bluuebunny/crossref_metadata_2025 huggingface dataset:
The Plasma Concentrations of the Anorexigenic PYY and Orexigenic Ghrelin Decrease and Increase Respectively during Chemotherapy in Children with Acute Lymphoblastic Leukaemia, as the Leukemic Burden Is Gradually Eliminated and the Body Weight Improves.
Authors: Moschovi Maria , Vounatsou Maria , Papassotiriou Ioannis , Chrousos George P. , Tzortzatou-Stathopoulou Fotini
Published: October 2019

Anorexia and cachexia are common manifestations in children with acute lymphoblastic leukaemia (ALL) at diagnosis. Possible mediators of the anorexia-cachexia syndrome are hormones, cytokines, and adipokines from peripheral tissues, and neurotransmitters, neuropeptides, cytokines, and other hormones in the hypothalamus. Peptide YY (PYY) and ghrelin are gastrointestinal track-derived hormones involved in the short- and long-term regulation of food intake and energy balance. PYY, synthesized mainly by endocrine cells of the terminal ileum and colon, is released into the systemic circulation in response to a meal and participates in signalling the end of the meal at the hypothalamus. PYY exerts its pro-satiety actions possibly through an Y2 receptor-mediated mechanism. Ghrelin, secreted predominantly from X/A-like endocrine cells of the oxyntic glands of the stomach, is primarily secreted in the fasting state, with plasma concentrations falling within one hour of a meal. Its role in food intake and energy balance is opposite to that of PYY, as it exerts orexigenic effects through activation of the hypothalamic neuropeptide Y-Y1 (NPY-Y1) pathway. We evaluated the secretion of PYY and ghrelin at diagnosis and during chemotherapy in children with ALL. Ten patients aged 2-7years were included in this perspective study. All patients were treated following the same protocol (HOPDA97)1. A physical examination was performed and blood chemistries were evaluated by standard techniques. Preprandial PYY and active ghrelin levels were determined by specific radioimmunoassays (Linco Research, Inc., USA). Measurements were performed at diagnosis prior to chemotherapy and at several time points prior to each next cycle of chemotherapy for up to 18 months (6–10 measurements per patient). Baseline PYY levels were 213.2±85.3pg/ml, increased significantly to 283.9±72.9pg/ml after the induction and consolidation phase of chemotherapy, and returned progressively to pre-treatment levels at the 6th cycle of the maintenance phase. Baseline active ghrelin concentrations at diagnosis were low (32.6±8.6pg/ml), fluctuated throughout the study period and stabilized at significantly higher levels (57.4±31.6pg/ml) after the 8th cycle of maintenance phase of chemotherapy. These data suggest that in children with ALL and anorexia-cachexia the levels of PYY decrease with time, as the leukemic burden is eliminated. In contrast, active ghrelin levels are relatively low at diagnosis, remain low during the early cycles of chemotherapy, but normalize with the elimination of the leukemic burden, paralleling the body weight gain trajectory.
Maternal Hemoglobin Concentration during Pregnancy and Risk of Infant Leukemia.
Authors: Peters Antoinette M. , Blair Cindy K. , Verneris Michael R. , Neglia Joseph P. , Heerema Nyla A. , Robison Leslie L. , Ross Julie A.
Published: October 2019

Little is known about the etiology of childhood leukemia. Elevated birth weight (> 4000 g) is gaining acceptance as a risk factor, particularly for children diagnosed < 2 years of age, but the underlying biological or physiological explanation for this association has yet to be defined. At least three recent studies have demonstrated a positive association with childhood leukemia and maternal anemia during pregnancy. Physiologic anemia of pregnancy, which results from normal plasma volume expansion, is thought to produce optimal blood viscosity for the low flow area of the placenta and is associated with the highest average birth weights in the offspring. We therefore hypothesized that maternal physiologic anemia of pregnancy would have a positive association with infant leukemia. To test this hypothesis, we utilized data from a case-control study conducted by the Children’s Oncology Group (COG) that consisted of 240 incident cases of acute infant leukemia (< 12 months of age) diagnosed between 1996 and 2002 and 255 controls obtained by random digit dialing. Maternal blood counts were obtained by medical record abstraction. Information regarding the patients’ diagnoses and cytogenetic/molecular abnormalities were obtained from COG institutions. Physiologic anemia of pregnancy was defined as a hemoglobin concentration of < 11 g/dL in the second or third trimester of pregnancy (WHO classification). Anemia earlier in pregnancy is more frequently due to nutritional deficiencies and can be associated with poor fetal outcomes and thus was excluded. Maternal hemoglobin values from the second or third trimester were available for 178 case and 180 control mothers. Data were analyzed using unconditional logistic regression. We found no evidence that physiologic anemia of pregnancy was associated with birth weight of > 4000 g (odds ratio (OR) 1.05, 95% confidence interval (CI)=0.55–1.99) Overall, the OR for physiologic anemia of pregnancy and risk of infant leukemia was 0.85 (95%CI=0.53–1.37). The association remained non-significant when cases were divided into acute myeloid leukemia (AML) (n=63) and acute lymphocytic leukemia (ALL) (n=115) with ORs of 0.64 (95%CI=0.32–1.30) and 0.98 (95%CI=0.58–1.66), respectively. The association was also not significant when cases were stratified by MLL gene abnormality status (OR=0.77; 95%CI=0.42–1.40 and OR=0.88; 95%CI=0.45–1.73, for cases with (n=92) and without (n=62) an MLL gene abnormality, respectively). These associations remained non-significant when the data were adjusted for birth weight, maternal race, and birth order. More stringent criteria for anemia also did not modify the results. We found no evidence for an increased risk of infant leukemia in the offspring of mothers with physiologic anemia of pregnancy. This work was supported by NIH R01 CA79940 and the Children’s Cancer Research Fund.
Aldehyde Dehydrogenase Expression in Primitive Human Hematopoietic Progenitor Cells with Side Population Characteristic and in Samples from Patients with Acute Myeloid Leukemia.
Authors: Meissauer Ute , Hoffmann Joerg , Scharenberg Christian , Neubauer Andreas , Brendel Cornelia
Published: October 2019

