bluuebunny/crossref_metadata_2025 huggingface dataset:
A Psychosocial Assessment of Patients before and after Autologous Stem Cell Transplantation.
Authors: Bolwell Brian J. , McLellan Linda , Foster Larry , Dabney Jane , Welsh Erin , Kuczkowski Elizabeth , Curtis Julie , Bell Kimberly , Baker Janet , Bernhard Laura , Cherni Kelly , Rybicki Lisa , Sekeres Mikkael A.
Published: April 2020

There are relatively few reports in the medical literature describing psychosocial assessment of bone marrow transplant patients; what data exists primarily focuses on allogeneic transplant recipients. We have begun to prospectively assess psychosocial parameters of patients undergoing autologous transplantation using the Functional Assessment of Cancer Therapy-BMT (FACT-BMT) tool. The general questions consist of four subscales developed and normed in cancer patients that measure; physical well-being; social/family well-being; emotional well-being; functional well-being; and a specific module to address BMT-specific concerns. Each subscale is positively scored, with higher scores indicating better functioning. A baseline survey is collected by the social worker pre-transplant and a follow-up survey is administered and collected approximately 6 weeks post-transplant by the Transplant Coordinator. 56 consecutive patients undergoing autologous stem cell transplant have FACT-BMT data both pre-transplant and approximately one month post-discharge. Median age was 50. 52% are male; underlying diagnoses include NHL (45%), Hodgkin’s disease (32%), myeloma (16%), AML (5%), testicular cancer (2%). 93% had chemosensitive disease at the time of transplant. All patients received peripheral blood progenitor cells (PBPCs), and all received a chemotherapy-only preparative regimen. All patients were hospitalized for approximately three weeks for the transplant. For most of the variables measured by the FACT-BMT tool, there was no significant difference in pre-transplant and post-transplant scores. The one variable that did change was emotional well-being: patients scored statistically significantly higher post-transplant as compared to the pre-transplant score (p<0.001). We also have collected baseline FACT-BMT data on 42 consecutive allogeneic BMT recipients, as well as 12 recipients of non-myeloablative allogeneic BMT transplants. There is no significant difference in any pre-transplant variables measured by the FACT-BMT score between autologous recipients, ablative allogeneic recipients, and non-myeloablative allogeneic recipients. We conclude that patients undergoing an autologous stem cell transplant have a higher sense of emotional well-being after engraftment and hospital discharge. Presumably this reflects positive feelings about accomplishing this intensive treatment for their underlying malignancy, and suggests that emotional and physical recovery after auto-BMT is reasonably rapid. A larger dataset will hopefully allow a more detailed comparison of allo and auto BMT recipients.
A Randomized Trial of Short-Course Preemptive Ganciclovir Compared with Conventional Ganciclovir Therapy To Prevent Cytomegalovirus Infection after Allogeneic Stem Cell Transplantation.
Authors: Park Keun W. , Lee Jeeyun , Park Jinny , Ho Young Kim , Lee Mark H. , Lee Se-Hoon , Kang Jung H. , Kim Kihyun , Jung Chul W. , Kim Won S. , Park Joon O. , Im Young H. , Park Young S. , Kang Won K. , Park Keunchil
Published: April 2020

We studied the efficacy and safety of a short course of ganciclovir to prevent cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In general, preemptive ganciclovir is administered twice daily for 1–2 weeks (induction phase) and then once daily until 6 days after cessation of viremia and antigenemia (maintenance phase). We randomly assigned allogeneic HSCT recipients who had positive shell vial culture for CMV or CMV antigenemia to receive preemptive ganciclovir therapy with or without induction phase (5 mg/kg body weight, twice a day for one week). 32 and 34 patients were randomized to the standard treatment arm and the short course arm, respectively. There were no statistically significant differences in patient characteristics such as age, sex, type of disease, type of transplantation, seropositivity of CMV antibody in donor, seropositivity of CMV antibody in recipient, type of conditioning regimen or GVHD prophylaxis regimen between two groups. The median time to clearance of CMV viremia and antigenemia was 7 d and 9 day, respectively (P = 0.333). Seven patients in the short course arm failed for viral clearance after preemptive therapy and were cross-overed to the standard preemptive therapy, which resulted in clearance of antigenemia and viremia in all patients. The toxicity profile was higher in the standard treatment arm with 5 neutropenia and 1 drug-induced hepatitis whereas there was only 1 neutropenia in the short-course arm. Of 5 patients who experienced neutropenia, 2 died of sepsis. This study shows that the preemptive ganciclovir therapy with maintenance phase alone may be equally effective to the standard treatment arm with less toxicity profile in prevention of CMV disease in allogeneic HSCT recipients. The omission of induction phase in CMV preemptive therapy may allow patients to avoid unnecessary hospital admissions.
Tinzaparin in Problem Pregnancy (TIPP): Retrospective Analysis of Therapeutic Outcomes in High-Risk Pregnant Patients Treated with Tinzaparin.
Authors: Andersen Judith C. ,   TIPP Participants MD
Published: April 2020

BACKGROUND: Pregnancy represents a “physiologic” maternal thrombophilic state, with presumed evolutionary goals of ensuring secure fetal implantation, placental stability, and control of peripartum maternal bleeding. Specific pregnancy-induced maternal changes include increased activated Protein C resistance; decreased active Protein S; increased levels of vitamin K-dependent procoagulants, factor VIII, von Willebrand factor, and fibrinogen; and increased levels of plasminogen activator inhibitor (PAI-1). Superposition of pregnancy upon inherited or acquired thrombophilias may have untoward consequences for both mother and fetus. Venous thromboembolism (the leading cause of maternal morbidity and mortality in pregnancy) is five times more likely to occur in pregnant women than in nonpregnant women of similar age. Placental insufficiency and recurrent fetal loss are strongly associated with inherited and acquired thrombophilia, and antithrombotic interventions with aspirin, unfractionated heparin and low molecular weight heparins (LMWHs) have decreased maternal morbidity and improved fetal outcome. LMWHs offer decreased incidence of bleeding, heparin-induced thrombocytopenia with thrombosis (HITT), and osteoporosis, as well as predictable dosing efficacy. An industry sponsored series of roundtable discussions with US hematology and high-risk obstetrics practitioners revealed that a collective deterrent to use of tinzaparin (the most recently introduced LMWH with favorable pharmacokinetics and once-daily dosing) was the limited amount of published safety and efficacy data in this patient population.

