bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Assessment of Inflammatory Cytokines and Symptom Severity during 100 Days of Allogeneic BMT for AML/MDS Patients.
Authors: Wang Xin S. , Cleeland Charles S. , Williams Lori , Reuben James , Lee Bang-Ning , Mobley Gary , Giralt Sergio
Published: October 2019

BMT patients develop multiple symptoms At nadir after transplantation that include pain, fatigue, poor appetite, and disturbed sleep. Animal models of sickness behavior suggest such symptoms may be related to increases in inflammatory cytokines. The objective of this study was to prospectively assess the relationship between symptom severity and changes in inflammatory cytokines.

Methods: Weekly symptom assessment with the M. D. Anderson Symptom Inventory was done for 30 AML/MDS patients during the first 100 days of Allo-BMT. A panel of inflammatory cytokines (IL-1ra, IL-6, IL-8, IL-10, IL-12, TNF-a) was assayed at several time points: pre BMT, conditioning, BMT day, BMT Day1, nadir, BMT day14, 21, 28, 60, 90–100.

Results: Multiple symptoms peaked at nadir, with some symptoms (fatigue and pain) remaining at high levels after nadir. Figure 1 shows the Lowess curves for selected symptoms on MDASI. Physical symptoms had much larger fluctuation than affective symptoms during the study. Figure 2 presents Lowess curves of the serum levels of cytokines (log base 10). IL-6 and IL-8 showed significant increase during nadir, significantly correlating with fatigue, lack of appetite, drowsiness, dry month, and feeling physically sick (all P<.01).

Conclusion: There is an observed relationship between increased symptom severity levels and increased inflammatory cytokine (mainly IL-6 and IL-8) levels during the acute phase of allo-BMT in AML/MDS patients. The question of a causal link between cytokine levels and symptom severity requires further study.

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Gemtuzumab Ozogamicin Combined with Hyper-CVAD in Relapsed Refractory CD33-Positive Acute Lymphoblastic Leukemia.
Authors: Stromberg Olga , Stenke Leif , Bernell Per
Published: October 2019

Adult patients with relapsed or refractory ALL have a dismal clinical prognosis. The CD33 antigen is expressed on leukemic cells of approx 30% of all ALL cases. For such patients, a combination of an anti-CD33 MoAb with chemotherapy may provide an effective therapeutic option, although clinical data are yet scarce. Here we describe our experience using gemtuzumab ozogamicin (Mylotarg), an anti-CD33 antibody linked to calicheamycin, combined with cytostatics as reinduction chemotherapy for two relapsed, refractory CD33-pos ALL patients.

Case 1. A male 32 yr old patient diagnosed with pre-B-ALL in April 2004. He showed no poor-risk criteria at diagnosis but needed two induction courses to enter complete remission (CR). After having received two cycles of consolidation therapy and a maintenance treatment he relapsed in October 2004. He then failed to respond to reinduction chemotherapy with RIEHM AA (Holoxan, Oncovin, Emthexat, Betamethason, Cytarabine, Etoposid) and MEA-Asp (Novantrone, Cytarabine, Etoposid, Asparaginase). As a 3rd reinduction option he was given “hyper-CVAD” (Cyklofosfamid, Oncovin, Doxorubicin, Dexamethason) combined with Mylotarg (6mg/sqm on day 10). The patient then achieved a full CR on day 28 and was scheduled for a subsequent allogeneic transplantation with an unrelated donor. However, due to an extended toxic colitis he was unable to receive consolidation treatment and again relapsed on day 36 after CR. Shortly thereafter the patient died in a septic shock.

Case 2. A 19 yr old female patient was diagnosed with pre-B-ALL without poor-risk criteria in November 2001. After standard induction therapy she achieved CR and received maintenance treatment until May 2002. In May 2003 bone marrow relapse occurred, but she entered a 2nd CR after reinduction chemotherapy and successfully underwent an allogeneic stem cell transplantation from a matched unrelated donor in September 2003. A second relapse occurred in January 2004. The patient then received reinduction with hyper-CVAD combined with Mylotarg, as described above. This resulted in a 3rd CR. Subsequently she received an identical consolidation course followed by DLI in March 2004. She remained in CR until February 2005 when she again relapsed and died in respiratory insufficiency.

Conclusion. The combination of gemtuzumab ozagamicin and hyper-CVAD may provide a logical, feasible and possibly effective therapeutic option for relapsed and refractory CD33-pos ALL patients.
Clinical and Laboratory Study of CAG Regimen in Treating AML Subtypes Hard To Cure.
Authors: Xu Jianmin , Ji Lili
Published: October 2019

Background and objective: Relapse AML, refractory AML, AML in the old and secondary AML are all AML subtypes hard to cure. They characterize in insensitive to chemotherapy agents, short duration of CR(complete remission), easy to relapse.Yamada et al brought forward CAG regimen, which has been proven effective in treating AML subtypes hard to cure. This regimen can treat these AML subtypes with the CR rate at 62%–86%, media survival of 8–17 months. The adverse reaction of CAG regimen is more moderate than that of standard chemotherapy or salvage therapy. Patients’ life quality gets better when they are treated with CAG regimen. The rationale of CAG regimen is as follows:

G-CSF receptors have been reported to be expressed in blastic cells in almost all the patients with AML; CFU-AML can be killed preferentially by prolonged exposure to low dosage of Ara-c in the presence of G-CSF with relative preservation of normal CFU - GM; G-CSF focuses on the precursor of myeloid lineage, the upstream cells are effected slightly; the Acla-mediated cytotoxicity of CFU-AML, which is effective in treating MDR cells, is reported to be enhanced by short-term combination with G-CSF.