High activity of the detoxifying enzyme aldehyde dehydrogenase (ALDH) has been attributed to primitive hematopoietic stem cells in the murine and human system. ALDH activity can be measured by a functional assay employing BODIPY-aminoacetaldehyde (BAAA) as a fluorescent intracellular substrate. High ALDH activity within hematopoietic stem cells is associated with CD34 and AC133 surface expression.

Given the co-expression of these markers in acute myeloid leukemia (AML), we sought to investigate whether ALDH-activity can be detected in early blood stem cell disorders and in primitive hematopoietic progenitor cells with the side population phenotype. Employing a commercial Aldefluor™ -kit thirteen peripheral blood and bone marrow samples from patients with AML were stained for ALDH activity. Four samples exhibited a clearly distinctive positive staining pattern when compared to the inhibitor control, i.e. 16–91% of AML blast cells were considered as ALDH positive. The staining pattern was similar to marrow samples from healthy donors or peripheral blood sample controls from G-CSF-mobilised healthy stem cell donors.

In addition we investigated ALDH activity in primitive bone marrow side population (SP) cells from healthy individuals. Although the ALDH substrate BAAA is actively extruded out of cells and especially SP stem cells by an ABC-transporter-activity, we established a co-staining method for Hoechst 33342 and BAAA by inclusion of specific ABC-transporter inhibitors.

Both SP cells and ALDH-positive cells appeared as a clear distinctive population with some overlap between both populations. Quantitative RT-PCR of different sorted stem cell samples confirmed that SP cells had higher ABCG2-expression than ALDH positive cells and ABCG2-expression was higher in ALDH positive cells compared to the total cell fraction or granulocytes.

We conclude that ALDH is expressed in some but not all AML blast cells. This is in accordance with the cytogenetic heterogeneity of this disease and may have therapeutic implications because of the detoxifying activity of the ALDH enzyme. In addition ALDH activity can also be found on a minor population of very primitive marrow progenitor cells. Whether high ALDH activity is a feature of the leukemic stem cell requires further investigation.
Results of Randomized Study on Dexrazoxane Administration in Children with De Novo Acute Leukaemia.
Authors: de Berranger Eva , Thebaud-Leculee Estelle , Wickaert Isabelle , Vaksman Guy , Mazingue Francoise , Francart Charles , Dalle Jean-Hugues , Nelken Brigitte
Published: October 2019

Anthracyclins and anthracenediones represent major drugs for both myeloid and lymphoblastic acute leukemia. Among their efficient mechanisms, these drugs induce free radical production responsible of cardiac toxicity. Even though toxicity is mainly dose related, there is an inter-individual sensitivity, and then it appeared very important to develop drugs able to protect cardiomyocytes. Dexrazoxane was developed in this goal in adult patients where its efficiency was demonstrated both to protect heart and to respect anticancer therapy results. We conducted a prospective single bind randomized study using dexrazoxane associated with first-line therapy in pediatric acute leukemia.

Patients and Methods: From Dec’00 to Sept’03, 16 patients (pts) were enrolled and randomized for receiving or not dexrazoxane (1000mg for 50mg of anthracyclines or anthracenedione doxorubicin dose equivalent) with chemotherapy. Cardiac function was evaluated by echocardiogram before induction and after each chemotherapy course of either CLG-EORTC 58951 trial arm VHR or French acute myeloid leukemia trial LAME01 and each year after treatment completion. The cardiologist operator did not know if child received dexrazoxane or not. The cumulative equivalent doxorubicin dose was 310mg/m2 for EORTC 58951 VHR group and 460mg/m2 for LAME01. The primary end-point was cardiac function evolution. The secondary end points were OS, EFS and the respect of initial therapy schedule.

Results: 16 pts (9M/7F), median age 8.5y (range: 2.4 – 16.1) were enrolled. Initial diagnoses were AML: 11 and ALL: 5. Five AML pts and 3 ALL pts received dexrazoxane. Median follow-up was 28.5 months (10–47). 12 pts were alive, 6 in each arm of study. One pt relapsed in arm with dexrazoxane and 3 in the other arm. Two pts died of disease and 2 from infection equally dispatched in the 2 study arms. Mean left ventricular shortening fraction was 39.4+/−1.9% and 35.6+/−1.2% in pts without dexrazoxane and 40.2+/− 2.2% and 38.7+/− 2% in pts with dexrazoxane before chemotherapy and 1 year after diagnosis. All these values were comparable. Mean duration between day1 of each chemotherapy course was the same in different arms of study.