STUDY DESIGN: Fifty pregnancies in women treated with tinzaparin between January 2003, and June 2004, in American maternal/fetal medicine programs for high risk from prior pregnancy-associated VTE, presence of high risk pre-existing thrombophilias, or recurrent fetal loss are undergoing retrospective analysis for maternal and fetal outcomes; safety; and compliance with therapy. A specific identifier-blind data collection tool will capture historical and examination data and diagnostic studies that establish and follow risk as well as tabulate antithrombotic and adjunctive medication/supplement regimens. “Live birth” and “fetal loss” questionnaires will capture maternal and fetal course, complications, anesthesia and delivery decisions, and tissue pathology, as appropriate.

RESULTS: Data analysis will be complete by late November 2004. In the absence of large randomized trials of efficacy and safety, such a study may provide guidelines for safe and effective use of tinzaparin in American high-risk pregnancy.
Outcome of Adults with Precursor B-Cell and Mature B-Cell (Burkitt-Cell) ALL/Lymphoma in a Large Inner City Hospital.
Authors: Mims Martha P. , Edwards Maria , Udden Mark M.
Published: April 2020

Acute lymphoblastic leukemia is the most common acute leukemia in children, but accounts for only about 20% of adult acute leukemias. In children overall survival at 5 years is about 70% as a result of intensive treatment regimens. Application of such treatment regimens to adults has improved the 5 year survival to about 30–35% in large studies. We report here a retrospective analysis of all 18 cases which presented to our hospital during the last 2 1/2 years. All patients were treated with intensive chemotherapy regimens (primarily Hyper CVAD alternating with MTX/AraC) including maintenance therapy for patients with precursor B-cell ALL. The mean age of all patients was 39.6 ± 15.2 years., 11 patients were male and 7 female. Thirteen patients presented with precursor B-cell ALL (8 male/5 female); the mean age of these patients was 36.3 ± 16.1 years. Five patients presented with Burkitt-cell leukemia (3 male/2 female), the mean age of these patients was 48 ± 8.9 years; 4 patients were HIV positive. Overall, 7 of 18 patients are alive, 5 are in remission, 1 did not achieve remission and is being evaluated for stem cell transplant, and 1 is completing the first cycle of chemotherapy. The 7 surviving patients include 5 with precursor B-cell ALL (4 male/1 female) and 2 Burkitt-cell patients (both female, both HIV+, both with CD4 count > 400). An analysis of high risk features in pre B-cell ALL patients showed only one patient older than 60, 1 with adverse cytogenetics (9:22 translocation), one with WBC count >50,000/ml at presentation, and 2 who required more than 1 course to achieve CR. Positivity for CD20 has been reported by some to be an adverse prognostic factor in pre B ALL. In our study 8 of 13 pre B ALL patients were CD20 positive, 3 of these patients survive as compared to 2 of 5 CD20 negative patients. Women with pre B ALL had significantly poorer outcomes than men with only 1 of 5 surviving; all women with CD20 positive disease succumbed. Among the Burkitt-cell patients, the 2 survivors were HIV positive women with the highest CD4 counts. Three of 18 patients (16.6%) died during induction; 1 presented to our hospital in first relapse 3 years after first CR, 1 developed overwhelming fungal infection, and 1 suffered probable anaphylactic reaction. More than 75% of patients with pre B ALL were Hispanic, and while 3 are still living, only one has completed induction and consolidation and is still in remission. The reasons behind the poor survival of the Hispanic subgroup are not clear, however, it should be noted that all patients who were CD20 positive in this group have either died or failed to achieve remission. In this series 27% of patients had mature B-cell disease, which is much higher than the 5% estimated incidence in adults overall. Despite the preponderance of HIV positive patients, the survival of these patients compares favorably with that reported in the literature.
Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Comparative Study of Flow Cytometry and Quantitative Real-Time Polymerase Chain Reaction (RQ-PCR).
Authors: Misra Ashish K. , Sartor Mary , Sutton Rosemary , Venn Nicola C. , Cross Shamira , Bradstock Ken , Norris Murray , Dalla-Pozza Luciano
Published: April 2020

Approximately 25% of children with acute lymphoblastic leukemia (ALL) relapse after frontline therapy. Current stratification methods using clinical/biological criteria fail to identify a significant proportion of these children. Numerically more patients classified as standard/medium risk relapse than those with high-risk ALL. Early identification of this group with intensification of therapy may prevent this.

We compare two techniques, multi-parameter flow cytometry (FCM) and real-time polymerase chain reaction (RQ-PCR) to monitor minimal residual disease (MRD) in bone marrow after initial therapy in newly diagnosed patients. We report our initial experience in patients with B-lineage ALL from a single institution (CHW) treated on the ANZ Haematology-Oncology Group Study VIII protocol for ALL.

