’s disease and diverticulosis were uncommon. The most common presenting symptom was bleeding per rectum seen in 13 patients (46.5%). Other symptoms included abdominal pain, diarrhea and anemia. All patients had early stage disease (stage1–22 patients, stage2–6 patients) at diagnosis. Of the 28 patients, 16 underwent initial surgery followed by chemotherapy, 7 were treated with chemotherapy alone, and 5 patients had inadequate data to determine time to progression or overall survival. Chemotherapy was anthracycline based, with the most common regimen being CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone). There was no difference in overall survival or time to progression between the 16 patients who received combined modality therapy compared to the 7 patients who received chemotherapy alone. Of the 16 patients who underwent surgical resection followed by chemotherapy, all 5 patients who relapsed, relapsed at other sites in the colon. Conclusion: Surgery as part of combined modality therapy did not appear to improve the outcome of patients with primary DLBCL of the colon. Systemic chemotherapy with an anthracycline-based regimen in combination with rituximab is therefore likely to be sufficient treatment for these patients. Follow-up for these patients should include a colonoscopy to monitor for recurrences at other sites in the colon.
Specific Intensive Chemotherapy Plus Rituximab for Advanced Burkitt’s Lymphoma or Leukemia in HIV-Positive and Negative Adult Patients.
Authors: Ribera Josep-Maria , Oriol Albert , Esteve Jordi , Bergua Juan , Larregla Santiago , Brunet Salut , delPotro Santiago , Escoda Lourdes , Moreno-Rico Maria-Jose , Jimenez Javier Lopez , Feliu Evarist
Published: October 2019

A previous PETHEMA protocol (PETHEMA ALL3/97) proved that HIV-positive patients with Burkitt’s lymphoma (BL) and Burkitt-like acute lymphoblastic leukemia (ALL3) had similar outcome than HIV-negative patients (Haematologica2003; 88:445–53). We aimed to study the impact of the addition of rituximab to our previous protocol in terms of toxicity and efficacy, with special attention to HIV-positive patients. Consecutive patients between 18 and 55 years and diagnosed with advanced stage (stage III-IV or bulky stage II) BL/ALL3 between July 2003 and August 2006 received induction therapy including a pre-phase with cyclophosphamide (CPM) and prednisone (PDN), followed by cycle A (rituximab, iphosphamide, VCR, dexamethasone -DXM-, HD-MTX, ARA-C and VM-26), cycle B (rituximab, VCR, HD-MTX, CPM, DXM and doxorubicin) an cycle C (rituximab, DXM, VDN, HD-MTX, HD-ARAC and VP-16) up to six cycles (A1,B1,C1,A2,B2,C2) followed by two additional rituximab doses. CNS prophylaxis consisted of IT MTX+ARA-C+DXM given twice in cycles A and once in cycles B for a total of 8 doses.

Results: 36 patients (17 HIV-negative and 19 HIV-positive) were included. Both groups of patients were comparable for age, gender, ECOG score, BM and CNS involvement, bulky disease, LDH and albumin serum levels. Fifteen patients had bone marrow infiltration of whom 3 reached ALL3 criteria. Four out of 19 HIV positive patients begun treatment with HAART at the time of diagnosis and 15 were already under treatment. Median follow-up was 1.7 years (range 0.8–4.1). Main results of therapy are summarized in table 1. No significant differences in CR, DFS or OS were observed between HIV-positive and negative patients. Grade 4 neutropenia and thrombocytopenia were almost constant and lasted a median of 7 and 5 days respectively (range 0 – 39). Other frequent grade 3–4 toxicities were hepatic (5% of cycles), mucositis (18%) and infectious (18%). Episodes of grade 3–4 extrahematological toxicity were more frequent in HIV-positive patients (77% of episodes of mucositis, p=0.04 and 72% of infections). Treatment delays >7 days due to toxicity of previous cycle were also more frequent in HIV-positive patients (41% vs 24%, p= 0.04). In conclusion, our results prove that the addition of rituximab to a specific BL/ALL3 treatment is also feasible and highly effective for HIV-positive patients with similar results to HIV- negative patients in terms of efficacy although with higher toxicity.

