bluuebunny/crossref_metadata_2025 huggingface dataset:
Relapse Free Survival of Elderly AML Patients Is Comparable to That of Younger Adults When Treated with a Modified Dose Intensive Cytarabine Regimen.
Authors: Langston Amelia A. , Heffner Leonard T. , Hutcherson Donald , Neely Jessica , Flowers Christopher , Waller Edmund K. , Lonial Sagar , Khoury Hanna J. , Winton Elliot
Published: October 2019

Introduction and Methods: Despite the development of new targeted therapies for treating AML, cytarabine (Ara-C) remains the most reliably effective agent, particularly when given in high dosage (HIDAC). The outcome of AML therapy in pts > 60 years of age remains dismal with slightly more than half of pts achieving remission, and < 15% becoming long term survivors. Elderly pts do not tolerate typical HIDAC regimens because of cerebellar and other toxicities, so we have employed a modified HIDAC regimen: Ara-C 2 gm/m2/day over 4 hours once daily on days 1–6, combined with daunorubicin 45 mg/m2 days 2,3,4 for induction. Consolidation consisted of one cycle of the same chemotherapy followed by two additional cycles of mHIDAC alone, unless the pt went on to autologous or allogeneic HPCT. We report a single institution experience with 59 consecutive pts ≥ 60 y/o (including 20 pts ≥ 70 y/o), and compare outcomes with 139 similarly treated pts < 60 y/o. Excluded were pts with antecedent MDS or chemotherapy-related AML, APL, and pts with major organ dysfunction.

Results and Discussion: The CR rate for pts age ≥ 60 was 66% vs 81% for those < 60 (p=0.02). The distribution of pts into cytogenetic risk categories was similar, except for an under-representation of good risk cytogenetics among older pts (3% vs 14%, p=0.025). Overall survival for older pts was worse than that for younger individuals primarily due to an excess of early deaths, however, disease free survival among complete responders was similar for the 2 age groups (see below). There were 11 (16%) early deaths within 60 days among older pts, 4 with residual leukemia and 7 during aplasia. Early death occurred in 7 (5%) of the younger pts, 2 with residual leukemia and 5 during aplasia. There were 4 deaths (3 infectious and 1 stroke) during consolidation, 3 in the older and 1 in the younger group. There were also 2 late deaths in remission (both older pts) which were unrelated to AML or therapy. Clinically significant cerebellar toxicity was observed in 4 (6.8%) of the older pts and 3 (2%) of the younger pts, for a total of 7 episodes associated with 535 courses of Ara-C delivered (1.3%). 60% of older pts were able to complete 2 or 3 courses of consolidation therapy. Our data confirm the challenges of treating older pts with AML, but suggest that a significant subgroup can tolerate and benefit from aggressive therapy which includes dose intensification of Ara-C. This mHIDAC regimen is effective and well tolerated, and repeated administration to older pts is feasible.

Overall Survival Overall Survival Relapse-Free Survival Relapse-Free Survival
Improved Survival of Lymphoma Patients after Introduction of Rituximab.
Authors: Dillman Robert O. , Chico Sherri
Published: October 2019

In a previous intramural study using tumor registry data, we found no difference in survival for all 222 patients diagnosed with low-grade (LG) or intermediate-grade (IG) non-Hodgkin’s lymphoma (NHL) during 1980–1989 compared to all 404 such patients who were diagnosed during 1990–1999 (ASH 2002). However, the anti CD20 monoclonal antibody rituximab, which was introduced in 1998, has been associated with improved survival in randomized trials of patients with intermediate grade B cell lymphomas. In this study we carried out two analyses. The first compared relative survival for 368 Hoag lymphoma patients diagnosed during 1995–2000 (median age 65 years) to national data from the Surveillance Epidemiologic and End Result (SEER) program. The 5-year relative survival rate for Hoag patients compared to SEER was 72% vs. 59% for 1995–2000, in sharp contrast to the relative 5-year survival rates observed during 1989–1994 which were only 46% for Hoag lymphoma patients vs. 51% for SEER. The second comparison was for observed survival for all 362 Hoag patients with LG or intermediate-grade IG B cell NHL, who were diagnosed during 1998–2003 (median age 65, 105 deaths), compared to 352 Hoag patients with LG or IG B-cell NHL, who were diagnosed during 1990–1997 (median age 63, 175 deaths). The respective 5-year survival rates were 58% vs. 51% (p=.032, 2-tailed log-rank test). We conclude that survival has improved for Hoag patients with lymphoma both by intramural historical comparisons and extramural contemporary comparisons. Improvement took place during the time that rituximab was adopted as standard therapy at Hoag, and suggests that the survival benefits that have been observed in randomized trials are also taking place in the general population of B cell lymphoma patients.
Minimal Disseminated Disease (MDD) in BM of Childhood T-Cell Lymphoblastic Lymphoma (Stage III), Detected by Flow Cytometry (FC) and Real Time Quantitative Polymerase Chain Reaction (RQ-PCR).
Authors: Stark Batia , Luria Drorit , Manor Sigal , Ronen Taly , Kodman Yona , Avrahami Gali , Yaniv Isaac , Avigad Smadar
Published: October 2019