Multiparameter FCM was performed using two different four colour combinations of antibodies:

CD19APC/CD45PerCP/CD10FITC/CD20PE and CD19APC/CD45PerCP/CD34FITC/CD9PE. A series of dual parameter displays were generated to define normal B cell differentiation pathways and this allowed the discrimination of malignant precursor B cells. RQ-PCR used clone specific primers and Taqman probes selected after sequencing the immunoglobulin heavy chain and/or T cell receptor gene rearrangements detected in the diagnosis DNA. The RQ-PCR assays had greater sensitivity and were highly reproducible. The timepoints used for analysis were Day 33 (D33) and D79, following induction and consolidation respectively. Of 45 patients, 44 (98%) had informative RQ-PCR markers: 12 (27%) with high MRD levels at D33 (>10−3) while 3 (6.7%) had high levels at D79. In contrast by FCM 5 (11.1%) had positive MRD (>0.1%) on D33 compared with 7 (15.6%) on D79. The 3 with high MRD on RQ-PCR at D79 were also identified by FCM. 2 of these 3 patients had been classified as standard/medium risk by conventional criteria. These two techniques may be complementary in identifying patients with significant MRD. Only a proportion of patients were identified by both methods. Long term follow up and ongoing recruitment will help delineate the optimal surveillance/stratification strategy by correlating these findings with outcome.
Daunorubicin, Cytarabine and Fludarabine (DAF) for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Phase II Study by the Polish Adult Leukemia Group (PALG).
Authors: Holowiecki Jerzy , Grosicki Sebastian , Krzemien Slawomira , Skotnicki Aleksander , Warzecha Krzysztof , Zdziarska Barbara , Stella-Holowiecka Beata , Krawczyk-Kulis Malgorzata , Kopera Malgorzata , Wojciechowska Maria
Published: April 2020

In 1992–93 a synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (AraC) resulting in increase of Ara-CTP concentration in myeloblasts was proved. In the previous study by the Polish Adult Leukemia Group (PALG 1999 Study) we demonstrated that addition of cladribine to standard daunorubicin + cytarabine induction potentiates antileukemic activity of the regimen in acute myeloid leukemia (AML).

The goal of the current study was to assess the safety, tolerance and antileukemic activity of a new DAF regimen consisting of daunorubicin 60 mg/m2/d iv 1–3, AraC 200 mg/m2 ci 1–7, and fludarabine 25 mg/m2/d 1–5.

Twenty-five AML patients aged 40 (range 19–62) years with primary refractoriness 60% (n=15) or in relapse 40% (n=10) were included in the study between 2003–2004. DAF was administered as a second (n=24) or as a third line of induction treatment (n=1).

Twelve patients (48%) achieved complete remission (CR), 1 (4%) had partial remission (PR), and 10 (40%) did not respond (NR, leukemia regrowth). Two patients died in aplasia from infectious complications (8%).

All patients developed severe thrombocytopenia and granulocytopenia (WHO grade III or IV). Median time to neutrophil >0.5 G/L recovery and platelet >50 G/L recovery equaled 21 d. (11–30) and 20 d. (11–27), respectively.

Eleven (44%) patients exerienced severe (WHO grade III or IV) neutropenic infections (bacterial n=9, fungal n=2). Other serious adverse events were infrequent: vomiting 24% (n=6), mucositis 24% (n=6). Severe hepatotoxicity, nephrotoxicity and cardiotoxicity was not observed.

Median hospital stay lasted 28 (11–41) days. Patients required 5.5 (0–13) PRBC transfusions and 5.5 (1–14) platelet transfusions. Hematopoietic growth factors were not administered.

Results of this phase II study indicate that DAF is a relatively well-tolerated and safe regimen with high anti-leukemic potency in relapsed/refractory AML. Based on these findings a randomized, multicenter study comparing DAF to the standard DA induction has been designed for newly diagnosed AML patients.
Venous Thromboembolic Events in Patients with Diffuse Large B cell Non- Hodgkin’s Lymphoma.
Authors: Komrokji Rami S. , Uppal Nikhil P. , Khorana Alok A. , Lyman Gary H. , Kaplan Karen L. , Fisher Richard I. , Francis Charles W.
Published: April 2020

Background:

Venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) is a well-known complication of cancer. VTE frequency varies according to the underlying malignancy. Diffuse large B cell Lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma (NHL). VTE during initial treatment of DLBCL is a complication recognized by treating physicians. Little information is available regarding the frequency of VTE and its association with outcomes in DLBCL. We conducted a retrospective cohort study to determine the frequency and timing of VTE during initial treatment of DLBCL, as well as identifying risk factors associated with VTE, and the clinical impact of VTE on survival.

Methods:

We reviewed records of consecutive patients diagnosed with de novo DLBCL seen at University of Rochester from January 1990 to December 2001. Patients with transformed DLBCL, CNS lymphoma, HIV-related NHL, and patients whose complete records were unavailable were excluded. We considered only episodes of VTE that occurred during the initial treatment of DLBCL. For analysis of risk factors for VTE, Chi-square test or Fisher’s exact test was used to compare the categorical variables and t-test was used to compare continuous variables. Kaplan-Meier estimate was used to compare overall survival between patients with or without VTE. Log-rank test was used to compare statistical differences between survival curves.

Results:

A total of 211 patients with DLBCL were included. VTE occurred in 27 patients (12.8%). DVT occurred in 22, PE occurred in 3, and both DVT and PE in 2. Of all VTE, 37% occurred at diagnosis of DLBCL, and 82% in the first three cycles of treatment. VTE involved the lower limb in 44%. Baseline characteristics were similar between patients with or without VTE regarding age, sex, race, ECOG performance status, histology, B symptoms, LDH, and bone marrow involvement. Fewer patients with VTE, however, were stage I compared to the no VTE group (3.7% vs 27.3 %, P = 0.017). Furthermore, patients with VTE were more likely to be in the high-risk international prognostic index (IPI) category (29.6% vs 10.3%, P = 0.048). Median survival time for patients with VTE was 1.04 years (95% CI 0.75–1.33) compared to 5.2 years for patients with no VTE (95% CI 1.8–8.6) (Log rank test, P = 0.038).