Total (%) (n=36) HIV+ (%) (n=19) HIV- (%) (n=17) CR after two cycles 30 (83) 15 (79) 15 (88) Toxic death (1st 2 cycles) 5 (14) 3 (16) 2 (12) Resistance 0 0 0 Toxic death in CR 2 (6) 2 (11) 0 Relapses during treatment 1 (3) 0 1 (6) Relapses off treatment 0 0 0 Project. 1-year prob. DFS 90% 87% 93% Project. 1-yr prob. OS 78% 73% 82%
Preliminary Results of a Phase II Study of HCVIDDoxil Alternated with Methotrexate-Cytarabine in Patients with Newly Diagnosed T-Cell Lymphoma.
Authors: Pro Barbara , Fayad Luis , Romaguera Jorge , Fanale Michelle , Younes Anas , Hagemeister Fredrick B. , Samaniego Felipe , McLaughlin Peter , Rodriguez M.A. , Kwak Larry , Dang Nam H.
Published: October 2019

Background The prognosis of patients with T-cell lymphoma (TCL) remains poor with conventional chemotherapy regimens and innovative approaches are needed. We evaluated the efficacy and safety of the regimen HCVIDDoxil, with pegylated doxorubicin substituting doxorubicin in the HCVAD regimen, alternated with MTX-Ara-C in patients with newly diagnosed TCL.

Methods Previously untreated patients (pts) with Zubrod performance status 3 or less, age > 18 years, and adequate marrow, cardiac, liver and renal function were included in this study. Patients with ALK + anaplastic large cell lymphoma (ALCL), skin involvement alone, HIV positive serology, and evidence of CNS involvement were excluded. Patients received HCVIDDoxil (iv cyclophosphamide 300 mg/m2 iv Q 12 h X 6 doses days 1–3, mesna 600 mg/m2 iv daily over 24 hours by continuous infusion days 1–3, doxil 25 mg/m2/day iv on day 2, vincristine 1.4 mg/m2 (max. 2 mg) iv days 4 and 11, dexamethasone 40 mg iv or po daily X 4 days 1–4 and 11–14) alternated with MTX/Ara-C (MTX 200 mg/m2 iv over 2 hours on day 1, then 800 mg/m2 iv over 22 hours on day 1, Ara-C 3 g/m2 iv Q 12 hours X 4 doses on days 3–4). Courses were repeated every 3 weeks for a maximum of 8 cycles. Endpoints were response rate and progression-free survival.

Results Between October 2003 and July 2007, 38 patients (pts) were included, 20 pts with PTCL, 6 pts with ALCL-ALK-, 4 pts with NK-TCL, 4 pts with HSL, and 4 pts with AIL. Median age was 54 (range, 23–70). Thirty-three (86%) pts had stage III/IV, 5 stage I/ II. Twenty-five (65%) pts had extranodal disease, and 14 (36%) pts had bone marrow involvement. A median of 5 cycles were delivered. To date 32 pts are evaluable for response. The ORR was 87%, with CR in 19 pts (59%) and PR in 9 pts (28%). Common Grade ¾ adverse events were thrombocytopenia in 31 pts (96%), neutropenia in 24 (75%), anemia in 23 (71%), and febrile neutropenia in 7 (32%). Six of the complete responders progressed (31%, median TTP 188 days), and 13 of the responses are ongoing (+6-+36 months).

Conclusions In this high-risk population the regimen HCVIDDoxil alternated with MTX-Ara-C induced a high response rate. Further follow-up is needed to evaluate if the high response rate results in improved disease-free survival. As expected, the major toxicity was myelosuppression. Enrollment in this study continues.
Induction of Both CCAAT/Enhancer Binding Protein β and ε Are Required for All Trans Retinoic Acid-Induced Granulocytic Differentiation of Myeloid Leukemia Cells.
Authors: Lu Min , Xia Lijuan , Friedman Alan D. , Waxman Samuel , Jing Yongkui
Published: October 2019