Discussion and conclusion: Dexrazoxane may be used safely in children receiving anthracycline. No difference in OS and DFS appear in our study. Median follow-up was probably too short for distinguishing any cardiac alteration and patient number was low. In addition, shortening fraction may be not the better cardiac indicator and wall stress could be more efficient. Further investigations are on-going.
Comparison of Two Induction Regimens, High Dose Cytarabine /Mitoxantrone vs Hyper-CVAD, for Adult Acute Lymphoblastic Leukemia/Lymphoma.
Authors: Jeong Woondong , Liu Delong , Katragadda Sreedhar , Shi Qiuhu , Ahmed Tauseef , Seiter Karen
Published: October 2019

Seventy-three consecutive adult patients with newly diagnosed ALL and lymphoblastic lymphoma were treated with either high-dose cytarabine /mitoxantrone (Ara-C/Mito) or Hyper-CVAD between January 1994 and January 2005 at the Westchester Medical Center. The regimens were chosen according to investigators’ preferences. The two induction regimens were either Ara-C 3 g/m2/d for 5 days and mitoxantrone 80 mg/m2 on day 2 (52 patients) or Hyper-CVAD regimen (21 patients) containing four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate and Ara-C. All patients who were in CR received consolidation and maintenance therapy after induction. In Ara-C/Mito group, 45 (87%) of 52 patients achieved a complete remission (CR), 2 (4%) had resistant disease and 5 (9%) had died during remission induction in median follow-up of 48 months (range, 0.5 – 109 months). In Hyper-CVAD group, 16 (76%) of 21 patients achieved a CR, 4 (19%) had resistant disease and 1 (5%) had died during remission induction in median follow-up of 12months (range, 0.5 – 43 months). The difference of CR rate between the two groups was not statistically significant. (p=0.31). The overall survival (OS) of AraC/Mito group was 21 months (95% confidence interval [CI], 13 – 38 months), with a 3-year and 5-year OS of 36%, and 30%, respectively. In Hyper-CVAD group, OS was 26 months (95% CI, 26 -NR ), with a 3-year OS of 40%. The difference of OS between the two groups was not statistically significant (p=0.24). In Ara-C/Mito, median CR duration was 34 months (95% CI, 13-) and in Hyper-CVAD, median CR duration was not reached. In a combined multifactorial analysis of the two groups for prognostic factors, Age (<35) was the only favorable factor toward OS (p=0.03). Other prognostic factors including cytogenetics, cell type, WBC, LDH, were not statistically significant.

In conclusion: Ara-C/Mito and Hyper-CVAD appear to be comparable in terms of CR rate, toxic death, and OS in this single institution retrospective analysis. It will be interesting to compare the two induction regimens in a large multicenter randomized study.

AraC/Mito vs Hyper-CVAD Regimen N Med F/U CR CR duration OS 3yr OS 5yr OS NR: median not reached. M: month AraC /Mito 52 48m 87% 34m 21m 36% 30% Hyper-CVAD 21 21m 76% NR 26m 40% NR p=0.31 p=0.24
Burkitt’s Lymphoma in Korea: Clinical Manifestations and Efficacy of Modified CALGB 9251 Regimen (BNHL).
Authors: Lee Danbi , Kim Shin , Ko Ock Bae , Koo Ja Eun , Chong Young Pill , Huh Jooryung , Suh Cheolwon
Published: October 2019

Background: Clinical manifestations of sporadic Burkitt’s lymphoma of Asia including Korea has not been well informed. When Korean patients with Burkitt’s lymphoma were treated following the protocol proposed by the Cancer and Leukemia Group B (CALGB) 9251, grade 4 mucositis was reported in every patient. Thus, we had modified CALGB 9251 protocol and named BNHL.

Aims: This study was aimed to show the clinical manifestations and to evaluate efficacy and toxicity of BNHL in patients with Burkitt’s lymphoma in a Korean single center.

Methods: Between January 1998 and July 2005, 25 patients who were diagnosed as Burkitt’s lymphoma at Asan Medical Center were available to evaluate the clinical features. Among 25 patients, 12 patients treated with BNHL were available. In BNHL protocol, we reduced the dose of methotrexate (1,500 → 1,000 mg/m2/day on Day 1) and etoposide (80 → 50 mg/m2/day on Day 4 and 5) in cycle 2, 4, and 6, and the dose of methotrexate (1,500 → 1,000 mg/m2/day on Day 1) in cycle 3, 5, and 7 from the protocol of CALGB 9251.

Results: Median age was 50.4 years (range: 17–77) and 15 patients were male. Among 25 Burkitt’s lymphoma, 20 patients had extranodal involvement, and 9 patients had 2 or more extranodal involvements. Extranodal sites were bone marrow, GI tract, genitourinary organ, bone, and lung, in decreasing order. Among total patients, 16 were in stage III or IV, and 9 were in stage I or II. Twelve patients had B symptoms, and 16 patients had high or high intermediate score of age adjusted international prognostic index (IPI). For 12 patients treated with BNHL, median follow-up duration was 13 months (range: 3–20 months). Among patients treated with BNHL, 9 patients achieved CR, and 3 patients achieved PR. The event free survival (EFS) rate at 1 year was 54% (95% CI, 39–69%) and median EFS was not reached. Among 9 patients who achieved CR, 2 patients were relapsed. Three patients died as a result of treatment-related complications (2 patients) or progressive disease (1 patient). Median overall survival (OS) was not reached yet, and 1-year OS rate was 64% (95% CI, 50–78%). All patients treated with BNHL had hematologic toxicities of grade 3 or 4 neutropenia/thrombocytopenia. Grade 3 or 4 non-hematologic toxicities were; mucositis (67%), infection (58%), hepatic toxicity (42%), peripheral neuropathy (25%), and azotemia (25%).