Figure Figure

Conclusion:

VTE is a frequent complication of initial treatment of DLBCL. The majority of cases occur at diagnosis or during the first three cycles of treatment. High-risk IPI is associated with increased incidence of VTE during initial treatment of DLBCL. VTE is a poor prognostic factor and is associated with inferior survival. Clinical trials of thromboprophylaxis are warranted.
Extranodal Non-Hodgkin’s Lymphoma. A Study of 182 Patients with Analysis of Prognostic Factors.
Authors: Pogliani Enrico Maria , Rossini Fausto , Coccini Veronica , Larocca Alessandra , Verga Luisa , Marinoni Sara , Brizio Anna , Elli Elena
Published: April 2020

Starting from 1980, 182 cases of primary extranodal non-Hodgkin’s lymphoma were diagnosed in our Division.

Gastrointestinal NHL were the most frequent: 66 patients (36%), followed by head and neck (42 = 23%), skin(23 =13%), urogenital tract (16 = 9%), CNS (10 =5%), chest (9 = 5%), spleen (7 = 4%), bone (5 = 3%) soft tissues (4 = 2%).

Median age was 55,4 (range 20–91); median age was lower in chest, bone and intestinal NHL.

77 patients had stage I disease (48,8%), 74 stage II (46,5%) and 8 patients stage III (5%).

In the whole group, 134/182 (73.6%) patients achieved complete remission (CR); CRs were 81.8% in gastroenteric NHL, 75% in urogenital, 69.5% in skin, 66.6% in head and neck.

Overall survival in the two most important groups are as follows: head and neck: 61% at 50 months and 55% at 100 months; gastrointestinal tract: at 50 months was 80%, at 100 months 75%.

When prognostic factors were considered for the whole group, stage and modified I.P.I. (MIPI) were significantly associated with rate of complete remission and overall survival.

Stage I pts had a significantly better rate of complete remission 83.1%, vs. 68.9% for stage II and 37.5% for stage III. Overall survival of stage I pts was significantly better than for patients with stage II or stage III disease (80% vs. 72.5% at 50 months; 80.1% vs. 62.7% at 100 months).

Modified International Prognostic Index, MIPI is a score ranging from 0 to 5 according to age (>60), LDH (over normal values), ECOG P.S. (>1), Ann Arbor stage (II or III), extranodal sites (>1). Thirty six patients had a MIPI score of 0, 80 pts MIPI 1, 50 pts MIPI 2 and 16 had a MIPI score of 3 or more. A significant correlation between MIPI and achievement of CR was shown with 88.8% of pts with MIPI 0 achieving CR, 78.5% in MIPI 1, 28% in MIPI 2 and 25% in MIPI 3 or more. Overall survival for the four groups was as follows: 96%, 75%, 62%, 61% at 50 months; 96%, 70%, 54%, 24% at 100 months.
Primary Anaplastic Large Cell Lymphoma of the Breast Occurring in Patients with Silicone Breast Implants.
Authors: Popplewell Leslie , Chang Karen , Olevsky Olga , Nademanee A. , Forman Stephen
Published: April 2020

Primary breast lymphoma (PBL) accounts for up to 1% of all primary breast tumors, and 2.2% of all extranodal lymphomas. The vast majority of PBL are of B-cell origin, most commonly of the diffuse large cell histology. Fewer than 20 cases of T-cell PBL have been reported. We report 6 cases of T-lineage PBL occuring in patients who had previously received silicone breast implants for purposes of breast augmentation. None of the patients had a previous diagnosis of malignancy or unrelated prior breast surgery. In each case, the implants had been placed between 5 and 20 years previously. In each case, lymphoma was confined to breast by staging, and met previously defined criteria for PBL. In 5 cases, the lymphoma was identified as a solid mass involving the breast tissue. In one case, lymphoma cells were identified by flow cytometry in a fluid collection surrounding the implant. The implant was replaced, and the patient has subsequently treated with systemic chemotherapy despite negative PET scan. Thus far, reaccumulation of fluid has not occurred several months following replacement of the implant. In patients for whom follow-up information is available, two recurred following initial therapy and received autologous stem cell transplantation in second complete remission, and remain disease free at 2 years post-transplantation. Since 1995, six cases of PBL associated with breast implants have been reported in the literature, all of which are of T-cell lineage. The majority are of anaplastic large cell type. None of these cases have been previously reported, and this is the largest collection of such reported from a single institution. While previous reports have discounted any link between breast implants and lymphoma, this appears to be a specific association of an unusual lymphoma subtype occuring after a significant time period. Given the increasing number of silicone implant procedures recorded each year in the U.S., this represents an environmental association ripe for further investigation. Establishment of a national database would be appropriate to monitor any potential trends in this entity.

PBL Anaplastic Lymphoma, Immunohistochemistry

Age at Diagnosis ALK-1 CD2 CD3 CD20 CD30 CD43 CD45 32 − + − + + 41 + + + + 40 − + − − + − 54 − − − − + + − 49 + − + + + 62 − − − + − + 31 + − − − + − +
Impact of FDG-PET Imaging Versus Conventional Staging Modalities on Staging and Treatment Decisions in Large B-Cell, Follicular, and Hodgkin’s Lymphomas.
Authors: Maillard Ivan , Elstrom Rebecca L. , Kumar Rakesh , Bozkurt Murat F. , Sankaran Srikant , Guan Liang , Zhuang Hongming , Herman David , Downs Lisa , Alavi Abass , Schuster Stephen J.
Published: April 2020