Despite overlapping features between T cell Lymphoma and T cell ALL and generally good response to T-ALL type of treatment there are some clinical and biological differences between the two entities. The aim of this study was to evaluate in children with stage III T cell Lymphoma the prevalence of minimal BM dissemination at diagnosis, its prognostic significance and early response kinetics. Bone Marrow (BM) at diagnosis from 14 children with T- cell lymphoblastic lymphoma (T-LBL) was assessed for minimal disseminated disease (MDD) by flow cytometry (FC) with four colour antibody combinations and real time quantitative PCR (RQ-PCR) with specific junctional regions for T-cell receptor and immunoglobulin heavy chain gene rearrangements. 13 pts. had stage III mediastinal lymphoma, and one stage II cervical disease. Morphological BM involvement of almost 5% blasts was suspected in only one patient. All, but one, were treated according to the NHL-BFM 90/95 protocols medium risk group (without irradiation). In addition, 7 pts were assessed for early response on week 5 and 12 of treatment with PCR only (2 pts) FC only (2 pts) and both methods (3 pts). Lymphoma associated immunophenotype with a sensitivity of at least 0.01% was detected in all patients (100%) (2 combinations), and PCR targets with a sensitivity of 0.01% and 0.1% in 10 and 2 examined patients respectively (92%). A sample with a level of above 5X10−4 was considered as positive MDD or minimal residual disease (MRD) by both methods. By FC, 10 patients exhibited positive and 4 negative BM MDD levels at diagnosis. By RQ -PCR, 7 patients presented positive and 4 negative BM MDD levels. Both methods gave consistent results with only one case of discordance: negative in PCR and positive in FC (>5x10−4). In 7 other pts there was a difference of between 0.5 and 1 log level that did not change the classification of involvement (in 5 pts PCR higher, in 2 pts FC higher). At a median follow up of 5 years, 3 patients relapsed (2 in the mediastinum and one in BM) their MDD level at diagnosis was 2x10−3 (2 pts), 6x10−2. MRD level in 4 patients out of 5 patients with a high MDD level (1–6x10−2) at diagnosis, decreased by 2 logs (<5x10−4) on week 5, and on week 12 all were below <2x10−4. The one patient with a higher level (1.5x10−2) at day 33 suffered a relapse.

In conclusion: in the majority of patients with mediastinal stage III T-cell lymphoma molecular BM dissemination (>5x10−4) was present. It’s prognostic significance in the context of ALL-BFM therapy could not be demonstrated. However, early BM molecular treatment response in T-cell Lymphoma may correlate with outcome, similarly to T-cell leukemia.
Hepatitis C Virus Infection and B-Cell Non-Hodgkin’s Lymphoma.
Authors: Grudeva Janet G.
Published: October 2019

Backgroud: An increasing number of bacterial and viral infections have been linked with specific subtypes of lymphoma. Preliminary evidence suggests that hepatitis C virus (HCV) might play a pathogenetic role in autoimmune-related, non-malignant B-cell lymphoproliferation, as well as a subset of B-cell non-Hodgkin, s lymphomas (B-NHL), often with extranodal localization.

Design and methods: The study was conducted in the Department of Hematology and consisted 149 (86 male, 63 female) untreated patients with a new diagnosis of B-NHL for 5-years period (2000–2004). HCV infection was investigated by testing for HCV antibodies in serum samples. The controls were 587 patients (without intravenous drug users) in other departments of the same hospital.

Results: HCV infection was documented in 13 cases (8,4%) with NHL. The infected patients were not clinically relevant cryoglobulinemic activity, increased rate of autoimmune disorders and extranodal localizations prevalence. There was statistically significant difference between the NHL and control group (p<0,01) and no statistically significant difference between man/women carriers (p>0,05) into the NHL group. Overall, the clinical outcome of HCV-positive NHL does not seem to be different from that of NHL patients without HCV infection. However, the evidence of a significant liver injury may predict a worse prognosis in these cases.

Conclusions: Our date suggest that HCV infection may be associated with B-NHL. With regard to the mechanism(s) by which HCV might favor B-cell expansion and malignant transformation, most date support an indirect pathogenetic role of the virus as an exogenous trigger. A direct oncogenetic role of HCV by direct cell infection and deregulation has only been hypothesized on the basis of the lymphotropism of the virus.
Caspase 3 Expression in Mantle Cell Lymphoma: An Immunohistochemical Study of 84 Patients.
Authors: Schrader Carsten , Klapper Wolfram , Riis Paul , Meusers Peter , Brittinger Guenter , Siebmann Jens U. , Kneba Michael , Parwaresch Reza
Published: October 2019

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. We investigated immunohistochemically the expression of the apoptotic marker caspase 3 in relation to the clinical course. Biopsy specimen from 84 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, Caspase3. The Caspase3 expression was analyzed in three groups: less than 1 positive cell per high power field (HPF), more than 1 positive cell per HPF and more than 2 positive cells per HPF. The expression was compared with the overall survival data analysed according to Kaplan and Meier. In 75 cases the caspase 3 staining could be analyzed. The caspase 3 expression had a range of 0.1–4.7 positive cells per HPF (median value:1.1, mean:1.3). Patients with mantle cell lymphoma that had less than 1 caspase 3 positive cell per HPF (33 cases) had a median overall survival time of 48 months compared to 27 months for patients with more than 1 positive cell per HPF (24 cases) and 15 months for more than 2 positive cells per HPF (18). The Kaplan-Meier analysis showed a significant difference in the overall survival time between these groups (p<0.0001). The immunohistochemical detection of caspase 3 in mantle cell lymphoma is a predictor for survival in MCL.
Methylenetetrahydrofolate Reductase and Methionine Synthase Polymorphism and Risk of Non-Hodgkin’s Lymphoma.
Authors: Nam Hee , Kim Yeo-Kyeoung , Lee Il-Kwon , Yang Deok-Hwan , Park Kyeong-Soo , Lee Je-Jung , Kim Hyeoung-Joon
Published: October 2019