There have been few reports published on the mechanism of CAG regimen, especially on the study in vivo. Our study aims to know the process of the CAG regimen functions in vivo by study of clinical use and series of tests.

Methods: Observe the outcome,change of CBC and BM, adverse reaction of 11 AML patients treated with CAG regimen from Jan. 2003 to Apr. 2005. We enrolled 4 patients treated by CAG regimen as study group, 2 patients treated by DA regimen as control group. Mononuclear cells were isolated from heparinized bone marrow samples by Ficoll-Hypaque centrifugation to be conducted morphological observation, livability test, apoptosis index measurement on FCM(PI and Annexin V stain), and clonal culture.

Results:

CAG regimen treats AML by means of inducing AML blastic cells synchronous apoptosis, having little effect on normal myeloid cells. We treat 11 patients of AML subtypes hard to cure with CAG regimen from Jan. 2003 to Apr. 2005. CR rate is 27.27%, OR rate is 72.73%. The adverse reaction is moderate. Given the CAG regimen, the count of peripheral WBC rises at first, decreases to the lowest level afterward, then recovers at last. The peak count of WBC of 3 CR cases occurs later than that of other patients, at d4 or d7. While that of NR patients occurs at d2. Ara-c and Acla-mediated cytotoxity on normal myeloid cells and megakaryocyte can be alleviated by G-CSF, thus CAG has little influence on the productivity of myeloid precursors.

CFU-AML can be killed preferentially by CAG regimen in the presence of G-CSF.

Conclusion: CAG regimen treats AML by means of inducing apoptosis with better prognosis and more moderate adverse reaction. We hypothesize that CAG regimen recruits S phase cells and kills them by inducing apoptosis.
Outcome after Relapse in Childhood Acute Lymphoblastic Leukaemia - Results of a Single Center for a Period of 15 Years.
Authors: Celkan Tiraje , Karaman Serap , Ozkan Alp , Apak Hilmi , Canpolat Aylin , Yildiz Inci
Published: October 2019

Approximately 25–30 % of children newly diagnosed with acute lymphoblastic leukemia (ALL) will eventually experience leukemic relapse. Bone marrow is the most common site of recurrence. Usually achieving a durable second remission is complicated by toxicity and resistance of the disease. Here we documented our patients in order to see the prognosis of relapsed pediatric ALL cases.

RESULTS. From August 1990 to August 2005 children diagnosed with ALL and treated with BFM based protocols in Cerrahpasa Medical Faculty Pediatric Hematology-Oncology Department were enrolled to this study. There were 225 children aged median 6 years( 3 months–18 years) (136 boys/89 girls), 28 % SR, 50 % MR, 22 % HR. The whole group EFS is 72,6 % and RFI 81,8 %. Twenty-nine (12,8 %) patients were relapsed. Bone marrow recurrences were isolated in 19 patients, and combined with an extramedullary site in 8 patients (4 CNS, 2 testis, 1 retinal,1 dermal). Only two patients had isolated extramedullary site (testis) relapse. The median time to recurrence was 23 months (range 4–128 months). Five patients refused a secondary treatment. Of 24 chemotherapy given patients, 6 patients were lost just after induction therapy due to toxicity before a reliable remission evaluation was done. In three early relapses a second remission could not be attained. Twenty-one patients (72.4 %) achieved a second remission (median length, 4 months; range, 1–114 months)( mean16 ± 80 months). The 5-year survival probability among all patients was 27.2 % ± 8.2 %. Of 8 surviving patients, 3 are in remission more than 5 years, 3 are in remission 2–5 years of period and only 2 less than 1 year. One patient who relapsed for second time is in 3th remission for 65 months period. Bone marrow transplantation was the done for only 3 patients, one is very newly done, the other two relapsed after engrafmant and were lost.

CONCLUSIONS. Despite acceptable long-term second EFS rates for a minor group of patients, childhood ALL recurrences signal a poor outcome being the problem of childhood ALL therapy.
Efficacy and Safety of Fludarabine Combined with Cytarabine in the Treatment of Patients with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL).
Authors: Jiang Bin , Wang Wei , Bao Li , Huang Xiaojun , Lu Jin , Wang Debing , Lu Daopei
Published: October 2019

Objective: The objective of this study was to evaluate the efficacy and safety of fludarabine (Flu) combined with cytarabine (Ara-c) in the treatment of relapsed and refractory ALL.

Methods: From March 2003 to February 2005, 28 patients in our institution with adult relapsed and refractory acute lymphoblastic leukemia were treated with Flu and Ara-c chemotherapy. The median age of patients was 28 years (range, 11–64 years). Twenty-four patients were treated with Flu IV Ara-c: Flu (30 mg/m2/day as a 30 minute infusion IV dl-4) and Ara-c (1000 mg/m2 ql2h, 6–10 times IV). The Ara-c infusions commenced 4 hours after the fludarabine infusion. Four patients were treated with following regimen: Flu (30 mg/m2/day as a 30 minute infusion IV dl-4), Ara-c (100 mg/day q12h 6–10 times), and mitoxantrone (4 mg/d dl~4 IV).