Clinical staging of lymphomas has a critical role in determining appropriate therapy and in therapeutic response assessment. While anatomic imaging by CT or MRI, together with physical examination and bone marrow biopsy (conventional staging modalities or CSM), have historically provided the basis for staging and response assessment, positron emission tomography using 18-fluoro-2-deoxyglucose (FDG-PET) has increasingly been employed in the management of patients (pts) with lymphomas. Studies comparing FDG-PET with anatomic imaging have generally found that FDG-PET identifies more sites of disease; however, the impact of FDG-PET imaging on assignment of clinical stage and treatment decisions is unclear. We retrospectively examined the impact of FDG-PET imaging on assignment of disease stage and treatment decisions compared with CSM alone in 91 pts with large B-cell lymphoma (LBCL; n=30), follicular lymphoma (FL; n=29) and Hodgkin’s lymphoma (HL; n=32). 25/30 LBCL (83%), 26/32 HD (81%) and 17/29 FL pts (59%) were evaluated at initial diagnosis by FDG-PET imaging and CSM, while others were evaluated during subsequent relapse. FDG-PET and CSM defined the same stage in 69/91 pts (76%). Stage assignment was most concordant in LBCL with only 5/30 (17%) of cases having different stages, while stage assignments were discrepant in 7/32 (22%) of cases of HL and in 10/29 (34%) of cases of FL. Of the 22 pts with discrepant results, FDG-PET resulted in upstaging of disease in 11 pts and downstaging in 11 pts. Independent confirmatory tests resolving the discrepancy were obtained in 3 of 11 pts upstaged (27%) and 7 of 11 pts downstaged by FDG-PET (64%). Abnormal FDG uptake in lymph nodes accounted for all cases upstaged by FDG-PET in which no confirmatory test was available (8/8 pts). Among 10 cases resolved by biopsy, discrepant sites included bone marrow (n = 4), bone (n = 1), pelvic or abdominal structures (n = 3), and lymph nodes (n = 2). FDG-PET results were true positive in 2/10, true negative in 1/10, false positive in 1/10, and false negative in 6/10 cases (including 4 cases with BM involvement). Incorporation of FDG-PET led to treatment changes in a minority of patients (2%). We conclude that FDG-PET is an efficient single imaging modality in pts with LBCL, FL and HL, providing information complementary to CSM. However, changes in treatment based on FDG-PET results are rare. Discrepancies between FDG-PET and CSM should be resolved by biopsy when feasible, particularly in cases in which treatment would be altered.
How Much Rituximab Do We Need: A Multicenter, Randomized Trial Comparing 1, 3 or 6 Infusions of Rituximab Added to 6 Cycles of CHOP Chemotherapy in Untreated Patients with Advanced Follicular Non-Hodgkins Lymphoma (HD2000-Trial).
Authors: Hensel Manfred , Scheuer Lars , Salwender Hans , Finke Juergen , Buerkle Dieter , Duerk Heinz Albert , Kaebisch Andreas , Naumann Ralf , Staiger Hans-Juergen , Schmidt-Wolf Ingo , Kornacker Martin , Leo Eugen , Fischer Joseph , Ho Anthony D.
Published: April 2020

Purpose: The combination of chemotherapy with the chimeric anti-CD20 antibody Rituximab has been reported to be highly active in the treatment of follicular lymphoma. The frequency and dosage of rituximab required to induce the maximum effect in follicular NHL is not defined. To evaluate how often rituximab should be added to standard chemotherapy to achieve maximum remission rates, we have initiated a prospective randomized multicenter phase II study.

Methods: Patients (pts) with stage III/IV CD20 positive follicular NHL who were chemotherapy naïve were randomly assigned to receive 6 courses of a standard CHOP-21 chemotherapy, accompanied by rituximab 375 mg/m2 at day 0 only with the first CHOP course (arm A), with the first 3 CHOP courses (arm B) or with all 6 CHOP courses (Arm C). The major endpoint was the rate of molecular remission in bone marrow and peripheral blood in initially t(14;18)-positive pts, assessed by PCR. Other endpoints of the study were overall and complete response rates, toxicity rate and time to progression.

Results: Since September 2000, 104 pts with a median age of 57 years (range 30–80) were recruited. 33 pts were randomized to arm A, 35 to arm B and 36 to arm C. So far 69 pts have been documented completely after all 6 cycles and are evaluable for side effects. All three treatment arms were well tolerated. The incidence of adverse events and Grade 4 toxicity was similar in all groups. One treatment related death was observed 2 months after completion of therapy due to hepatitis B. The overall response rate (ORR) of the whole group, which was evaluable in 69 pts so far, was 90 % (62 of 69 pts), with 20 complete and 42 partial remissions.

Conclusion: This multicenter, randomized, phase II trial addresses for the first time the optimal frequency and dosage of rituximab infusions in the combined immuno-chemotherapy. In the first interim analysis of the ongoing trial, similar hematologic, gastrointestinal and infectious toxicity was observed in all treatment arms.
Relapse Following Chemotherapy in Aggressive Non-Hodgkin’s Lymphoma Occurs Frequently in Original Sites of Disease.
Authors: Wolf Max , Morgan Susan J. , Wirth Andrew , Reynolds John , Stone Janey , Prince Miles
Published: April 2020

Consolidative radiotherapy (RT) for aggressive NHL assumes that relapse is most likely in sites of initial disease involvement, however there is limited data examining this assumption. We examined patterns of failure in patients (pts) following systemic chemotherapy (CT), to determine factors predicting for site of recurrence.

Methods: In 2 ALLG intermediate-grade NHL studies, 234/519 pts (45%) achieved complete remission (CR) with anthracycline-based CT of whom 169 had full data available. Median age was 55 yr (range: 19–76); ECOG PS ≤2, 94%; bulky disease (≥10 cm), 42 (25%); elevated LDH, 79 (47%); stage I, 14 (8%); stage II, 49 (29%); stage III, 37 (22%); stage IV, 69 (41%). Regimens given were CHOP (45), MACOP-B (48), standard CEOP (epirubicin 75 mg/m2 substituted for doxorubicin) (38) and high dose (cyclophosphamide 1500 mg/m2, epirubicin 150 mg/m2) CEOP (38). Ten pts received RT to involved sites.