Conclusions: Korean patients with Burkitt’s lymphoma had worse age-adjusted IPI score than that in western countries. Extranodal involvements were more frequent. Despite these poor risk factors, BNHL modified from CALGB 9251 showed satisfactory efficacy and acceptable toxicities in Korean Burkitt’s lymphoma.
Mechanisms Controlling Selective Death of Leukemia Stem Cells in Response to Parthenolide.
Authors: Guzman Monica L. , Li Xiaojie , Corbett Cheryl , Hassane Duane C. , Jordan Craig T.
Published: October 2019

Studies have shown that human acute myelogenous leukemia (AML) originates from a rare population of leukemic stem cells (LSCs). LSCs are found in nearly all AML subtypes and are sufficient to initiate and maintain leukemic growth in both long-term cultures and NOD/SCID mice. Since conventional chemotherapy drugs typically target actively cycling leukemic blast cells, the quiescent LSC population is likely to be drug resistant. Recently, we have described agents that can selectively kill LSC while sparing normal hematopoietic stem cells (HSC), thus demonstrating that quiescent LSC can be effectively destroyed. In particular, the sesquiterpene lactone parthenolide (PTL) is active as a single agent and can induce robust LSC-specific apoptosis. Therefore, we sought to further elucidate the mechanisms that result in leukemia-specific death. To this end, we have shown that PTL inhibits NF- κB and activates p53 in AML cells. Moreover, we have found that AML cells are highly-oxidized relative to their normal less-oxidized counterparts as determined by dihydrofluorescein diacetate (H2DCF-DA) fluorescence. Although PTL treatment was found to increase the basal oxidative load of both normal and leukemic cells, these increases were ultimately associated with only leukemia-specific death. High levels of reactive oxygen species are associated with genotoxic stress. Therefore, we hypothesized that PTL-mediated increases of the oxidative load in AML cells would be sufficient to produce genotoxic stress in AML cells, but not normal cells. We thus examined pathways involved in sensing and responding to oxidative and genotoxic stress. These studies demonstrate that upon PTL treatment, AML cells phosphorylate p53 on serine 15, and increase transcription of several downstream p53 pro-apoptotic genes, including GADD45, Bax, and p21. In addition, we detected phosphorylation of ATM on serine 1981, γ-H2AX, and phosphorylation of Chk2 on threonine 68. Importantly, these events are not observed in normal hematopoietic cells treated with PTL. These findings suggest a DNA damage/repair response to PTL in AML cells, and that normal cells appear to be resistant to this mechanism. Collectively, these data indicate that oxidative stress and DNA damage pathways may be a central component of PTL-induced apoptosis. We propose a model whereby AML cells exist in a physiological state in which PTL is able to preferentially invoke genotoxic stress in AML. Based on empirical evidence, we suggest that AML LSC also exist in such a state, and that PTL mediated inhibition of NF- κB and induction of stress leads to selective apoptosis of malignant cells, sparing normal cell populations.
Clinical Significance of Monoclonality by Flow Cytometry in Histologically Negative Bone Marrow in Patients with Diffuse B Cell Non Hodgkin’s Lymphoma.
Authors: Lahav Meir , Lucianski Michael , Radnay Judith , Shapiro Hava , Gronich Naomi , Manor Yosef , Lishner Michael
Published: October 2019

Bone marrow (BM) involvement in diffuse large B cell non Hodgkin’s lymphoma (DLBCL) results in stage IV staging and has negative impact on survival. Up to 40% of patients with DLBCL have BM involvement by routine histology of marrow biopsy. The identification of lymphoid monoclonality is widely used in diagnosis of lymphoma, by flow cytometric and molecular methods. The clinical significance of monoclonality by these methods has not been systematically addressed in clinical setting. An International Workshop of response criteria in non Hodgkin’s lymphoma recommends that histologically normal marrow with small clonal population detected by flow cytometry should be considered normal until there are clinical studies that demonstrate a different outcome for this group. Recently it was reported that clonality detected by PCR amplification carries worse prognosis in patients with DLBCL. In our institution bone marrow biopsies of all patients with lymphoma are routinely evaluated by flow cytometric analysis since 1993. We evaluated the clinical course of all our patients with DLBCL diagnosed or followed up between 1993 and 2004 and compared the clinical course of patients with histologically positive marrow, histologically and cytometry negative marrow and histologically negative marrow and monoclonal lymphoid population detected by flow cytometry. Monoclonality was defined as ration of light chain expression kappa: lambda>3:1 or lambda: kappa > 2:1 in at least 2% of the gated population. Selected cells were analyzed by two or three color combinations: CD5 versus CD19, CD20 versus CD10 and kappa chain versus lambda chain occasionally with the addition of CD19 or CD20. Among 110 patients, 80 had negative marrow histologically and on cytometry (BM-FC-), 16 were positive on both parameters (BM+FC+) and 14 were histologically negative and cytometry positive (BM-FC+). All three groups were similar in parameters as age, performance status, hemoglobin and LDH levels. BM-FC- and BM-FC+ were similar in IPI scores. BM-FC- patients had significantly longer survival time that BM+FC+ and BM-FC+ patients. There was no significant difference in survival of BM+FC+ and BM-FC+ patients.