Results: Efficacy: The overall response rate was 48.1%. Ten of the 27 ALL patients achieved a CR (37%), and 3 patients achieved a PR (11.1%). Median CR duration was 8 months (ranges, 2–34 months). Among 14 Ph- ALL patients, 4 achieved a CR (28.6%); of 8 Ph+ ALL patients, 5 (62.5%) achieved a CR, 2 achieved a PR, and 1 was NR. Among 5 patients with T-ALL, only 1 achieved a CR. The patients with acute mixed lineage leukemia achieved a CR. Among 19 patients with full immunophenotyping data, there were 3 CRs, 1 PR in the 5 ALL patients with myeloid antigens (My+), and 3 CR and 2 PR in 14 ALL patients without myeloid antigens (My−). Four Ph+ My+ ALL patients achieved a CR. Safety: Flu combined with Ara-c resulted in myelosuppression in all patients, 27 patients had WBC <1′109/L, and the median time to WBC <1′109/L was 11 days (range, 5–27 days). The lowest PMN emerged 9 days (range, 3–18 days) after the regimen commenced. Twenty-five patients had PLT <20′109/L, and the median duration was 8 days (range, 1–30 days). The lowest PLT count occurred 11 days (range, 3–18 days) after the regimen commenced. Sixteen patients had pyrexia with 8 definite pathogenic bacterium, 3 bacterial infections, 1 CMV infection, 2 fungal infections, and 2 multiplicity of infection. The major nonhematologic toxicity was gastrointestinal symptoms (35.7%, 10/28), such as nausea, vomiting, diarrhea, anorexia (i.e. WHO grade 1 or 2), and the symptoms disappeared soon after the regimen completed.

Conclusion: Favorable efficacy and safety were obtained in relapsed and refractory ALL patients treated with Flu and Ara-c, especially in Ph+ ALL and My+ ALL patients. In the future, larger studies are warranted to evaluate the efficacy and safety of Flu and Ara-c.
Acute Leukemia in Patients Sixty Years of Age and Older: A Retrospective Review.
Authors: Leger Chantal S. , Lee Ann , Leitch Heather A. , Galbraith Paul F. , Li Charles H. , Vickars Linda M.
Published: October 2019

Acute leukemia, especially acute myeloid leukemia (AML), occurs more frequently in the elderly population. Treatment outcomes for this condition have traditionally been poor and very few patients survive for prolonged periods following diagnosis. We performed a retrospective chart review of all patients sixty years of age and older diagnosed with acute leukemia at St. Paul’s hospital, Vancouver, Canada, from June 1984 to July 2004. One hundred and three patients were diagnosed with acute leukemia [AML- 81; ALL- 15; ALN (acute leukemia not otherwise specified)- 7]. The median age was 72 (range 60–88) years. Fifty-seven (55%) and 46 (45%) patients had de novo and secondary leukemia, respectively. Sixteen patients (28%) had an unfavourable karyotype. Fifty-three patients (51%) received induction chemotherapy (treated) and 50 (49%) were provided with supportive care only (untreated). Treated patients were younger [67 years (60–79)] than untreated patients [76 years (61–88)], (p<0.0001), and no patients >/= 80 years were treated (n=17). Of the treated patients, 33 (62%) achieved a complete remission (CR), 10 (19%) had resistant disease and 10 (19%) died from complications related to treatment. The median overall survival for the entire group was 103 (1–1229) days, and for treated versus untreated patients was 216 (1–1213) and 38 (2–1229) days, respectively (p=0.0021). The disease free survival in treated patients achieving a CR (n=33) was 262 days (9–722). Less than 5% of patients were alive at 4 years from diagnosis. Univariate variables predictive of prolonged survival included receiving induction chemotherapy (p=0.0027), de novo as opposed to secondary leukemia (p=0.0420), and younger age, with a relative increase in death in older subgroups (60–69, 70–79, 80+), (p=0.0311). Induction chemotherapy was the only independent predictor of prolonged survival in multivariate analysis (p=0.0027). There was no statistically significant difference in the number of treated patients and treatment outcomes between 1984–1993 and 1994–2004. In conclusion, this single-institution series of 103 patients aged sixty years and older with acute leukemia, shows that the prognosis of this disease in older patients is extremely poor. Even though induction chemotherapy seems to prolong survival in patients who are fit to receive treatment, the prognosis remains grim and most patients ultimately die of leukemia, supporting a role for investigational regimens focusing solely on this age group. It is no longer appropriate to follow regimens that have remained largely unsuccessful and unchanged over 20 years.
Transgene Deletions in Long-Term Circulating Donor Gene-Modified T Lymphocytes Infused at Time of Hematopoietic Transplantation.
Authors: Mercier Patricia , Deschamps Marina , Ferrand Christophe , Robinet Eric , Certoux Jean-Marie , Sauce Delphine , Lioure Bruno , Deconinck Eric , Tiberghien Pierre
Published: October 2019