Results: Median follow-up time was 7.5 yr (range: 2.3–11.6). At close out, 69 pts (41%) had relapsed and 9 (5.3%) had died. Relapse sites: 24 pts local (14.2%), 21 remote (12.4%), 24 both (14.2%). Log-rank tests revealed earlier stage to be associated with increased time-to-first-failure (p=0.039) but not age, CT, histology (B or T cell), response (CR vs. CRu), bulk, RT or IPI. At 4 yr the estimated percentages of failure-free patients were 71%, 78%, 45% and 67% in stages I to IV, respectively. Early stage predicted local vs distant relapse (p=0.027) (Fisher’s exact test), with failures solely at original sites being 0, 2, 13.5 and 14.5% in stages I to IV respectively.

Conclusion: In this study, 70% of relapses included original sites, 35% solely so. Advanced stage was the strongest predictor of early and local relapse. No other criteria were associated with probability of relapse at original sites. RT potentially could prevent 1/3 of relapses and contribute to prevention of another 1/3, as systemic therapy becomes more effective.
Critical Amplification by Gas6 of the Epo-Dependent Erythropoietic Response to Anemia: Novel Opportunities for Anemia Treatment.
Authors: Angelillo-Scherrer Anne , Burnier Laurent , Fish Richard , Plaisance Stéphane , Martinez-Soria Eduardo , Maxwell Patrick , Collen Désiré , Izui Shozo , Conway Edward M. , Carmeliet Peter
Published: April 2020

Many patients with anemia fail, for unknown reasons, to respond to erythropoietin (Epo) - the key mediator of the erythropoietic response. Here, we report that loss of the growth arrest-specific gene 6 (Gas6), a polypeptide binding the receptor tyrosine kinases Tyro 3, Axl and Mer, caused a significant depletion of the reserve of erythroid progenitors in mice. As a result, the compensatory erythropoietic response to anemia induced by hemolysis or blood loss was defective in mice lacking Gas6 (Gas6−/ −). The impaired erythropoietic response was attributable to the hyporesponsiveness of Gas6−/ − erythroblasts to the survival activity of Epo. Only when recombinant Gas6 (rGas6) was administered together with Epo, did these factors synergistically rescue the mutant mice from anemia. Administration of rGas6 alone to Gas6−/ − mice also provided protection from phenylhydrazine (PHZ)-induced anemia, presumably due to the ability of Gas6 to enhance the pro-survival effects of Epo on erythroblasts. This was supported by in vivo and in vitro findings: (i) In the absence of Gas6, more erythroblasts died in the spleen of PHZ-treated mice, despite markedly elevated levels of Epo. (ii) Compared to WT, Gas6−/ − erythroblasts responded less to the pro-survival effects of Epo in vitro, suggesting that Gas6 signaling influences Epo receptor (EpoR) signaling. Absence of Gas6 did not alter tyrosine phosphorylation of the EpoR, but reduced Akt phosphorylation in erythroblasts when treated with Epo. Akt phosphorylation in Gas6−/ − erythroblasts was, however, restored to WT levels, when co-treated with Epo and rGas6. These findings indicate that Epo/EpoR-mediated erythroblast survival and proliferation is stimulated by Gas6 via the PI3K/Akt pathway. (iii) WT erythroblasts secrete Gas6 when treated with Epo. Together, erythroblasts, via a “Gas6 feedback system”, regulate, in an autocrine manner, their own responsiveness to Epo by reinforcing signaling downstream of EpoR. This mechanism is delicately balanced, since treatment of WT anemic mice with rGas6 alone reversed the acute anemia induced by hemolysis without causing polycythemia. A similar beneficial response in hematocrit restoration was observed when a transgenic mouse model with chronic anemia was treated with rGas6. In these mice, co-administration of rGas6 and Epo resulted in sustained rise in the hematocrit, to higher levels than achieved with Epo or rGas6 alone. Gas6 is therefore effective in chronic anemia, augments the effects of Epo, and may have Epo dose-sparing effects, and thus may provides novel and safe therapeutic approach to treat patients with Epo-resistant anemia.
Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study.
Authors: Rodriguez Maria Alma , Sarris Andreas , Dang Nam H. , Fayad Luis , Goy Andre , Hagemeister Fredrick , McLaughlin Peter , Pro Barbara , Romaguera Jorge , Samaniego Felipe , Younes Anas , Cabanillas Fernando
Published: April 2020

Sphingosomal vincristine (SV) is a novel formulation of vincristine encapsulated in sphingomyelin liposomes or ‘sphingosomes’. SV was well tolerated with 45% ORR in multiply relapsed aggressive NHL (ASH Abst.412, 1999). The addition of rituximab to CHOP improves response in aggressive B-cell lymphomas in the elderly (Coiffier et al., NEJM2002:346; 235–42). Based on these data, a phase II study of RCHOP, substituting SV for free vincristine, was undertaken in patients with previously untreated aggressive NHL (excluding rituximab if T-cell lymphoma).

Methods: Patients were treated with standard dose CHOP that included SV 2.0 mg/m2 without dose capping ± rituximab 375 mg/m2, given every 21 days for 6 to 8 courses (ASH Abst.338, 2002).