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are key enzymes in folate metabolism, which is essential for DNA methylation and synthesis. It is known that polymorphisms in its genes have been associated with some forms of cancer including lymphoma. Previous studies have shown MTHFR 677TT was associated with decreased risk of non-Hodgkin’s lymphoma(NHL). However, recent two reports have shown MTHFR 677TT was associated with increased risk. To evaluate the association between the MTHFR C677T and MTR A2756G polymorphisms and risk of non-Hodgkin’s lymphoma, large-scale population-based case-control study was conducted in Chonnam University Hwasun Hospital between March 1997 and June 2005. Three hundreds sixty-five patients with histologically comfirmed lymphoma and 1,162 controls were evaluated. Genotyping was done using PCR-RFLP. The cases consisted of 203 diffuse large B-cell lymphomas(DLBCL), 77 T-cell lymphomas, 62 other B-cell lymphomas, and 23 unclassifiable lymphomas. The MTHFR 677CT and 677TT genotypes were inversely associated with NHL and DLBCL, respectively. Using subjects with the MTHFR 677CC as reference group, the odds ratio of MTHFR 677CT and 677TT were (0.70, 95% CI 0.54–0.90) and (0.46, 95% CI 0.32–0.68) for NHL. The association was more evident for DLBCL (OR 0.56, 95% CI 0.40–0.78 for 677CT; OR 0.40, 95% CI 0.24–0.65 for 677TT). Dose-response effect was evident for the MTHFR T-allele (p < 0.01). There was no significant association of MTR A2756G with NHL. These results suggest that the MTHFR polymorphism may play an important role in the pathogenesis of NHL, particularly DLBCL.
Favorable Outcomes with CHOP Therapy in Plasmablastic Lymphoma in HIV Positive Patients.
Authors: Javidan Masumeh Rafati , Amin Alpesh J. , Guron Gunwant
Published: October 2019

Plasmablastic lymphoma (PBL) is a rapidly progressive variant of diffuse large-cell lymphoma predominantly diagnosed in HIV positive patients. It is frequently associated with latent EBV infection and is often lacking expression of CD20 and CD45. A retrospective study of HIV positive patients diagnosed with PBL to determine outcomes after CHOP therapy. Two HIV positive patients diagnosed with PBL and treated with CHOP were identified. The first patient is a 48 year old male with CD4 count of 80 cells/mm3 on HAART, who presented with a rectal mass. Pathologic exam revealed granulation tissue with marked inflammation. A second colonoscopy because of ongoing rectal bleeding was done. Histologic exam was interpreted as infiltrating poorly differentiated carcinoma. The third biopsy obtained via colonoscopy (after developing bowel obstruction) was reported as a high grade tumor with neuroendocrine features. The patient received one dose of cisplatin 60 mg/m2 and irinotecan 60 mg/m2 and radiation therapy. Patient underwent a diverting colostomy. The immunohistochemical exam of the tissue was negative for CD20, CD3 and positive for CD 138, suggestive of the diagnosis of plasmablastic lymphoma. In situ hybridization for EBV was positive. The patient received 6 cycles of CHOP (cytoxan 750 mg/m2, vincristine 1.4 mg/m2, doxorubicine 50/m2 and prednisone 100 mg) chemotherapy and 6 more cycles of radiation therapy. He is in complete remission 16 months after the diagnosis, and continues to be followed. The second patient is a 44 year old female on HAART with CD4 count of 415 cells/mm3, who presented with the swelling of the right jaw for three weeks. The histologic exam of the tissue, obtained by the incision biopsy of the mass, favored plasmablastic lymphoma. Immunohistochemical analysis tested positive for CD3, CD138 and CD45. In situ hybridization for EBV RNA was positive. Patient received 3 cycles of CHOP regimen and radiation to the jaw. She has not shown any evidence of relapse and is in complete remission 22 months after diagnosis, and continues to be followed. Durable remissions, 16 and 22 months, were achieved with CHOP therapy in HIV positive patients with PBL. This study supports the use of CHOP as an effective treatment of PBL in HIV positive patients.
Ki-1 Positive Anaplastic Large Cell Lymphoma Due to Immune Deficiency.
Authors: Chang Monique , Kujawa Jennifer , Garrison Michael , Hindenburg Alexander
Published: October 2019

Cases of Ki-1 positive anaplastic large cell lymphoma (ALCL), including ALK (t 2,5) positive and negative expression, have largely been associated with immunosuppressed transplant recipients, human immunodeficiency virus (HIV) positive patients and patients with a prior history of a lymphoproliferative disorder. We reviewed the literature and found cases of secondary Ki-1 positive ALCL in immunocompromised patients including patients with a prior history of lymphoid malignancy. Some of these latter cases may have been diagnosed initially as Hodgkin’s disease and later reclassified as Ki-1 positive ALCL. In post-transplant and HIV positive patients, severe and prolonged immunosuppression likely led to the development of Ki-1 positive ALCL. We postulate that although rare, the occurrence of Ki-1 positive ALCL in patients previously treated for a lymphoid malignancy is possible due to a pre-existing immune deficiency state. We report a case of ALK- ALCL occurring 10 years following treatment of HCL with persistent depressed T4/T8 ratio one year after achieving a complete remission of the ALCL.

Secondary Cases of Ki-1 Anaplastic Large Cell Lymphoma Cases of Post-transplant Ki-1 Positive Anaplastic Large Cell Lymphoma Allograft # of Case Reports ALK (t 2,5) Renal 16 12 unknown, 4 positive Cardiac 3     1 negative, 2 positive Liver 1 1 positive Cases of Ki-1 Positive Anaplastic Large Cell Lymphoma in Patients With HIV or Treated with Immunosuppressants for Non-Malignant Disorders Cause of Immune Deficiency # of Case Reports ALK (t 2,5) HIV + 10 10 unknown Immunosuppressive tx for Evan’s syndrome 1 negative Azathioprine for Crohn’s Dz. 1 unknown Cases of Secondary Ki-1 Positive Anaplastic Large Cell Lymphoma in Patients Treated for Malignancy Primary Malignancy # of Case Reports ALK (t 2,5) Hodgkin’s Disease 3 3 unknown Hairy Cell Leukemia 2 1 unknown, 1 negative Mycosis Fungoides 2 2 unknown
R-CHOP vs R-mini-CEOP in Elderly Patients with Diffuse Large B Cell Lymphoma: An Interim Report from Intergruppo Italiano Linfomi (IIL).
Authors: Merli Francesco , Vitolo Umberto , Luminari Stefano , Mazza Patrizio , Stelitano Caterina , Rossi Giuseppe , Baldini Luca , Ilariucci Fiorella , Levis Alessandro
Published: October 2019

Objectives: CHOP plus Rituximab (R-CHOP) is considered the standard treatment for elderly patients affected from Diffuse Large B Cell Lymphoma (DLCL). The primary objective is to compare in an intent to treat analysis the Event Free Survival (EFS) between R-CHOP and a regimen especially devised for elderly (R-mini-CEOP). Secondary objectives are:

to verify the feasibility of a multidimensional score for excluding the frail patients from the study to demonstrate that Rituximab could improve the result of a regimen different from CHOP.