A phase I/II trial of Herpes-Simplex Virus-thymidine kinase (HSV-tk)-expressing gene modified T cells (GMTC) administration at time of HLA-identical sibling bone marrow transplantation (BMT) demonstrated that such an approach could modulate deleterious alloreactivity after BMT (Tiberghien et al., Blood 2001). The Neomycin resistance gene (NeoR) was transferred together with the HSV-tk gene in a retroviral vector to allow for in vitro GMTC selection. More than 6 years after BMT, 4 patients are alive in complete remission, off immunosuppression, free of chronic graft-versus-host disease (GvHD). Long-term circulating GMTC are continuously found in all 4 patients, as assessed by quantitative PCR (QPCR) for NeoR gene (6 years post-BMT: 0.031 +/- 0.017% of PBMC). Unexpectedly, presence of NeoR gene was readily detected by single run PCR whereas a nested PCR was necessary for HSV-tk gene detection. As PCR assays for both genes have a similar sensitivity, this result suggested that deletions may be present in GMTC. For each patient, PBMC were polyclonally activated and expanded before a one week G418-mediated selection. The % of GMTC in the post-selection samples, as assessed of NeoR QPCR, was > 80% in 3 patients while of only 7% in the last patient, thus demonstrating long-term NeoR transgene expression in at least a fraction of circulating GMTC more than 6 years after BMT. Successfully re-selected GMTC were cloned. As expected, most clones (25 out of 26) were found to be NeoR by PCR. In contrast, only 2/26 were HSV-tk+: one clone contained the full length HSV-tk gene while the second contained the ganciclovir (GCV)-resistant truncated form of the HSV-tk gene (Garin et al., Blood 2001). Clones generated from freshly produced-GMTC were found to be both NeoR+ and HSV-tk+ thus demonstrating that such gene deletions did not occur with a significant frequency during the GMTC production nor during the cloning process. We have previously established that an immune response against GMTC occurred in most patients (Mercier et al., ASH 2004). Immune responses were found against both transgenes and predominantly so against HSV-tk. Immuno-selection of initially rare GMTC containing a deleted transgene without expression of immunogenic peptides might significantly contribute to the high proportion of long-term circulating GMTC containing mutated HSV-tk genes. Such deletions within the transgenes most likely explain the coexistence of an immune response against the transgenes and persistent circulating GMTC. Nevertheless, GCV-sensitivity of circulating GMTC and more importantly so, of GvHD during the first 4 months after BMT suggests that the high frequency of the mutated GMTC occurred late enough after BMT to not interfere with GCV-mediated control of GvHD.
Elderly Acute Myeloid Leukemia: A Retrospective Analysis of 89 Cases in China.
Authors: Lu Zesheng , Du Xin , Long Yi , Weng Jianyu , Lin Wei , Huang Zilun
Published: October 2019

Although acute myeloid leukemia (AML) is generally responsive to chemotherapy, most patients with this disease are older than 60 years and have relatively resistant neoplasms. AML in the older patient is distinctive, both biologically and clinically, from that occurring in patients younger than 60. The intrinsic resistance of AML in the older patient is exemplified by the higher incidence of chromosomal abnormalities. Furthermore, blasts obtained in elderly patients with AML are more likely to express proteins that mediate multidrug resistance, such as the p-glycoprotein encoded by the MDR1 gene. A combination of an anthracycline and a cytarabine is the most commonly used induction regimen in acute myeloid leukemia (AML), but most of Chinese older adults with AML didn’t agree with the standard doses of induction therapy. The study is to analysis the attenuated therapy for Chinese older adults. 89cases of newly diagnosed aged over 60 were observed from February 2000 to July 2005, including 50 male and 39 female, media age is 68yr. Patients were accepted attenuated therapy, either mitoxantrone per day on days 1, 2(MA);35 mg/m2 pirarubicin(TA) 7–8mg/m2 idarubicin per day on days 1, 2 (IA). Each patient was given 100mg/m2 cytarabine intravenously per day for 7 days. Total CR rate was 34% after 2 regimens, 2 years survival rate was 12.5%. The CR and 2-year survival rates of acute leukemia in Chinese elderly AML were low. Physicians should be encouraged to offer standard doses of induction therapy.
Phase I Study of Gemcitabine, Fludarabine and Mitoxantrone for Relapsed or Refractory Leukemia.
Authors: Misra Debashish , Moore Joseph O. , Gockerman Jon P. , Diehl Louis , de Castro Carlos , Yang Yiping , Gasparetto Cristina , Abernathy Amy , Horwitz Mitchell , Long Gwynn D. , Chute John , Peterson Bercedis , Chao Nelson J. , Rizzieri David A.
Published: October 2019

Purpose: To estimate the maximum tolerated duration (MTD) of gemcitabine given as a continuous infusion in combination with fludarabine and mitoxantrone for patients with relapsed or refractory leukemia.

Patients and Methods: Patients received gemcitabine at 10mg/m2/min (day 1) with fludarabine at 25mg/m2/day for 5 days (days 1–5) and mitoxantrone at 10mg/m2/day for 3 days (days 1–3). The duration of gemcitabine infusion was escalated using the modified continuous assessment method (mCRM) at 3 hour increments (3, 6, 9, 12, and 15 hours). This three-drug regimen was build upon our previous studies with fludarabine, mitoxantrone and continuous infusion gemcitabine (Blood2003;102:250b Abstract). The MTD was estimated as the duration of gemcitabine infusion in combination with fludarabine and mitoxantrone at which 33% of the patients would experience a dose limiting toxicity (DLT). DLT was defined as either neutropenia for more than 28 days with less than 5% blasts in the marrow, a non-hematologic grade 4 toxicity lasting ≥ 3 days, or a non-hematologic grade 3 toxicity lasting ≥ 7 days.

Results: Ten patients with relapsed or refractory leukemia have been treated so far since Aug 2004 and fully evaluated. The median age was 55 years (range 30 – 67). The median number of prior regimens was 3 (range 1 – 5) and the median range of prior cycles was 4 (range 1 – 6). As expected, hematologic toxicity, mucositis and nausea were common but did not meet criteria for DLT in any patient. One patient had parainfluenza lung infection with alveolar hemorrhage and this was the only DLT on the study. 2/10 patients achieved CR. Both patients are alive, 20 weeks and 52 weeks later, respectively but have received further therapy in the form of chemotherapy or allogeneic stem cell transplantation.