We conclude that the clinical outcome of patients with DLBCL with histologically normal bone marrow and monoclonality on flow cytometry is similar to those with histologically positive marrow. These results may imply that lymphoid monoclonality on flow cytometry should be regarded as bone marrow involvement and treated as such.
Fixed-Dose Single Administration of Pegfilgrastim vs Daily Filgrastim in Patients with PTLD Undergoing a Sequential Therapy of Rituximab and CHOP Chemotherapy.
Authors: Trappe Ralf , Matthias Papp-Vary , Oertel Stephan , Hanno Riess
Published: October 2019

Infectious complications are frequent events in patients with post-transplant lymphoproliferative disorders (PTLD) undergoing CHOP-based cytotoxic chemotherapy and previous studies had demonstrated the need for growth factors to conduct chemotherapy in these patients. To evaluate whether a single subcutaneous injection of pegfilgastrim (6mg) is as safe and effective as daily filgastrim (5 μg/kg/day), 84 cycles of CHOP-21 chemotherapy in patients with PTLD have been analyzed. Patients were treated with four weekly doses of 375mg/m2 of rituximab as a single therapeutic agent at days 1, 8, 15 and 22. CHOP chemotherapy had been administered at days 50, 72, 94 and 116 and was supported by GCSF. In case of disease progression during administration of rituximab or during the 4-week interval between antibody therapy and CHOP administration the patients directly entered chemotherapy. In total, 7 patients undergoing 23 cycles of CHOP chemotherapy received a single subcutaneous injection of 6mg pegfilgastrim on day 3 after application of CHOP and were compared retrospectively with 20 patients receiving 5 μg/kg/day of filgastrim starting from day 3 after application of CHOP. In the pegfilgastrim group 5 patients were renal transplant recipients, one was a liver transplant recipient and one was a heart transplant recipient. In the filgastrim group 10 patients were renal transplant recipients, 6 were liver transplant recipients, four were heart transplant recipients. 1 patient was a combined heart/lung transplant recipient, one was a combined kidney/pancreas transplant recipient and one patient was after bone marrow transplantation. 4/7 patients of the pegfilgastrim group had stage III or stage IV disease, while 14/20 patients in the filgastrim group had stage III or stage IV disease. Age ranged from 20 to 76 years with a median age of 57 years in the pegfilgastrim and from 16 to 80 years with a median age of 55 years in the filgastrim group. The incidence of grade III/IV infections in the pegfilgastrim and filgastrim groups were 2 in 23 applied cycles of chemotherapy and 7 in 61 cycles of applied chemotherapy, respectively. The incidence of grade III/IV leucopenia in the pegfilgastrim and filgastrim groups were 15 in 23 cycles in the pegfilgastrim group and 29 in 61 cycles in the filgastrim group. The results of the two groups were not significantly different for incidence of grade III/IV infections and grade III/IV leucopenia. A single injection of pegfilgastrim administered at day 3 post CHOP-based chemotherapy showes a comparable efficacy and safety profile to daily injections of filgastrim in patients with PTLD.
A New BACOPP Schedule Is Feasible and Effective in Elderly Hodgkin’s Lymphoma Patients - Interim Results of a Multicenter Phase-II Trial of the German Hodgkin Study Group (GHSG).
Authors: Nogova Lucia , Sieniawski Michal , Nisters-Backes Hildrud , Jennissen Veronika , Diehl Volker , Engert Andreas , Josting Andreas
Published: October 2019

Introduction:

The outcome of Hodgkin’s lymphoma (HL) patients (pts) increased over the last decades. However, treatment results in HL pts > 60 years are poor, particularly in patients with advanced stage disease. Large prospective studies are still lacking in this group. Based on the results for adult HL pts, we adapted the BEACOPP schedule for elderly HL pts with an increased dose of doxorubicin while omitting etoposide.

Methods:

From December 2003 to Mai 2005, 52 HL pts with a median age of 66 (range 61 – 75 years) and newly diagnosed HL in unfavourable clinical stage (CS) I, II and CS III, IV were prospectively recruited to receive 6 to 8 cycles of bleomycin (10 mg/m2), doxorubicin (50 mg/m2), cyclophosphamide (650 mg/m2), vincristine (1.4 mg/m2), procarbazine (100 mg/m2), and prednisone (40 mg/m2) (BACOPP) followed by local radiotherapy to residual lymphoma. Epoetin beta (30.000 IE once weekly) was administered to avoid therapy induced anaemia.

Results:

Up to day, 29 pts (14 males and 15 females) were evaluable for feasibility and response of treatment. Overall response rate after chemotherapy was 83% (38% CR and 45% PR). So far 2 pts (7%) developed progressive disease during chemotherapy. The treatment was generally well tolerated with WHO grade 4 toxicities: 31% leukopenia, 14% thrombopenia and 0% anaemia. Till now one patient died several weeks after treatment under sepsis.

Conclusion:

The first interim analysis of this new BACOPP schedule showed that this regimen is feasible in elderly HL pts. Full analysis of updated results will be presented.
Fludarabine, Mitoxantrone and Dexametasone in the Treatment of Relapsed and Refractory Low-Grade Non-Hodgkin Lymphoma.
Authors: Sawczuk-Chabin Joanna , Kalinka Ewa , Centkowski Piotr , Budziszewska Katarzyna , Ceglarek Bernadeta , Najda Jacek , Blasinska-Morawiec Maria , Sulek Kazimierz , Holowiecki Jerzy , Konopka Lech , Warzocha Krzysztof ,   for Polish Lymphoma Research Group
Published: October 2019