Patients and methods: Patients were previously submitted to 4 multi-item scales: Activities of Daily Living scale (ADL), Instrumental Activities of Daily Living Scale (IADL), comorbidity scale and geriatric scale. The patients who got over were randomised between R-CHOP (day 1:Rituximab 375/m2; Cyclophosphamide 750 mg/m2; Doxorubicin 50 mg/m2; Vincristine 1,4 mg/m2; days 1–4: Prednisone 60 mg/m2) and R-mini-CEOP (day 1: Rituximab 375 mg/m2; Cyclophosphamide 750 mg/m2; Epidoxorubicin 50 mg/m2; Vinblastine 5 mg/m2; days 1–4: Prednisone 60 mg/m2). Both regimens recycled at 21 days and scheduled G-CSF in the days 2–7. An intermediate restaging was scheduled after the first 3 courses.

Results: From March 2003 until July 2005 19 patients were classified “frail”, while 133 patients coming fom 21 Hematology/Oncology Departments were enrolled into the trial. Most of these patients had a severe clinical presentation. Median age was 73 years old. LDH upper than normal value was found in 56% of this group of patients. 72% were in stage III-IV. 25% presented a bulky disease at diagnosis. The two different treatment group were well balanced for number and clinical charatheristics. 72 patients (37 treated with R-CHOP and 35 with R-mini-CEOP) completed the chemotherapy and were assessed for the response. CR rate was 82%. PR rate was 13 %. Five percent progressed during treatment or had no response to the chemotherapy. The overall survival estimated at 13 months was 81 % versus 34 % in frail group (p=0.0001). Despite the use of G-CSF the more frequent side effect was a leucopenia of grade 3–4, which occurred in the 37% of the patients. Severe infections (grade 3–4) occurred in 7% of the patients and in one case was lethal. Toxic deaths were 2%.

Conclusions: The results in terms of CR and feasibility are encouraging. Events which suggest to stop the randomisation have not occurred. The multidimensional score system seems a good tool to identify the patients who are able to tolerate a full dose regimen.
Treatment of Hematological Malignancies in Central Nervous System with Idarubicin and Teniposide Containing Regimens.
Authors: Wang Chun , He Xiaojun , Cai Qi , Zhu Jun , Bai Haitao
Published: October 2019

Background: The prognosis of central nervous system(CNS) involvement in hematological malignancies remains poor. Clinical investigation for better protocols is mandatory. Some reports from small samples of clinical trials suggested that the systemic chemotherapy with the agents that better cross the blood-brain barrier may result in disease remission in some patients with CNS lymphoma. Based on the pharmacokinetic properties of each drug, we have developed and evaluated the chemotherapy regimens for patients with hematological malignancies involving central nervous system.

Objective: To evaluate a idarubicin (IDA) and teniposide based regimen in the treatment of hematological malignancies with CNS involvement.

Patients and Methods: From April 2003 to July 2005, fourteen patients were enrolled onto the study. There were 8 male and 6 female, with a median age of 53(22–75) years. Three patients with primary CNS lymphoma (PCNSL) and 5 patients with secondary CNS lymphoma (SCNSL) were treated with the combination regimen of IT, including idarubicin(8mg/m2/d×3) and teniposide (75mg/m2/d×3). Six cases of acute myeloid leukemia with both bone marrow and CNS relapse, including 2 patients with acute promyelocytic leukemia and 4 patients with acute monocytic leukemia, were treated with the combination regimen of ITA, including IT and conventional cytosine arabinoside. The cycles were repeated at 3-weekly intervals. Patients were followed carefully for evaluation of toxicity and response to treatment.

Results: Of the 8 patients with CNS lymphoma, three cases achieved complete remission(CR), four cases achieved partial remission(PR) after 2 cycles of IT regimen. Only one case died of cerebral hemorrhage two days after the delivery of chemotherapy. Among the 6 patients with CNS leukemia, four cases achieved CR and 2 cases achieved PR after 1 cycle of ITA regimen. Three cases achieved CRs of both CNS and bone marrow, which indicates that the regimen may be effective for concurrent relapse of both CNS and bone marrow. Of the 5 patients in coma, all of them regained consciousness during the course of chemotherapy. Rapid effect and well tolerance were observed, which made the following comprehensive treatment possible and were especially valuable for the patients in coma. Although the study was not primarily designed to investigate long term outcomes, the first patient treated with IT regimen remained CR for 26 months at the last follow-up.