Toxicity by Duration of Gemcitabine Infusion Duration of Infusion (hrs) # of Patients with DLT/Total Probability of Toxicity at this Dose Probability that Dose is MTD 3 0/1 0.001 0.0 6 0/2 0.009 0.005 9 0/3 0.1 0.22 12 1/4 0.36 0.59 15 0/0 0.6 0.18

Conclusion: Only one patient on this study had a DLT. This combination therapy is myelotoxic and has some anti-leukemia activity with 2/10 patients achieving CR. The duration of gemcitabine infusion as part of the above three drug regimen will be studied further on this ongoing study to more accurately estimate the MTD and determine if phase II trials are warranted.
Phenolhexyl Isothiocyanate, a New Histone Deacetylase Inhibitor, Can Prevent Tumor Formation and Inhibit Leukemia Cell Growth In Vivo.
Authors: Lu Lulu , Ma Xudong , Becklemisheva A. , Chaio J.W. , Liu Delong
Published: October 2019

We have demonstrated that phenolhexyl isothiocyanate (PHI) induces growth arrest and apoptosis in leukemia cells HL-60 through inhibition of the activity of histone deacetylases (HDAC), the enhancement of histone acetylation and activation of p21. In this study, we examined the effects of PHI on the growth of HL-60 leukemic xenograft in immunodeficient mice. The PHI was given to the mice by gavage. The maximum tolerated dose by the mice was determined following standard design. To determine the in vivo effect of PHI on leukemia growth, a sub-MTD dose was given to the control and the treatment groups with 17 mice in each group after injection of 1.0 x 10e6 HL-60 cells per mouse. There was a significant reduction in the incidence of tumor formation (94.1% control group vs 58.5% PHI group, p=0.004). In addition, there was also a significant difference in the tumor size between the two groups. Determined at autopsy, the mean weight of control tumors was 0.8 g vs. the tumors of the experimental group 0.35g, revealing a significant reduction of 44.4% (P<0.03). There were no detectable toxicity as evaluated by body and organ weight, and necropsy examination. The histology of the tumor showed increased apoptotic cell death. Apoptosis in the tumors was further confirmed by the cleavage of poly ADP-ribose polymerase (PARP), the target of proteolysis of caspases that execute apoptosis with Western blot analyses. The results suggest that PHI can prevent tumor formation and inhibit leukemia cell growth in vivo without significant toxicity that is routinely associated with conventional chemotherapeutic agents.
FLAG-(IDA)-Mylotarg in the Therapy of Relapsed and Refractory Acute Myeloid Leukemia.
Authors: Fabbiano Francesco , Mondello Francesca , Magrin Silvana , Felice Rosaria , Marino Carla , Turri Diamante , Mirto Salvatore
Published: October 2019

Patients with relapsed and refractory AML have a bad prognosis. In this setting it is often difficult to obtain a complete remission. In the last few years fludarabine and high dose Citarabine with or without Idarubicine and G-CSF have been frequently used (FLAG and FLAG-IDA schedules). The immunotoxin gemtuzumab ozogamicin (Mylotarg)(GO) Wyeth is a humanized IgG4 monoclonal antibody directed against the CD33 epitope, which is chemically linked to calicheamicin, a highly potent antitumor antibiotic. As a single agent it has been shown to be an effective agent in the treatment of relapsed AML with a tolerable toxicity profile. Recently the United Kingdom Medical Research Council (MRC) published the preliminary results of AML15 trial, which was designed to evaluate the effect of adding GO to each course of intensive induction or consolidation chemotherapy in patients younger than 60 years as first-line treatment. These results are encouraging. We are using this association in the treatment of relapsed and refractory adult AML. Until now 10 patients have been enrolled in this trial and we show our preliminary results.

Patients and methods. 3 patients were resistant to induction; 3 patients were in the first relapse and 1 in the third after conventional chemotherapy, 1 was relapsed after autologous transplant and 2 were relapsed after allogeneic transplantation. The demography and characteristics are shown in the table. 8 Pts were treated with Fludarabine 30 mg/sqm dd 1–5, Citarabine 2,0 gr/sqm dd 1–5, Idarubicine 10 mg/sqm dd 3–5, Mylotarg 3 mg/sqm d −1, G-CSF 375 mg dd 1–6. 2 patients with the same schedule without Idarubicine.

Results: 6 patients obtained Complete Remission, 2 died after therapy and 2 were resistant to this schedule.Out of the 6 patients in CR 4 are in continuous complete remission at 3, 3, 8 and 11 months Three of these underwent allogeneic BMT with no significant toxicity and are actually in CR.. Two relapsed at 3 and 7 months. In our experience the toxicity of FLAG-(IDA)-GO schedule is acceptable and the results are promising in refractory and relapsed AML.

pts age years disease status treat.response further therapies outcome 1 46 resistant CR BMT CR +11 M 2 52 resistant resistant -- died 3 69 1 th relapse CR -- relapse 7 M 4 65 3th relapse died -- 5 57 relapse after auBMT died -- 6 58 relapse after BMT resistant -- died 7 28 relapse after BMT CR 2nd BMT CR +6 M 8 42 1th relapse CR BMT CR +3 M 9 74 1th relapse CR -- CR +4 M 10 64 resistant CR __ relapse 3 M
High Rates of Epstein Barr Virus Expression in Hodgkin’s Lymphoma in Lebanese Children.
Authors: Abboud Miguel R. , Muwakkit Samar , Kattar Mireille , Khoury Ruby , Zaatari Ghazi , Razzouk Bassem
Published: October 2019

Introduction: Hodgkin’s disease (HD) accounts for around 6% of all cancers in Lebanese children ≤ 15 years of age. HD shows wide geographic variation in its association with EBV virus. The prognostic significance of Latent EBV infection in HD is still controversial

Purpose: To examine EBV (LMP-1) positivity in pediatric patients treated for HL at the American University of Beirut-Medical Center and the Children’s Cancer Center of Lebanon and its association with age, sex, histologic subtype and treatment outcome.