Results: Of 73 patients enrolled in the study, 68 were evaluable for response. Median age was 63 (range 22–80). IPI score was 0–2 in 44 pts and ≥ 3 in 24 pts. Patients received a median of 6 study treatments (range 1–8). ORR was 93% (63/68 pts) with 62 pts achieving CR and Cru (91%), and 1 PR (2%). 3 pts had PD (4%) and 2 were not assessed for response (3%). The median PFS and OS have not been reached at a median follow up of 29.5 months. Responses according to IPI score were as follows:

Results IPI 0–2 (n=44) IPI ≥3 (n=24) Total (n=68) ORR 93% (41) 92% (22) 93% (63) −CR 77% (34) 88% (21) 81% (55) −Cru 14% (6) 4% (1) 10 (7) −PR 2% (1) 0% (0) 2% (1) PD 5% (2) 4% (1) 4% (3) Not Assessed 2% (1) 4% (1) 3% (2)

The probability of being progression free at 25 months was 86% (5 relapses and 1 death, reason unknown) for pts with IPI 0–2 and 77% (6 relapses) for pts with IPI ≥3. Overall survival probability was 94% at 28 months (1 death in the group with IPI 0–2 and 2 deaths in the group with IPI ≥3). Neuropathy was generally mild (Gr.1–2). Hematological toxicities were as follows: 64% Gr.3–4 neutropenia, 6% Gr.3 anemia, and 14% Gr.3–4 thrombocytopenia.

Conclusions: CHOP plus rituximab regimen with sphingosomal vincristine substituted for free vincristine demonstrated promising activity with durable responses similar in both groups of patients with IPI score 0–2 and IPI ≥ 3. The treatment was well tolerated with only mild neurotoxicity.
Phase I/II Study of the Rituximab-EPOCT Regimen in Combination with G-CSF in Patients with Relapsed or Refractory Follicular Lymphoma Including Evaluation of Its Cardiotoxicity Using B-Type Natriuretic Peptide and Troponin T Levels.
Authors: Niitsu Nozomi , Khori Mika , Hayama Miyuki , Higashihara Masaaki , Tamaru Jun-ichi
Published: April 2020

Standard treatment for relapsed or refractory follicular lymphoma has not been established. Doxorubicin (DXR) is often administered during the initial treatment. The dosage or drugs chosen for salvage therapy are limited by DXR-induced cardiomyopathy. Pirarubicine (THP) was developed in Japan as a less cardiotoxic and highly effective anti-neoplastic drug. We previously reported that the THP-COPBLM regimen, in which THP was used instead of DXR, showed the same degree of efficacy as the COP-BLAM regimen and that cardiac sympathetic dysfunction and cardiac mitochondrial damage were less common with THP than with DXR (Leukemia12:1457, 1998). The R-EPOCT (rituximab with etoposide, vincristine, THP, cyclophosphamide, and prednisone) regimen, in which less cardiotoxic THP is used instead of DXR, with G-CSF was administered to 20 patients with relapsed or refractory follicular lymphoma. The safety (especially cardiotoxicity) and efficacy of this regimen were studied. As markers of cardiotoxicity, serum troponin T and plasma B-type natriuretic peptide (BNP) levels were measured. Adverse reactions occurred in 14 of the 20 patients, and mainly consisted of grade 3/4 hematological toxicity. In the evaluation of cardiotoxicity, the BNP level was slightly elevated in 2 patients before the treatment (22.4 pg/ml and 25.6 pg/ml; normal, less than 20 pg/ml). After 4 cycles of treatment, the BNP level in these two patients increased to 26.8 pg/ml and 28.8 pg/ml, respectively, but it returned to approximately the previous level one month after completion of treatment. The troponin T level was undetectable before and after the treatment in all patients. The response rate was 100%, with complete remission in 16 patients (80%). G-CSF administration increased both FcγRI expression on neutrophils and ADCC activity. Upon G-CSF administration during the second cycle of treatment, the level of FcγR1 (CD64) expression on neutrophils increased from 60.1 ± 3.6 (MFI) before G-CSF administration to 324.7 ± 33.2 (p = 0.0005) after 9 days of administration of 2 μg/kg G-CSF. After 11 days of G-CSF administration, the level of FcγR1 expression was 346.2 ± 24.2. The expression of FcαRI (CD89) on neutrophils was examined in a similar fashion. There was no remarkable change in the level of FcαRI expression before and after G-CSF administration. We conclude that the combination of R-EPOCT and G-CSF is well-tolerated. This regimen was not cardiotoxic. We are planning a randomized trial to compare the efficacy between R-EPOCT and a combination of R-EPOCT with G-CSF.
Bortezomib Sensitizes Non-Hodgkin’s Lymphoma Cells to Apoptosis Induced by Antibodies to TRAIL Receptors R1 and R2.
Authors: Smith Mitchell Reed , Jin Fang , Joshi Indira
Published: April 2020

TRAIL-R1 and -R2 signaling induces apoptosis via a pathway that activates caspase 8. The proteosome inhibitor bortezomib may act via several pathways. Agonistic antibodies to TRAIL-R1 and -R2 and bortezomib are in clinical trials in solid tumors and hematologic malignancies. To develop rational combinations for future clinical studies, we investigated the actions of these agents on non-Hodgkin s lymphoma (NHL) cell lines. The t(14;18)+, EBV- NHL cell lines DoHH2 and WSU-FSCCL were treated with agonistic monoclonal antibodies to TRAIL-R1 (HGS-ETR1) and -R2 (HGS-ETR2) (Human Genome Sciences, Rockville, MD) and/or bortezomib. While HGS-ETR 1 and HGS-ETR 2 are effective inducers of apoptosis in FSCCL, DoHH2, which expresses dim TRAIL-R1 (DR4, HGS-ETR1 target) and TRAIL-R2 (DR5, HGS-ETR2 target), shows minimal growth inhibition or apoptosis induction by HGS-ETR1 or HGS-ETR2. Bortezomib has modest effects on DoHH2 cells in growth inhibition and apoptosis assays. HGS-ETR1 and HGS-ETR2 induction of apoptosis in WSU-FSCCL is efficiently blocked by the caspase inhibitor ZVAD. In contrast, bortezomib effects are not blocked by ZVAD, indicating an independent mechanism of action. To determine if these separate pathways would provide enhanced combination activity, DoHH2 cells were pre-treated with bortezomib for 30 min, followed by incubation with HGS-ETR1 or HGS-ETR2. This led to supra-additive induction of apoptosis (annexin V staining). We conclude that bortezomib sensitizes DoHH2 cells to the action of HGS-ETR1 and HGS-ETR2. Further, bortezomib induces apoptosis in DoHH2 cells by an independent mechanism, and the combination of TRAIL-receptor signaling and bortezomib may be a useful combination to explore.
Rituximab Plus CHOP Followed by Maintenance Rituximab as Initial Therapy for Aggressive Non-Hodgkin’s Lymphoma (NHL); Initial Results of Induction Therapy, Including Rituximab Pharmacokinetics, in a Phase II Study.
Authors: Huang Jane E. , Saleh Alfred , Lee J. Thomas , Langmuir Virginia , Zhang Fan , Hainsworth John
Published: April 2020