Conclusion: The promising efficacy of idarubicin and teniposide containing regimens was observed in the treatment of hematological malignancies in central nervous system, indicating that the regimens may be the first line option as primary or salvage therapy in hematological malignancies in central nervous system.
Accelerated R-COP:A Pilot Study for the Treatment of Follicular Lymphoma.
Authors: Bertino Joseph R. , Roger Strair , Arnold Rubin , Mecide Gharibo , Dale Schaar
Published: October 2019

To test the hypothesis that dose intensity/dose density treatment may improve the complete response rate and remission duration in patients with follicular lymphoma (grades I and II, ECOG performance 0–2, Stages III and IV, progressive disease), a combination of known effective agents were administered as follows: rituximab,375 mg/m2; cyclophosphamide, 1000 mg/m2; and vincristine, 2mg (cap), IV every two weeks. Prednisone, 50 mg, was given p.o., every other day for 30 days then tapered over the next 30 days. G- CSF was administered days 7–10 following each treatment. Patients were evaluated for response after 5 and 10 cycles, that included imaging with CT and PET scans. Toxicity was mild to moderate, consisting mainly of paresthesias, requiring attenuation of the vincristine dose in some patients. There were no instances of neutropenic fever requiring hospitalization. In this pilot study, 6 of 7 patients previously untreated achieved a CR, and none have relapsed to date (6+ to 20+ months after completion of treatment). Two heavily treated patients, including relapse from agents used in this regimen, had PRs, lasting 2 and 8+ months. This program is well tolerated with a high CR rate, and may serve as a basis for future trials.
Motexafin Gadolinium (MGd) Has Clinical Activity in Relapsed/Refractory Low Grade Lymphomas (LG) and Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).
Authors: Kahl Brad S. , Advani Ranjana , Kay Neil , Lossos Izidore S. , Evens Andrew , Gordon Leo , Miller Richard A. , Phan See-Chun
Published: October 2019

Motexafin gadolinium (MGd, Xcytrin®) is a novel anti-cancer drug that selectively concentrates in cancer cells and disrupts redox dependent pathways by targeting oxidative stress related proteins such as thioredoxin reductase and metallothioneins. MGd has been shown to generate reactive oxygen species and induce apoptosis in tumor cells. We initiated a study to evaluate the safety and efficacy of MGd in two B-cell malignancies, relapsed/refractory LG and relapsed/refractory CLL or CLL/small lymphocytic lymphoma (CLL/SLL). MGd was given intravenously (IV) at 6mg/kg/day for 3 days q 2 weeks for LG and 5mg/kg/day for 10 days q 3 weeks for CLL/SLL. Ten patients (pts) with LG (2 grade 1, 5 grade 2, 1 grade 3 follicular, 2 marginal zone), 2 pts with CLL/SLL and 1 pt with CLL have been enrolled. Median age was 64.5 yrs (range 44–77), median prior treatment regimens was 3.5 (range 1–6) and median time from diagnosis to treatment was 52 mo. Many LG pts had failed prior aggressive treatment regimens including: CHOP (4), ICE (1), HyperCVAD(1), auto-bone marrow transplant (1); all failed rituxamab and 6 failed Zevalin. CLL/SLL and CLL pts had failed rituxamab (3), fludarabine (2), and R-CHOP (1). MGd related adverse events included skin and urine discoloration (6 and 4 pts), diarrhea, nausea, vesiculobullous rash, peripheral neuropathy (3 pts each). MGd related ≥gr 3 adverse events included skin rash (3 pts), fatigue, neuropathy, photosensitivity (1 pt each). Importantly, no MGd-related myelosuppression was observed. In 12 evaluable pts, there have been three PRs of 2+, 5+ and 8 months duration (2 follicular, 1 CLL). Two pts had SD (follicular, SLL) one of these had resolution of lymphoma related autoimmune hemolytic anemia. Responses occurred after ≤2 cycles of therapy and were seen in patients after extensive prior treatment (mean 4.3 prior regimens, range 3–7). MGd is a non-myelosuppressive drug with single agent activity in LG and CLL/SLL.
HuMax-CD20, a Novel Fully Human Anti-CD20 Monoclonal Antibody: Results of a Phase I/II Trial in Relapsed or Refractory Follicular Non-Hodgkins’s Lymphoma.
Authors: Hagenbeek A. , Plesner T. , Johnson P. , Pedersen L. , Walewski J. , Hellmann A. , Link B. , Robak T. , Wojtukiewicz M. , Pfreundschuh M. , Kneba M. , Engert A. , Sonneveld P. , Petersen J. , Radford J.
Published: October 2019

The fully human monoclonal IgG1 antibody HuMax-CD20 targets a novel epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mice more efficiently and exerts stronger complement activation than Rituximab. HuMax-CD20 kills Rituximab-resistant cells expressing low levels of CD20. Data are presented from an ongoing, open label, dose-escalation, multicenter clinical trial in patients with relapsed or refractory CD20+ follicular non-Hodgkin’s lymphoma. Four cohorts of 10 patients were treated with 4 weekly i.v. infusions of 300, 500, 700 or 1000 mg. The endpoints are adverse events, CT verified tumor response (central review) according to the Cheson criteria, B-cell depletion, time to next anti-lymphoma treatment, duration of response, BCL2 conversion and pharmacokinetics. Fourty patients have been treated. Mean age was 57 years; median number of prior treatment regimens was 2; 15 patients were previously treated with Rituximab. Rapid, efficient and sustained peripheral B-cell depletion was observed in all dose groups. No dose limiting toxicity has been reported. Only 8 short lasting episodes of grade 3 CTC were observed. Hematological toxicity was low and confined to 6 events of grade 1 neutropenia; no cases of thrombocytopenia were reported. The following pharmacokinetic parameters were derived (medians per dose group): Cmax 129, 185, 380 and 610 μg/ml, T½ 447, 245, 322 and 621 hr, Cl 9, 19, 10 and 7 ml/hr/kg and AUC 75000, 51000, 185000 and 326000 hr *μg/ml, for the 300, 500, 700 and 1000 mg dose groups, respectively. No correlation between pharmacokinetics and response was found. Objective responses (CR, CRu, PR) have been elevated in 36 patients and were obtained in all 4 dose groups; 4 CR + 1 CRu/8 (300mg), 1CR + 2 PR/9 (500mg), 2PR/10 (700mg) and 1 CRu + 4 PR/9 (1000mg). Objective responses were achieved in 8 of 14 (57%) evaluable patients previously treated with Rituximab, i.e. 3CR, 1 CRu and 4 PR. In total 18 patients showed stable disease; progression was observed in only 3 patients. Data on duration of response will be presented. In conclusion, this preliminary analysis demonstrates a favorable safety profile and encouraging efficacy of HuMax-CD20 in patients with follicular NHL. Objective responses were achieved in all dose groups with response rates up to 63% including a 57% response rate in patients previously treated with Rituximab.
Rapid Infusion of Rituximab with or without Steroid Containing Chemotherapy. A Single Centre Experience.
Authors: Salar Antonio , Casao Dolors , Pedro Carmen , Abella Eugenia , Calafell Montserrat , Alverez Alberto , Besses Carlos
Published: October 2019

Introduction: Infusion-related toxicity is frequent after the administration of Rituximab despite the fact that strict guidelines have been recommended. Recently, a rapid rituximab infusion schedule in combination with a steroid containing chemotherapy regimen was well tolerated and safe.