Methods: The charts of all pediatric patients treated for Hodgkin’s Lymphoma at the American University of Beirut Medical Center between 1980 and 1996, and at the Children’s Cancer Center of Lebanon from 2002 to 2005 were reviewed. Their paraffin blocks were studied for Epstein-Barr virus association by latent membrane protein-1 (LMP-1) immunohistochemistry.

Results: The charts of 34 patients with HD were reviewed. The median age was 7.5 years (range: 2–16 yrs); only 4 patients were above 13 years of age. The M: F ratio was 4.6:1, and the mean follow-up was 4.5 yrs (range 4 months −12y). 6 had stage I, 10 had stage II, 15 had stage III (5 patients IIIA and 10 patients IIIB disease), and 3 had stage IVA disease. 53% had advanced stage disease. 16 patients (47%) had mixed cellularity histologic subtype, 15 patients (44%) had nodular sclerosis subtype, and 3 patients had the lymphocyte predominance subtype. All nine patients who were tested for EBV- IgG were positive. Twenty-three patients were studied for the LMP-1 and 17 (74%) tested positive. These 17 patients make up 89% of the children under 13 years of age who were tested. LMP-1 positivity was associated with young age (≤13 yrs 100%), MC subtype (14 patients; 82.4%) and male sex (16 patients; 94%). Four patients with stage IIIB relapsed. Their treatment consisted of 6–9 cycles of COPP or COPP alternating with ABVD. Three of the relapsed patients were LMP-1 positive and had the MC subtype. Two patients had siblings who had HD; one of them who later relapsed was positive for LMP-1, had the MC subtype, and both he and his brother had immune deficiency and lymphoproliferative disorder.

Conclusions: Our findings show a high prevalance of EBV expression in HD in Lebanese children. These rates are higher than those reported from other neighboring countries and much higher than those of North American and European countries. This may be related to earlier in life infection with EBV. LMP-1 positivity in Lebanese children was associated with younger age, male sex and mixed cellularity subtype. The impact of LMP-1 on treatment outcome remains to be determined.
Pericardial Involvement in Newly Diagnosed Children and Adolescents with Pediatric Hodgkin’s Disease at a Single Children’s Cancer Hospital.
Authors: Bashir Hamid , Metzger Monika , Krasin Matt , Kaste Sue , Howard Scott , Hudson Melissa M.
Published: October 2019

Background: Because most cases are clinically silent, incidence, clinical course and outcome of pericardial involvement in Hodgkin disease are unknown.

Methods: Records of all 274 newly diagnosed Hodgkin disease patients treated at our institution between 1991 and 2004 were reviewed. Cases were selected on the basis of pericardial involvement with focal thickening or nodularity at the time of presentation identified by CT and/or pericardial effusion on echocardiogram. Variables noted, in addition to basic demographic data, were stage, histologic subtype, clinical presentation, treatment, serial EKG, echocardiography and CT findings, and resolution versus progression of disease. Statistical analysis was performed using SAS version 9.1.

Results: The incidence of pericardial involvement in our cohort was 5% (13 of 274 patients). Patient characteristics (age, sex, and race), stage of disease and presence of B-symptoms were equally distributed among affected and unaffected individuals. All 13 cases were nodular sclerosing histology (p=0.02) and 9 (67%) had a bulky mediastinal mass (p=0.002). Of the 13 patients, five had extension into the pericardium by CT, two of which also had pericardial effusion (one large and one massive). Eight patients had only pericardial effusions (trace to large) without other CT findings. Two patients required pericardiocentesis for symptomatic effusions and one underwent pericardial drainage procedure for impending tamponade. Two of the 13 patients relapsed but were successfully salvaged and all remain alive and free of disease at a median follow up of 8.7 years (range, 1.1–11.9 years) and 6.3 years (range 0.4–12.7 years) for patients without pericardial involvement.

Conclusions: In our experience, secondary pericardial involvement due to lymphoma is largely asymptomatic unless accompanied by significant effusion. Most of these resolve with treatment of underlying malignancy but require watchful observation for hemodynamic complications. Once treated for symptomatic effusion, there is no difference in mortality amongst various groups.

Figure Figure
Quality of Life (QoL) Impairment and International Prognostic Index (IPI) in New Aggressive Non-Hodgkin’s Lymphoma (ANHL) Patients.
Authors: Novik Andrei A. , Ionova Tatiana I. , Kishtovich Anton V. , Myasnikov Alexander A. , Chagorova Tatiana V. , Kopp Mikhail V. , Osipova Nina E. , Lebedeva Julia K. , Malakchova Natalia N. , Pankova Anastasia V. , Fedorenko Denis A. , Gorodokin Gary I.
Published: October 2019

The population of new ANHL patients is heterogeneous in terms of their biological parameters and the IPI scoring system is widely used to make the disease prognosis. Recently heterogeneity of ANHL patients in terms of their QoL has been shown. There are four groups of patients with the following grades of QoL impairment: none, mild, significant, and critical impairment. We aimed to study the distribution of new ANHL patients according to the grades of QoL impairment and to identify the relationship between the QoL impairment groups and the IPI groups.