The purpose of the study was to evaluate response, duration of response, and toxicity of fludarabine (F), mitoxantrone (M), and dexamethason (D) (FMD) in patients (pts) with relapsed or refractory low-grade non-Hodgkin lymphoma (LGNHL). 26 pts with advanced relapsed/refractory LGNHL exposed to previous chemotherapy (CHT) received 3–6 monthly cycles of FMD. The median age was 60 years (range 34–73), included 13 male (50%) and 13 female (50 %). The regimen consisted of F (25 mg/m2 i.v., day 1–3), M (10 mg/m2 i.v., day 1) and D (20 mg p.o., day 1–5). Parameters analyzed included response, toxicity and infection rates, number of previous CHT lines, performance status (ECOG), Ann Arbor scale, LDH, International Prognostic Index score, freedom from progression (FFP) and overall survival (OS). In total 78 cycles of FMD was administered. This induced 25% complete and 37,5% partial response, with a total response rate of 62,5%. After 14 months of the median follow-up of the pts remaining alive, median FFP was 11 months and median OS has not been achieved yet. Out of 78 administered cycles 16 (20%) were associated with toxicity, including 8 (10%) severe infections despite prophylaxis and 6 (8%) grade III/IV neutropenias. In addition, one case of grade III/IV thrombocytopenia and acute noninflammatory renal dysfunction were observed. Toxicity rate was not correlated with the number of previous CHT lines or ECOG, but IPI >2 was significant factor predictive for FMD-related toxicity (p=.037). Shorter OS was observed for the pts with ECOG>1 (p=.049), IPI>2 (p=.005) and FMD-related toxicity (p=.036). FMD is an active regimen for relapsed and refractory LGNHL. Toxicity rate is substantial and seems to predict survival.
A Phase II Trial of FM (Oral Fludarabine and Mitoxantrone) Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) for Previously Untreated Follicular Lymphoma (FL) Patients.
Authors: Zinzani Pier Luigi , Tani Monica , Stefoni Vittorio , Alinari Lapo , Marchi Enrica , Fina Mariapaola , Baccarani Michele
Published: October 2019

Follicular lymphoma (FL) has been considered as low-grade malignant B-cell lymphoma usually characterized by an indolent course with a continuous pattern of relapse and a median survival of 10 years. The therapeutic approach to FL is particularly controversial. One of the effective strategies is the combination of fludarabine-containing regimens (particularly, Fludarabine and Mitoxantrone) with anti-CD20 monoclonal antibody. Single-agent radioimmunotherapy activity, in particular Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin), has been demonstrated in heavily pretreated FL patients. The results of these studies support a further evaluation of 90Y Ibritumomab Tiuxetan in combination with chemotherapy earlier in the time course of FL. Recently, some phase II trials showed that the sequential combination of conventional chemotherapy (CHOP) and 90Y Ibritumomab Tiuxetan has useful activity in the treatment of FL patients, with no unexpected toxicities observed. We conducted a prospective, single-arm, open-label, non-randomized, multicenter, phase II to evaluate the efficacy and safety of 90Y Ibritumomab Tiuxetan of a novel new approach combining induction chemotherapy with oral Fludarabine and Mitoxantrone (FM) followed by consolidation with 90Y Ibritumomab Tiuxetan for patients with previously untreated elderly FL. Patient eligibility was represented by: patients age 18 years or older with biopsy-proven, untreated, bidimensionally measurable stage II, stage III, or stage IV FL expressing the CD20 antigen; performance status of 0 to 2, a pretreatment granulocyte cell count of 1500/μL or greater, and a platelet count of 100.000/μL or greater. All patients were notified of the investigational nature of this study and signed a written informed consent approved in accordance with institutional guidelines, including the Declaration of Helsinki. The study was approved by the institutional review board. Patients were treated with standard FM chemotherapy (in this case, Fludarabine was administered orally at the dose 40 mg/m2/day for 3 consecutive days) every 21 days for 6 cycles. Patients were restaged 4 to 8 weeks after completion of the sixth cycle of FM chemotherapy. Patients achieving at least a partial response after 6 cycles of FM chemotherapy were eligible for consolidation with 90Y Ibritumomab Tiuxetan provided the granulocyte count was greater than 1500/μL, the platelet count exceeded 100.000/μL, and the bone marrow examination at the completion of CHOP chemotherapy demonstrated no more than 25% involvement with lymphoma. All patients were to receive a single dose of 90Y Ibritumomab Tiuxetan 14.8 MBq/kg (0.4 mCi/kg) up to a maximum dose of 1184 MBq (32 mCi). A total of 60 patients have to be enrolled and preliminary results of this trial will be presented.
Long Term Follow up of the Patients with Non-Hodgkin’s Lymphoma Treated with Rituximab in Combination with CHOP Regimen.
Authors: Li Jun-Min
Published: October 2019

Objectives: We performed this prospective study with single arm to evaluate the long term efficacy and safety of rituximab in combination with CHOP regimen in B cell non-Hodgkin’s Lymphoma (NHL) patient.

Methods: All patients received 4~8 cycles of CHOP plus rituximab. For each cycle, Rituximab (375 mg/m2 per dose) was given on day 1 and CHOP regimen on day 3. CHOP regimen consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (maximum dose, 2.0 mg/d) given intravenously on day 3, and oral prednisone 60 mg given from day 3 to 7.