Purpose: To investigate the feasibility of a rapid infusion of rituximab with or without steroid containing chemotherapy.

Methods: Inclusion criteria: lymphoproliferative disorder CD20+ and having been treated with a first infusion of rituximab according to the product monograph. Exclusion criteria: lymphocytosis > 5 x 109/L, toxicity grade 3/4 in the previous infusion of rituximab or dose > 375 mg/m2. Schedule: First infusion of rituximab according to the product monograph; Further infusions over a total time of 90 minutes (20% in the first 30 minutes and the remaining 80% over 60 minutes). Premedication: acetaminophen and diphenhidramine, plus methylprednisolone only in those patients receiving steroid containing chemotherapy.

Results: A total of 50 patients were treated for a total of 165 infusions. Patient characteristics: median age 62 yr (range 28–83), 49 % males, DLBCL 36%, follicular 47%, mantle 6%, MALT 7%, other 4%. Chemotherapy regimens: R-CHOP 28%, R-EPOCH 9%, R-ESHAP 4%, R-other chemotherapy 8%, rituximab monotherapy 10%, rituximab maintenance 41%. Number of rituximab administrations with and without steroids: 68 and 97 infusions, respectively. Median time from previous rituximab infusion was 29 days (range 7–272). Sixteen rapid infusions were administered with an interval greater than 90 days from the previous standard infusions. This rapid rituximab administration schedule was very well tolerated. No grade 3/4 adverse events were seen. Two patients referred symptoms during rituximab infusion (both grade 1): abdominal discomfort that disappeared spontaneously and sore throat that required to slow down the infusion speed. All these reactions occurred in patients who did not receive premedication with steroids.

Conclusions: Rituximab administration in a 90-minute infusion schedule is well tolerated and safe in this group of patients. This approach is beneficial, both in patients who are administered steroids and in patients who are not.
Proliferative Activity of Megakaryocytes in Myelo- and Lymphoproliferative Diseases.
Authors: Gawronski Krzysztof , Sulek Kazimierz , Sidor Malgorzata , Domagala Maria
Published: October 2019

Aim of the study: Evaluation of significance of investigation of Ki67 and AgNOR staining as an indices of proliferative activity of megakaryocytes.

Material and methods: Bone marrow smears from 151 patients suffering from hematological malignancies: polycythemia vera (PV) − 14 cases, myelofibrosis (MF) − 14, essential thrombocythemia (ET) − 15, chronic myeloid leukemia (CML) − 11, myelodysplastic syndromes (MDS) − 18; acute myeloid leukemia (AML) − 30, acute lymphoblastic leukemia (ALL) − 10, low grade non-Hodgkin’s lymphomas (NHL) with bone marrow infiltration − 20, multiple myeloma (MM) − 19. Cytological slides were stored in the room temperature more than 24 hours and then stained using immunocytochemical method for Ki67 and cytochemical method for AgNOR. Slides were analyzed using illuminating microscope with digital image analysis (software LUCIA). Mean particles area, mean nuclear area and maturity of nucleus in AgNOR staining as well as intensity of Ki67 expression were evaluated, according to arbitrary scale (strong, medium, light, no reaction).

Results: Look at the table 1 and table 2.

Conclusions:There is a good correlation between expression of Ki-67 and AgNOR’s in megakaryocytes as well as between nuclear maturity and indices of Ki-67 and AgNOR in myeloproliferative disorders. Differences in AgNOR’s and Ki 67 staining area between myeloproliferative diseases and another hematological malignancies are also significant.

Table 1: Values of indices of the Ki67 and AgNOR in megakaryocytes Diseases Mean nucleus surface μm2 Mean AgNOR particle area in nucleus of megakaryocytes μm2 Mean Ki67 particle area in nucleus of megakaryocytes μm2 Intensity of Ki67 expression in megakaryocytes Grade of megakaryocytes maturity PV 667,29 0,68 0,19 Medium III and IV ET 812,32 0,82 0,29 Strong / Medium III and IV MF 767,92 0,55 0,26 Strong / Medium III / IV CML 734,30 0,57 0,15 Medium / Light III / IV MDS 645,67 0,06 0,03 Light III / IV AML 679,04 0,04 No reaction No reaction IV ALL 712,23 0,03 No reaction No reaction IV NHL 798,56 0,04 No reaction No reaction IV MM 629,49 0,04 No reaction No reaction IV

Table 2: Intensity of Ki67 expression in megakaryocytes in hematological disorders Diseases Strong – % of cells Medium – % of cells Light – % of cells No reaction – % of cells PV 36 43 14 7 ET 56 33 11 0 MF 51 32 16 1 CML 16 43 34 7 MDS 9 12 68 11 AML 0 0 0 0 ALL 0 0 0 0 NHL 0 0 0 0 MM 0 0 0 0
Population-Based Risk Assessment for Multiple Myeloma: A Novel Approach for Identifying Potential Environmental Associations.
Authors: Ojha Rohit P. , Phillips Martha M. , Thertulien Raymond
Published: October 2019