Background: This study was designed to investigate the activity, safety, and pharmacokinetics of rituximab (Rituxan®, R) plus CHOP induction therapy followed by maintenance R in previously untreated patients with aggressive NHL. The initial results of R-CHOP induction therapy are reported here.

Methods: 105 patients with aggressive NHL (diffuse large B-cell or follicle center/follicular grade III by REAL; Type D, F, G or H by IWF) were enrolled into this open-label, multi-center, community based, single-arm, Phase II trial. Patients received 6 or 8 cycles (per standard practice at each site) of R-CHOP induction therapy (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, doxorubicin 50 mg/m2 IV on Day 1, prednisone 100 mg/day Days 1–5). R 375 mg/m2 was given on Day 1 of each cycle, except for cycle 1, when it was given 2–3 days before CHOP administration. Subjects with documented responses (CR/CRu or PR) to induction receive maintenance R (4 weekly infusions) beginning 28 days after the completion of induction and repeated every 6 months for 2 years. The primary endpoints were CR/CRu after the completion of induction and the incidence of R infusion-related toxicity in induction and maintenance. Overall response rate (ORR), infusion times, serious adverse events (SAE), and the partial rituximab pharmacokinetic profile were also measured.

Results: Baseline characteristics of patients enrolled were: median age 59 y (49.5% ≥60 y), IPI ≥3 in 31.4 % patients, Ann Arbor Stage II,III, IV in 21.9%, 39.0%, and 39.0% of patients, respectively. CR/CRu at the end of induction in 105 patients was 51.4% (80.0% ORR). 1.9% of patients had progressive disease (PD) during induction. SAE occurred in 33% of subjects during induction with the most common event being febrile neutropenia (14.3%). 5 subjects died during induction (pulmonary embolus, ruptured abdominal aortic aneurysm, pneumonia x2, unknown cause). Grade 3–4 rituximab infusion-related toxicity occurred in 3.9% of subjects during Cycle 1 which decreased to 0% by Cycle 5. 64.3% of patients received their R infusion within 3 hours on Cycle 2; this increased to 74.7% patients at cycle 6. The partial pharmacokinetic profile (peak and trough concentration) of R was measured in 10 patients and will be presented at the meeting.

Conclusion: Rituximab + CHOP chemotherapy is well tolerated and has an excellent response rate when given in the community setting. The outcomes of maintenance therapy in this study await further follow-up.
Brachytherapy Combined with CpG ODN Enhances Development of a Tumor Antigen-Specific CD8 Response.
Authors: Rich Nathan T. , Dahle Chris E. , Modrick Joseph M. , Buatti John , Weiner George J.
Published: April 2020

Background: CpG Oligodeoxynucleotides (CpG ODN) are TLR9 agonists that have potent immunostimulatory effects and function well as immune adjuvants. Preliminary data suggests that combining CpG ODN with apoptosis-inducing agents can enhance the development of a tumor specific immune response. We hypothesize that administration, in a temporally and spatially coordinated fashion, of a therapy that induces apoptosis of lymphoma cells with an immunostimulatory agent such as CpG ODN will enhance the development of an anti-lymphoma T-cell response.

Methods: C57Bl/6 mice were inoculated subcutaneously with 2x10^6 EG7 lymphoma cells (EL4 murine T cell lymphoma line with an Ova transgene). On day 11 mice were treated with brachytherapy (radiation therapy administered by temporary placement of an 125-I pellet within the tumor), intra-tumor CpG-ODN or both CpG ODN and brachytherapy. A standard radiation dose equivalent to exposure to a 5 mCi pellet for 10 minutes was used as brachytherapy for each mouse. Sham radiation (placement of a non-radioactive seed in the tumor) and control (non-CpG) ODN were used as controls. Seven days after treatment, spleens were harvested and stained with CD8a-FITC and Ova-tetramer-PE to identify Ova-specific CD8 cells. Non-specific tetramer binding was detected using LCMV-tetramer-PE as a control.

Results: The combination of brachytherapy and CpG ODN led to the development of an enhanced Ova-specific CD8 response as measured by the percent of CD8(+) cells that were positive for Ova-tetramer minus the percent that were positive for the control tetramer.

Percent of CD8 Cells that Stain with Ova Tetramer

No CpG ODN CpG ODN No Radiation 0.6 4.1 Radiation 0.7 10.0

Similar results were found in repeated experiments where brachytherapy and CpG ODN were administered daily times three.

Conclusions: Brachytherapy administered via temporary placement of a radioactive seed in a lymphoma, followed immediately by injection of immunostimulatory CpG ODN into the same tumor bed, results in enhanced development of a tumor antigen specific T-cell response. Ongoing studies are exploring the anti-tumor activity of this response, how it compares to the combination of external beam radiation and CpG ODN, whether such responses can be induced against native antigens, and how CpG ODN compare to other immunostimulatory agents when used in this capacity.