Results: 102 patients were enrolled in this trial, 65 of them are males and 37 are females, with the median age of 47.5 (range 16–76). The main subtypes were diffuse large B cell lymphoma (DLBCL, 82/102), follicular lymphoma (FL, 9/102), mucosa associated lymphoma (MALT, 3/102), marginal zone lymphoma (MZL, 3/102), lymphoplasmacytic lymphoma (LPL, 2/102) and mantle cell lymphoma (MCL, 3/102). The overall response (OR) rate was 91.2% and complete response (CR) rate was 71.6%. The OR and CR of DLBCL were 90.2% and 70.7%, respectively; and the OR and CR of indolent lymphoma (MALT, FL, and LPL) were 100.0% and 82.4%, respectively. The patients with lower (0,1) and higher (≥2) IPI score achieved CR rate and OR rate of 87.88% and 59.18%, and 100.00% and 83.67%, respectively. International prognosis index (IPI) score showed significant impact on both CR and OR rate (P=0.006 and 0.019, respectively). The patients with and without bulky disease achieved CR rate and OR rate of 50.00% and 74.29%, and 83.33% and 91.43%, respectively, and there was no statistical significance (P=0.100 and 0.332, respectively). The patients were followed after achieving objective response (CR+PR) for 2–64 months (median 20 months). Estimated 5 year progress free survival (PFS) rate and estimated 5 year overall survival (OS) rate was 60.33%±6.94% and 75.88%±6.94%, respectively. In DLBCL patients, PFS and OS rate was reached at 56.45%±8.26% and 74.12%±7.48%, respectively. 4 year PFS rate and OS rate of the patients with indolent lymphoma was 86.15%±9.11% and 100%, respectively. IPI score showed significant survival impact on OS and PFS in DLBCL patients, respectively (P=0.0339 and 0.0122, respectively); however, the bulky disease showed impact on PFS but not on OS (P=0.0472 and 0.106, respectively).

Conclusions: The results suggested that the rituximab in combination with chemotherapy regimen in most B cell NHL patient was effective and safe.
Assessing the Predictive Value of Plasma FLT3-L Levels for Hematologic Toxicity after Yttrium-90 Ibritumomab Tiuxetan ([90Y]-Zevalin) Given as Consolidation in Patients with Advanced B-Cell Follicular NHL Responding to First Line Therapy.
Authors: Morschhauser F. , Radford J. , van Hoof A. , Kuss I. , Chlistalla A. , Hagenbeek A.
Published: October 2019

Background: [90Y]-Zevalin is a radiolabeled monoclonal antibody approved for the treatment of relapsed or refractory low-grade follicular or transformed B-cell NHL. Myelosuppression following [90Y]-Zevalin is reversible with nadir counts at 7 to 9 wks after administration of Zevalin and grade 4 thrombocytopenia, neutropenia, and anemia occurring in 10%, 30%, and 3% of patients (pts), respectively. Currently, baseline platelet counts and the degree of bone marrow involvement are the most reliable predictors of hematologic toxicity. Recently, plasma FLT3-L levels have been shown to reflect more accurately bone marrow radiosensitivity to iodine I-131 radioimmunotherapy than peripheral blood counts in patients with solid tumors. The purpose of this analysis was to determine if plasma FLT3-L cytokine levels would help to predict the magnitude of hematologic toxicity after [90Y]-Zevalin treatment.

Methods/Results: In this prospective, multicenter, phase III clinical trial, [90Y]-Zevalin was studied as consolidation therapy (14.8 MBq/kg [0.4 mCi/kg; maximum 32 mCi]) versus no further treatment in 414 patients with advanced follicular-NHL responding to first-line induction therapy with single-agent chlorambucil, CVP, CHOP/CHOP-like regimens, or regimens containing fludarabine or rituximab. Pts were required to have an absolute neutrophil count (ANC) of at least 1500/μL and a platelet count of >150,000/μL. Hematologic toxicity was determined by collecting hematologic data (platelets, ANC, and hemoglobin [Hb]) before therapy and weekly thereafter for 14 wks. Plasma FLT3-L cytokine levels were evaluated in 71 of 208 patients before treatment with [90Y]-Zevalin. FLT3-L levels (pg/mL) were determined by immunoassay with a reference range from 48.3 to 173.8pg/mL. The mean FLT3-L level of all pts was 140.8 (range 49.5 to 300.4). The incidences of grade 3/4 thrombocytopenia, neutropenia, and anemia were 46.5%/8.5%, 40.8%/33.8%, and 8.5%/4.2%, respectively. Severe hematologic events were transient. The FLT3-L levels were not correlated with the nadir of platelets, ANC and Hb per patient during week 1 to 14. The correlation coefficent between FLT3-L and platelets, ANC and Hb was 0.10, −0.25 and −0.18, respectively for all pts. These results do not indicate a relationship between baseline FLT3-L and any of the 3 hematologic parameters.

Conclusions: Baseline FLT3-L levels did not identify pts who are likely to develop a grade 3/4 myelosuppression following [90Y]-Zevalin consolidation therapy. Overall, the incidence and severity of cytopenias were transient, reversible, and comparable to those obtained with [90Y]-Zevalin in relapsed/refractory follicular NHL.
Pomolic Acid-Induced Apoptosis in Cells from Chronic Myeloid Leukemic Patients Is Not Affected by the MDR Phenotype and Status of Disease.
Authors: Vasconcelos Flavia C. , Gattas Cerli R. , Fernandes Janaina , Rumjanek Vivian M.D. , Maia Raquel C.
Published: October 2019