Given the continued uncertainty of multiple myeloma (MM) etiology, environmental epidemiologic investigations remain an important approach for generating hypotheses regarding potentially significant exposures. We assessed MM incidence in Arkansas using a novel population-based approach that combines county agricultural and industrial characteristics with environmental hazard mapping techniques to determine case distribution throughout the state and to identify significant trends associated with case distribution. Our investigation revealed a significant association between manufacturing-dependent counties and MM incidence (OR = 1.26, p = 0.004), a significant inverse association between non-specialized counties and MM incidence (OR = 0.62, p < 0.00001), and no significant association between agriculture-dependent counties and MM incidence (OR=0.92, p=0.636). Analyses of sixteen selected industries and their associations with MM incidence revealed primarily wood-related industries (paper mills, sawmills, wood preservation, and softwood, veneer and plywood manufacturing) exhibited significant associations with MM incidence (OR= 1.79 – 2.02, p< 0.05). Trend analyses demonstrated increasing MM incidence with increasing proportion of the population employed in the aforementioned wood-related industries. This is the first such statewide assessment of associations between general environmental exposure and MM incidence within counties. The methods developed in this study can be applied to data from other states or regions to produce a larger body of information from several geographic areas regarding MM incidence or other disorders with suspected environmental associations. Subsequently, meta-analysis can be performed to support or refute the existence of apparent associations, provide insight regarding national trends of MM incidence, and potentially suggest additional sources of exposure for further investigation.
Prognostic Significance of Ki-67 Expression in Extranodal NK/T Cell Lymphoma, Nasal Type: A Proposed Prognostic Index, KLABS Index.
Authors: Kim Seok Jin , Yoon Soo-Young , Kim Byung Soo , Choi Chul Won , Choi Jungwoo , Kim In Sun , Lee Young-Hen , Kim Jun Suk
Published: October 2019

Ki-67 is a nuclear antigen expressed by dividing cells, therefore, the percentage of Ki-67-positive cells reflects the proportion of tumor cells actively proliferating. However, the prognostic value of Ki-67 expression is still controversial in non-Hodgkin’s lymphoma. Although a recent study in peripheral T-cell lymphoma showed a positive correlation with poor prognosis, the prognostic value of Ki-67 has never been studied in patients with extranodal NK/T cell lymphoma. Therefore, we performed this study to determine the value of Ki-67 expression in predicting prognosis and to propose a new prognostic model involving Ki-67 expression in patients with extranodal NK/T cell lymphoma. We studied 65 patients who were diagnosed with extranodal NK/T cell lymphoma from 1999 to 2005. All patients were treated with combination chemotherapy alone or followed by radiotherapy. We analyzed the percentage of Ki-67 expressing cells and determined its prognostic significance in terms of overall survival (OS) and disease-free survival (DFS). The immunohistochemical staining of Ki-67 was available for this study in fifty-five patients. The median age was 41 (range: 19 – 74 years), 89.1 percent of the patients (49/55) had an ambulatory performance status: Eastern Cooperative Oncology Group (ECOG) 0–1. Fifty-one patients presented as a localized disease: Ann Arbor stage I or II, and elevated level of serum lactate dehydrogenase (LDH) was observed in 14 patients. Thus, most patients showed the low or low-intermediate international prognostic index (IPI): low risk (74.5%, 41/55) or low intermediate risk (18.2%, 10/55). The percentage of Ki-67 expressing tumor cells was ranged from 5% to 95%, and the patients were separated into two groups: low Ki-67 (< 50%) versus high (≥ 50%). The patients in the high Ki-67 group had a shorter OS (95% CI 1.0-6.3, P = 0.046) and DFS (95% CI 1.1-5.5, P = 0.024) while the IPI failed to predict worse OS. Ki-67 expression could also predict the group with worse prognosis in 51 patients of low and low-intermediate IPI risk. Age, serum LDH, B symptoms, and tumor size were also associated with worse OS or DFS. Thus, based on the univariate and mutivariate analysis, we proposed a new prognostic index (KLABS index) with high Ki-67 expression, increased serum LDH, Age (≥ 60 years), presence of B symptoms, and bulky Size of tumors (≥ 10cm2) as follows: low risk, none or one of the above-mentioned factors; intermediate risk, presence of two factors; high risk, presence of three or more factors. This new index showed a high degree of correlation with survival outcomes in terms of OS and DFS (Figure A, B). This study demonstrated the prognostic significance of Ki-67 expression, and our new prognostic index may become a useful tool for predicting prognosis in extranodal NK/T cell lymphoma, nasal type.

Figure Figure
Immunodominant Minor Histocompatibility Antigen-Specific T Lymphocytes Eradicate BCR-ABL-Induced B-ALL and CML without Causing Graft-Versus-Host Disease in Mice.
Authors: Hu Yiguo , Sproule Thomas , Peng Cong , Kong Linghong , Goodrich Ami , Roopenian Derry , Li Shaoguang
Published: October 2019