All trans retinoic acid (ATRA) induces remission in patients with acute promyelocytic leukemia (APL) by induction of granulocytic differentiation. Since CCAAT/enhancer binding protein (C/EBP) α, β and ε play important roles in normal granulocytic differentiation we compared their expression and regulation in ATRA differentiation inducible NB4 and HL-60 cells to their ATRA differentiation resistant subclones R4 and HL-60/Res cells. All four cell lines robustly express C/EBPα but have low or absent C/EBPβ and ε expression. ATRA treatment increases the levels of C/EBPβ and ε protein in NB4 and HL-60 cells but not in the R4 and HL-60/Res cells which is correlated with the degree of differentiation induction. Knockdown of C/EBPβ or ε using shRNA decreases ATRA differentiation induction of HL-60 cells. HL-60 cells with BCR-ABL stable transfection lose expression of C/EBPα, and ATRA-induced differentiation and expression of C/EBPβ and ε are no longer seen. K562 cells which express BCR-ABL do not have detectable or inducible C/EBPα, β and ε after ATRA treatment and are resistant to ATRA differentiation induction. Ectopic expression of C/EBPα-estrogen receptor (ER) or C/EBPβ-ER, but not C/EBPε-ER, induces granulocytic differentiation in K562 cells after addition of estradiol or tamoxifen which activates these fusion factors. C/EBPα-ER or C/EBPβ-ER infected K562 cells is followed by induction of C/EBPε expression and knockdown of C/EBPε in C/EBPα-ER or C/EBPβ-ER infected K562 cells decreases induction of differentiation. The induction of C/EBPα, β, and ε expression by ATRA is investigated in ten additional myeloid leukemia cell lines and it is found that the expression of C/EBPβ and ε, but not C/EBPα, are induced in THP-1 and ML-1 cells which are responsive to ATRA differentiation induction. These results indicate that induction of C/EBPβ is required and C/EBPε plays a collaborative role with C/EBPβ in ATRA-induced differentiation of myeloid leukemia cells.
Anti-Apoptotic Proteins, HSP90 and Activated STAT3 Contribute to Busulfan Resistance of Myeloid Leukemia Cells.
Authors: Andersson Borje S. , Valdez Ben C. , Murray David , Ramdas Latha , de Lima Marcos , Jones Roy , Kornblau Steven , Champlin Richard E.
Published: October 2019

Busulfan(Bu)-based chemotherapy is a conditioning treatment prior to hematopoietic stem cell transplantation (HSCT) of patients with acute and chronic myelogenous leukemia (AML, CML). A major obstacle to successful HSCT is Bu resistance, which might be attributed to individual differences in drug pharmacokinetics and metabolism, or inherent resistance of cancer cells. We hypothesize that gene expression profiling of leukemia cells can be used to dissect the factors that contribute to their Bu resistance. Two Bu-resistant leukemia cell lines were established, characterized and analyzed by microarray and real-time RT-PCR techniques to identify differentially expressed genes. The CML B5/Bu2506 cells are 4.5-fold more resistant to Bu than their parental B5 cells. The AML KBM3/Bu2506 cells are 4.0-fold more Bu-resistant than KBM3 parental cells. Both resistant sublines evade Bu-mediated G2-arrest and apoptosis with constitutively up-regulated anti-apoptotic genes (BCL-XL, BCL2, BCL2L10, BAG3 and IAP2/BIRC3) and down-regulated pro-apoptotic genes (BIK, BNIP3, and LTBR).). Bu-induced apoptosis is partly mediated by activation of caspases; use of the inhibitor Z-VAD-FMK completely abrogated PARP1 cleavage and reduced apoptosis by ∼ 50%. Furthermore, Bu resistance in these cells may be attributed in part to up-regulation of HSP90 protein and activation of STAT3. Inhibition of HSP90 with geldanamycin attenuated phosphorylated STAT3 and made B5/Bu2506 and KBM3/Bu2506 more Bu-sensitive. Analysis of cells derived from patients classified as either clinically resistant or sensitive to high-dose Bu-based chemotherapy had alterations in gene expression that were analogous to those observed in the in-vitro model cell lines, confirming the potential clinical relevance of this model for Bu resistance. Our results suggest the important roles of apoptotic signaling mechanism, HSP90 and STAT3 and should be considered in the classification of AML patients who will likely benefit from busulfan-based pretransplant conditioning therapy and those who should be offered alternative treatment modalities.
Lenalidomide Displays Direct Anti-Non-Hodgkin’s Lymphoma (NHL) Cell Activity in Association with Enhanced SPARC Expression but Independent of Its Ability to Strongly Inhibit NHL Cell VEGF Production In Vitro.
Authors: Zhang Ling-Hua , Schafer Peter , Muller George , Stirling David , Bartlett J. Blake
Published: October 2019