73 new aggressive NHL lymphoma patients (Stage IIB-IV, mean age 55.2 SD=17.6, males/females – 39/34) were involved in this study. QoL assessment was conducted before treatment using SF-36. The method of integral profiles was used to calculate the integral QoL index (IQLI). Patients were stratified using IQLI. Gamma correlation between ranges of QoL impairment groups and IPI groups was used.

The following distribution of ANHL patients was demonstrated on the basis of different grades of QoL impairment: 9% - no impairment (IQLI - 0.6); 12% - mild impairment (0.3); 24% - significant impairment (0.13); 55% - critical impairment (0.02). The distribution of patients in these groups who were classified as high-intermediate or high risk according to the IPI was 28%, 67%, 83%, and 90%, respectively. High correlation between ranges of QoL impairment groups and IPI groups was observed: Gamma correlation – 0.6 (p<0.05).

In conclusion, aggressive NHL patients are heterogeneous in terms of their QoL. The majority of patients exhibit significant or critical QoL impairment. The higher the grade of QoL impairment, the higher the risk according to the IPI. Stratification of aggressive NHL patients based on IQLI along with the traditional IPI stratification could contribute to the improvement of the prognostic model for this heterogeneous group of lymphoid malignancies.
Primary Pancreatic Anaplastic Large Cell Lymphoma, ALK-: A Care Report.
Authors: Savopoulos Lecturer Christos G. , Tsesmeli Niki E. , Kaiafa Georgia D. , Zantidis Anestis Th. , Bobos Matheos T. , Hatzitolios Apostolos I. , Papadopoulos Athanasios , Kostopoulos Ioannis S.
Published: October 2019

INTRODUCTION: Primary pancreatic lymphomas constitute less than 0.5% of pancreatic malignancies and less than 2% of extranodal lymphomas. Primary pancreatic anaplastic large cell lymphomas (PPALCL) are extremely rare.

AIMS-METHODS: To present an extremely rare case of PPALCL

RESULTS: An 80-year-old man, who was under evaluation of a fever of unknown origin in a Private Health Center, was admitted to our Clinic for further investigation. He noted anorexia, weight loss and fatigue. On physical examination, he had a leg edema. His blood tests were unremarkable except for normochrome normocyte anaemia (Ht 31%, Hb 9,9 g/dl) and a great elevation of ESR (110 mm), LDH (1880 U/L)and β2-microglobulin (4,19 mg/L). In CT and MRI scan, available from patient’s file, a soft tissue mass located in the pancreas, especially the uncinate process and a slow signal flow of inferior vena cava, due to mass compression, had been observed. He had undergone a normal gastrointestinal endoscopy at that time whereas a new endoscopy, after his admission to us, revealed an ulcerated mass-like deformity of the duodenal bulb with a friable surface. Explorative laparotomy confirmed a diffuse spread of an unresectable malignant mass of the pancreas extending to the adjacent organs. Biopsy specimen was taken from the adhesion of pancreatic surface and gastric serosa, because of the brittle consistency and and necrotic surface of the mass. The duodenal and surgical biopsy results identified an ALCL of T-cell lineage, ALK negative. Bone marrow biopsy showed no evidence of lymphoma involvement. Chemotherapy treatment was not initiated because he died in Intensive Care Unit two days after the explorative laparotomy, due to hemodynamic instability.

CONCLUSIONS: Our case supports that primary pancreatic lymphoma should be a high diagnostic possibility in a patient with a pancreatic mass accompanied by elevated LDH and β2-microglobulin. Biopsy specimens’ results, from the mass or the adjacent infiltrated organs, confirm the diagnosis, identify the lymphoma and lead to an appropriate and timeable treatment.
Resveratrol Induces Cell Cycle Arrest in the OCI-LY18 B-Cell Lymphoma.
Authors: Faber Anthony C. , Chiles Thomas C.
Published: October 2019

Resveratrol is a polyphenolic compound with well-documented anti-tumor properties. Despite reports of its efficacy in chronic B lymphocytic leukemia, little is known regarding the antiproliferative and/or proapoptotic effects of resveratrol in other B-cell malignancies. Diffuse large B cell lymphoma (DLBCL) has recently been subdivided into three major categories or subtypes, each with apparently distinct etiologies, gene expression profiles, and responses to conventional chemotherapy. These three DLBCLs comprise germinal center B cell (GC), activated B cell (ABC), and primary mediastinal DLBCL. Herein, we report that treatment of the OCI-LY18 B-cell lymphoma with resveratrol induced cell cycle arrest and apoptosis in a dose-dependant manner. Preliminary analyses suggest that OCI-LY18 exhibits a surface immunophenotype indicative of a GC DLBCL. The molecular mechanisms underlying cell cycle arrest by resveratrol were also investigated. We report herein that resveratrol induced the expression of p27 concomitant with inhibition of cdk2 and a decreased phosphorylation of the retinoblastoma protein (pRb). Resveratrol also induced the up-regulation of p53. In addition, resveratrol treatment resulted in the phosphorylation of p53 on Ser15/37, modifications that corresponded to the upregulation of p53. These data suggest that resveratrol induces growth arrest in OCI-LY18 via a mechanism that involves upregulation of p27 and p53. These results suggest that resveratrol might be beneficial as a novel treatment of GC DLBCL.
Good but Variable Humoral Response to Trivalent Influenza Vaccination in Patients with Non-Hodgkin’s Lymphoma - Two Seasons Experience.
Authors: Centkowski Piotr , Brydak Lidia , Machala Magdalena , Kalinka Ewa , Blasinska-Morawiec Maria , Wegrzyn Joanna , Skotnicki Aleksander , Federowicz Irena , Walewski Jan , Wolowiec Dariusz , Sawczuk-Chabin Joanna , Bilinski Przemyslaw , Warzocha Krzysztof
Published: October 2019