Adoptive immunotherapy of human Philadelphia chromosome-positive (Ph+) leukemia has not been effective due to difficulties of identifying tumor-specific antigens for the disease. It has been reported that T lymphocytes activated by some minor histocompatibility antigens (mHAs) can efficiently treat mice receiving HL4 cells (a leukemia cell line) without causing graft-versus-host disease (GVHD). We investigated whether this anti-mHA immunotherapeutic strategy is applicable to treating Ph+ leukemia that includes B-ALL (B-cell acute lymphoblastic leukemia) and CML (chronic myeloid leukemia). Because the mHA, H60, is an immunodominant mHA among H7, H28, and H58 in mice (Choi et al, Immunity 17:593–603, 2002), we tested whether H60 can serve as an immunotherapeutic target in the treatment of B-ALL and CML in our retroviral bone marrow transduction/transplantation disease models (Li et al, J Exp Med189:1399–1412, 1999). We used C57BL/6-H60 congenic mouse splenocytes to immunize wild type C57BL/6 (B6) mice that do not have the H60 gene, and the activated T lymphocytes from the immunized B6 mice were injected into mice with BCR-ABL-induced B-ALL or CML (3×107 cells/mouse). We found that H60-specific T lymphocytes at a single dose completely eliminated leukemic cells within 10 days after the injection of the cells and cured B-ALL and CML, however, in mice receiving donor bone marrow cells transduced with empty vector and treated with H60-specific T lymphocytes, the non-BCR-ABL-expressing donor marrow cells lasted for more than 4 weeks, suggesting that H60-activated T lymphocytes have much stronger inhibitory effect on BCR-ABL-expressing leukemic cells than on normal marrow cells. In contrast, leukemia mice receiving naïve T lymphocytes died within 3 to 4 weeks post BCR-ABL induction of leukemia. Six months later, no residual leukemia cells were detected in the spleen and bone morrow of the leukemia mice receiving H60-activated T lymphocytes. In addition, no GVHD was observed in the mice. We also use H7/H28/H60 triple congenic B6 mice in our study, and found that H7/H28/H60-primed T lymphocytes were more effective in elimination of leukemia cells in mice compared with when the single H60 antigen was used in similar experiment. Especially, the H7/H28/H60-primed T lymphocytes were highly effective in treating B-ALL mice, and did not induce GVHD. These results indicate that mHAs are promising targets for immunotherapy of BCR-ABL-induced B-ALL and CML.
Investigating the Role of Dendritic Cells in Extracorporeal Photopheresis Using an In Vitro Model.
Authors: Holtick Udo , Marshall Scott R. , Haniffa Muzlifah , Hilkens Catharien M. , Wang Xiao N. , Dickinson Anne M.
Published: October 2019

Graft versus Host disease (GvHD) is the major limitation to successful allogeneic hematopoietic stem cell transplantation and contributes significantly to transplant related mortality and morbidity. Steroid refractory or steroid depending GvHD in particular is linked to poor survival or life quality. Conventional immunosuppression has very limited success in these conditions and increases susceptability for infection and relapse.

Extracorporeal Photopheresis (ECP) is a promising therapy for acute and chronic GvHD not responding to conventional immunosuppressive therapy. ECP treatment seems not to result in a pan-immunosuppression but has quite selective effects on the pathogenic process in GvHD.

The mechanisms of action of ECP in GvHD known so far include lymphocyte apoptosis, cytokine modulation and increased regulatory T cell numbers. It has been suggested that monocytes and dendritic cells (DC) were more resistant to ECP induced apoptosis, so that they might either be directly modulated by ECP or modulated by encounter with apoptotic cells and this way aquiring immunomodulating properties. Here we tested the first hypothesis analysing direct effects of ECP on monocyte derived dendritic cells in vitro.

Direct in vitro PUVA treatment leads to activation of monocyte derived immature DCs (upregulation of CD83, CD86, HLA-DR, reduced endocytosis capacity, increased migratory capacity), whereas mature DCs are not affected. However, immature and mature DCs undergo apoptosis later on within 24h-72h. Prestimualtion with either antigen (KLH), IL-12 or co-culture with CD40L expressing cells could not prevent apoptosis. Further DC stimulation through CD40L is abrogated 24h after treatment. DC cytokine analysis (IL-12, TNFα) is pending. After in vitro PUVA primary dermal DCs and Langerhans Cells migrated from skin biopsies undergo apoptosis similarly to monocyte derived DCs.

Going along with the early activation, the stimulatory capacity of in vitro PUVA treated immature DCs is enhanced in an MLR on naive T cells. IL-10 levels are decreased as compared to untreated or UVA treated cells. Secondary stimulation through either CD3/CD28 beads or mature DCs leads to reduced proliferation of naive T cells that were primarily stimulated with in vitro PUVA treated as compared to untreated immature DCs. Cytokine analysis after secondary stimulation is pending.

We conclude that in our model in vitro PUVA modulates the character especially of immature dendritic cells. However, immunostimulating and immunosuppressive characteristics could be described depending on the assay. Cytokine results after second stimulation (Th1/Th2) are pending. Apoptosis is a major finding and occurs both in monocytes and DCs after 24–72h. Our findings indicate that there might be direct ECP effects on monocytes and DCs going beyond the process of merely depleting antigen presenting cells. Further relevance is currently being investigated.
Generation of Dendritic Cells from Human Cell Expressed Cytokines.
Authors: Newman Rosie , Simpson Raina , Domagala Teresa , Lim Mei , Crofts Linda , Pilkington Glenn , Marks Denese
Published: October 2019

Traditionally, human cytokines have been expressed in non-human cells, including bacteria, yeast and mouse cells. However, the biological importance of species-specific post-translational modifications, in particular glycosylation, is increasingly being implicated as pivotal to protein function. Glycosylation is important for solubility, resistance to proteolysis, immunogenicity, biological recognition, biological activity, in vivo stability and clearance of glycoproteins including cytokines and growth factors, as up to 75% of their mass may consist of carbohydrate moieties. Clinical trials in cancer immunotherapy have attempted to benefit from the ability of autologous dendritic cells to boost antigen specific T-cell immunity. To date most clinical trials have generated dendritic cells using cytokines expressed in non-human cells. We have purified recombinant human cytokines expressed in modified human 293 cells. Human cell expressed human cytokines including IL-4, GM-CSF and TNF-alpha were used to generate dendritic cells from human peripheral blood mononuclear cells. The resulting cells exhibited a typical mature dendritic cell phenotype including expression of CD209, HLA-DR, CD40, CD80, CD83 and CD86, and were able to generate a T-cell response. In vitro comparisons of the biological activity of human cell expressed cytokines, in particular IL-4, with those expressed in other species has demonstrated that human cell expressed cytokines are more stable.

It is proposed that the enhanced biological stability of human cytokines derived from a human cell expression system would make these cytokines ideal for ex vivo derivation of immune cells such as dendritic cells for cancer therapy.