Lenalidomide is an oral anti-angiogenic, anti-proliferative and immunomodulatory drug that is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of previously treated multiple myeloma patients. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin’s lymphoma (NHL). We have previously shown that lenalidomide can directly inhibit the proliferation of NHL cells and synergize with dexamethasone in inducing cell cycle arrest at the G1/S transition leading to caspase activation and apoptosis. In this study we have studied the potential for lenalidomide mediated growth inhibition, apoptosis and inhibition of angiogenic factors in NHL. We have assessed proliferation, expression of p21 and SPARC tumor suppressor genes and the production of the angiogenic factor vascular endothelial growth factor (VEGF) in six established NHL cells lines in vitro. The effect of lenalidomide on NHL cells was determined after 1–3 days using 3H-thymidine incorporation, microbead array and real time PCR. We found that lenalidomide displays anti-proliferative effects on Namalwa, Jeko-1 and Rec-1 cells when used alone and in combination with dexamethasone. However, several NHL cell lines, such as Granta-519, DB, and JVM-2, appear to be resistant. We also found that lenalidomide strongly inhibited VEGF production (but not mRNA levels) by the three sensitive lines (but not the three resistant lines) at much lower concentrations than required for inhibitory effects on proliferation. Excess recombinant human VEGF or neutralizing anti-VEGF antibody had no effect on Rec-1 proliferation suggesting that there is no connection between these two effects. Lenalidomide strongly increased the expression of tumor suppressor genes, such as p21cip/kip and SPARC (secreted protein acidic and rich in cysteine). In particular, elevation of SPARC mRNA correlated with the anti-proliferative effect of lenalidomide and was not seen in the resistant cells, whereas elevated p21 was observed in both sensitive and resistant (DB) cells. The effect of SPARC gene silencing on lenalidomide-induced effects is being assessed in siRNA studies. In conclusion, lenalidomide demonstrates anti-proliferative activity against certain sensitive NHL cells, particularly in combination with dexamethasone. Potent anti-VEGF activity of lenalidomide appears to be independent of proliferation and supports its anti-angiogenic potential. Lenalidomide-induced up-regulation of SPARC mRNA appears to correlate with sensitivity and may have biomarker potential in NHL.
Safety, Tolerability, and Pharmacology of Bortezomib in Cancer Patients with Renal Failure Requiring Dialysis: Results from a Prospective Phase 1 Study.
Authors: Mulkerin Daniel , Remick Scot , Takimoto Chris , Ivy Percy , Karol Michael , Eton Omar
Published: October 2019

Background: Bortezomib (btz; VELCADE®) is a specific, reversible proteasome inhibitor approved for the treatment of patients (pts) with multiple myeloma (MM) and mantle cell lymphoma following at least one prior therapy. Retrospective analyses of phase 2/3 studies and case series have shown btz alone or in combination is active and tolerable in MM pts with various degrees of renal impairment, including pts on dialysis. We previously reported clinical and pharmacologic data from the first prospective, dose-escalating study of btz in adult cancer pts with various degrees of renal impairment (ASCO 2006, abstract 2032). Here we present updated safety and tolerability data for dialysis-dependent patients.

Methods: Pts with advanced cancer were stratified by renal function into controls and four groups ranging from mild impairment to dialysis dependence. Pts received btz on d 1, 4, 8, and 11 of a 21-day cycle; dose escalation (0.7, 1.0, 1.3 mg/m2) proceeded in cohorts of 3 pts based on dose limiting toxicities (DLTs) observed in cycle 1. Blood samples were taken on d 1 and 8 of cycle 1 for pharmacokinetic (PK) and pharmacodynamic (PD) analysis. Adverse events (AEs) were evaluated using NCI CTC v2.0. DLTs were grade 4 neutropenia for ≥7 d or neutropenic fever, grade 4 thrombocytopenia for ≥7 d, grade 4 hemoglobin for ≥7 d, and grade ≥3 non-hematologic toxicity.

Results: To date, 59 pts have been treated, including 16 controls, 34 pts with mild-to-severe impairment, and 9 dialysis pts. Among dialysis pts: 3 were treated at 0.7, 2 at 1.0, and 4 at 1.3 mg/m2; median age was 62 y (range: 42–74); tumor types were MM (n=4), follicular lymphoma (n=1), and solid tumors (n=4). Median number of treatment cycles received was 2 in controls and across renal impairment groups. Dialysis pts received a median of 2 treatment cycles (range: 1–4); 1 pt remains on therapy. Dose escalation was well tolerated, with no DLTs, in pts with mild-to-severe renal impairment. There were no DLTs in cycle 1 in dialysis pts. Toxicities were generally mild in all groups. Among dialysis pts, no unexpected toxicities were seen. One grade 4 treatment-related AE (elevated creatinine) has been reported; grade 3 treatment-related AEs include platelets/thrombocytopenia (3 pts), diarrhea, hemoglobin, leukopenia, lymphopenia, packed red blood cell transfusion, sensory neuropathy, and vomiting (1 pt each). The overall AE profile in dialysis pts was similar to that in controls and in pts with mild-to-severe impairment, although renal and metabolic AEs appeared more common in dialysis pts.

Conclusions: Btz at doses up to 1.3 mg/m2 on this schedule was well tolerated in pts with advanced malignancies with mild-to-severe renal impairment and dialysis dependence. PK and PD analyses for dialysis pts treated at 1.3 mg/m2 will be reported. Btz is a viable treatment option for pts requiring dialysis.