Pomolic acid (PA), isolated from Chrysobalanus icaco, is a pentaciclic triterpene highly effective in inhibiting the growth and promotes cell death in the human chronic myeloid leukemia (CML) K562 cell line. In addition, PA is also very effective in blocking the proliferation of K562-Lucena-1, a vincristine-resistant derivative of K562 that displays multidrug resistance (MDR) phenotype. Due to antiproliferative and antiapoptotic effect of PA on positive and negative MDR leukemic cells, and considering that some patients with CML exhibit resistance to imatinib, the aim of this work was to investigate if PA could have an effective role in induce apoptosis in cells from CML patients. Fourteen peripheral blood samples from CML patients in various stages (three in blastic phase and eleven in chronic phase being one juvenile patient) including previously clinically imatinib resistant patients were studied. Informed consent was obtained according to institutional guidelines. Cells from patients were plated in 96 well tissue culture plates for 24h and then treated with two different concentrations of PA: 12.5 μg/ml and 25 μg/ml. Drug-induced apoptosis was evaluated by annexin V/propidium iodide assessed by fluorescence-activated cell-sorting (FACS). Functional MDR phenotype was performed by measuring the fluorescent dye rhodamine-123 efflux in the presence or absence of the MDR blocker cyclosporin A. These experiments were analysed by FACS. Functional activity of MDR was observed in 9 out of 14 samples and it was independent of CML stage. Using 12.5 μg/ml and 25μg/ml concentrations, the apoptotic effect of PA ranged from 10.5 to 53.1 (median: 31.5) and 14.7 to 65.9 (median: 42.2), respectively. These results were also independent of CML stage being even effective in blastic phase and in juvenile CML, which have a clinically aggressive course. Our data demonstrate that PA is a potent anti-leukemic agent not only for MDR positive CML patients but also especially for the blastic phase in the setting of imatinib resistance.
Increased Expression of the Nitric Oxide Synthase (iNOS) in the Bone Marrow of Myelodysplasia (MDS) Patients.
Authors: Shami Paul J. , Elenitoba-Johnson Kojo S.J.
Published: October 2019

MDS constitutes a set of heterogeneous hematopoietic stem cell diseases that are manifested by cytopenias in spite of a cellular bone marrow. MDS carries an increased risk of acute myeloid leukemia (AML). Data suggest that overproduction of inflammatory cytokines in the marrow plays a role in the cytopenias of MDS. Nitric oxide (NO) has important functions in the immune system. Inflammatory cytokines trigger the expression of the inducible nitric oxide synthase (iNOS) and NO production. NO inhibits bone marrow progenitor cell growth and induces DNA mutations. Consequently, NO could play a role in the pathophysiology of MDS. We have evaluated iNOS expression in the bone marrow of MDS patients. Archival bone marrow biopsy samples from 10 MDS patients were compared to 10 normal bone marrow biopsies. The distribution by cases according to the FAB classification was 4 RA, 2 RARS, 3 RAEB, and 1 RAEB-T (Table). Immunohistochemical studies for human iNOS expression were performed using a polyclonal rabbit antibody. A sample was considered positive for iNOS expression when 10% or more cells were positive. Using this criterion, 7/10 MDS samples expressed iNOS while none of the normal bone marrows did (Table). iNOS expression was found exclusively in the myeloid lineage cells. Overexpression of iNOS in the bone marrow of MDS patients could lead to local overproduction of NO and therefore contribute to the ineffective hematopoiesis and cytopenias seen in early MDS. Chronic exposure to high levels of NO could enhance the risk of evolution to AML. iNOS could therefore constitute a new therapeutic target for MDS.

iNOS expression in MDS and normal bone marrows Diagnosis (FAB) Number of samples Number iNOS positive RA 4 3 RARS 2 1 RAEB 3 2 RAEB-T 1 1 Total MDS 10 7 Normal bone marrow 10 0
Selective Inhibition of I kappaB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing c-FLIP Level.
Authors: Roué Gaël , Pérez-Galán Patricia , López-Guerra Mónica , Villamor Neus , Campo Elias , Colomer Dolors
Published: October 2019

Mantle cell lymphoma (MCL) is an aggressive B lymphoid neoplasm with a mature B-cell phenotype and genetically characterized by the t(11;14)(q13;q32) leading to cyclin D1 overexpression with the consequent deregulation of cell cycle at the G1-S checkpoint. MCL cells also present a constitutive activation of the NF-kappaB pathway which leads to the overexpression of several anti-apoptotic regulators. We have analyzed sensitivity to the extrinsic apoptotic signal triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on six human MCL cell lines and primary cells from 10 MCL patients, which differ in their p53-dependent pathway status, growth characteristics and sensitivity to cytotoxic drugs. TRAIL has been shown to exert in vivo a selective anti-tumor activity with minimal toxicity on normal cells. We observed that TRAIL was able to trigger apoptosis in a majority of MCL cell lines and primary MCL tumor cells, while sparing normal peripheral B cells. TRAIL-induced cell death was characterized by a time- and dose-dependent loss of membrane potential, Bax and Bak activation, caspase activation and phophatidylserine exposure. MCL sensitivity to TRAIL was irrespective of TRAIL-R1 and TRAIL-R2 receptor levels, Bcl-2 family members or caspase regulators expression, but was closely linked to the activity of the NF-kappaB p50 factor and to the expression of c-FLIP, a NF-kappaB-regulated factor. C-FLIP accumulated into the TRAIL-dependent complex in resistant cells and its transient knockdown overcame MCL resistance to TRAIL. In parallel, NF-kappaB inhibitors differentially modulated TRAIL cytotoxicity. Indeed, sub-toxic doses of bortezomib increased TRAIL cytotoxic effects by up-regulating TRAIL-R2 receptor expression, but also led to the intracellular accumulation of c-FLIP, impeding full synergistic interaction in cells with highest c-FLIP basal level. In contrast, the IkappaB kinase (IKK) inhibitor BMS-354451 allowed to consistent reduction of NF-kappaB activity, decreased total and DISC-associated c-FLIP levels, and sensitized all MCL cells to TRAIL cytotoxic effects. These results indicate that pharmacological enhancement of MCL cells sensitivity to TRAIL does not depend on TRAIL receptors level but is rather regulated by NF-kappaB-regulated c-FLIP expression. Considering that both TRAIL and BMS-345541 have already demonstrated selective cytotoxicity against malignant cells, combining TRAIL, with pharmacological inhibitors of IkappaB kinase signaling may represent an attractive model for the design of a new and rational combination therapy for MCL.