We assessed humoral response to influenza vaccination (vacc) in two consecutive seasons 2003/2004 and 2004/2005 in 123 NHL patients. In season 03/04 50 patients (29 previously treated with chemotherapy - group A03/04 and 21 not treated - group B03/04) and 73 patients in season 04/05: 34 treated - A04/05, 39 not treated - B04/05 were vaccinated with trivalent subunit influenza vaccine. Antibody responses to influenza hemagglutinin (HI) and neuraminidase (NI) were determined in sera collected before vacc, after 1 month and after 6 months. One month after vacc geometric mean antibody titers (GMTs) of antiHI antibodies significantly increased (p<0.05) and mean fold increases (MFIs) ranged from 10.4 to 24.3 in A03/04, 10.9–11.7 in A04/05, 6.5–31.6 in B03/04 and 14.8–21 in B04/05, than fell after 6 months to 3.6–7.8 in A03/04, 3.7–4.4 in A04/05, 1.7–11.2 in B03/04 and 7.8–8.5 in B04/05. Prevacc protection rate, i.e. the number of subjects with the protective HI antibody titers >1:40, ranged from 3.4 to 10.3% in A03/04, 2.9-8.8% in A04/05, 0–4.6% in B03/04 and 0–5.1% in B04/05. After 1 month protection rates ranged from 78.1 to 87.5% in A03/04, 61.8–70.6% in A04/05, 73.3–93.3% in B03/04 and 66.7–74.4% in B04/05 and decreased after 6 months to 24.1–37.9% in A03/04, 32.4–35.3% in A04/05, 19–47.6% in B03/04 and 17.9–35.9% in B04/05. Response rates, i.e. the number of subjects with at least a 4-fold increase of antiHI antibody titers after vacc, ranged from 58.6–75.9% in A03/04, 50–67.6% in A04/05, 57.1–81% in B03/04 and 61.5–71.8% in B04/05. Six months after vacc it decreased to 17.2–34.5% in A03/04, 20.6–29.4% in A04/05, 19–38.1% in B03/04 and 15.4–33.3% in B04/05. In all patients’ groups, post-vacc antiNI GMTs were significantly higher (p<0.05) than pre-vacc. MFIs of antiNI antibodies 1 month after vacc ranged from 11 to 17.5 in A03/04, 4.1–9.4 in A04/05, 5.1–9.9 in B03/04 and 6.3–9.9 in B04/05, then fell to 2.9–6.9 in A03/04, 1.3–5.1 in A04/05, 3.4–4.9 in B03/04 and 2.8–3.6 in B04/05. In season 03/04 only hemagglutinin H1 antibody titers were significantly higher in CTR than in patients in contrast of season 04/05 when in patients the titers of H1, H3 and N1, N2, NB were significantly lower. We conclude that the response to influenza vaccine is similar in patients previously treated and not-treated with chemoterapy. It is highly immunogenic in NHL patients, but the level of specific antibodies is variable and may depend on immunogenecity of vaccine for actual season. After 6 months the antibody titers rapidly decline, thus the NHL patients may need the second dose of vaccine to maintain good protective level.
Apoptosis Regulating Proteins bax and p53 in Mantle Cell Lymphoma.
Authors: Schrader Carsten , Klapper Wolfram , Janssen Dirk , Riis Paul , Meusers Peter , Brittinger Guenter , Siebmann Jens U. , Kneba Michael , Parwaresch Reza
Published: October 2019

In malignant tumors beside cell proliferation also cell death plays role for cell survival. Apoptosis regulating genes can be divided into two groups: death antagonists and death agonists such as bax. The ratio of death agonists and antagonists determines if a cell goes into apoptosis. We investigated in a large collective the immunohistochemical expression of the apoptotic marker p53 and bax in relation to the clinical course. Biopsies were stained immunohistochemically with monoclonal antibodies against bax and p53 and the expression was subdivided in three groups: negative, weak positive and strong positive. The expression profiles were analyzed with the overall survival data according to Kaplan and Meier. Patients with mantle cell lymphoma that had negative p53 expression had a median overall survival time of 38.1 months compared to 22.3 months for patients with a weak and 11.3 months for a strong p53 expression (0<0.0001). The bax expression was in the majority of cases positive. Only one case showed a negative staining. Patients with weak and strong bax expression showed no differences in clinical outcome (median overall survival time: 23 vs 33 months, p=0.6051). The immunohistochemical detection of p53 in mantle cell lymphoma is a good predictor for the clinical outcome.
More Than 4 Cycles of ABVD for the Treatment of Stage I–II Hodgkin’s Lymphoma?.
Authors: Tartas Norma , Zerga Marta , Alfonso Graciela , Copello María P. Amoroso , Santos Isabel , Korin Jorge , Nucifora Elsa , Fantl Dorotea , Luchetta Patricia , Ferro Hugo , Chacón Carolina , Barazzutti Lucía , Scoles Alba , Rainieri Fernanda , Alberbide Jorge , VijnovichBarón Anahí , Kusminsky Gustavo , Foncuberta María , Avalos Julio Sánchez
Published: October 2019

Patients with stage I-II A non bulky Hodgkin’s lymphoma (HL) are successfully treated with 2–4 cycles of ABVD plus IF radiotherapy (RT). Although the negative impact in DFS and OS of B symptoms and bulky disease(X) is widely accepted, other risk factors such as number of lymph node regions involved or extensive spleen involvement have also been reported. What is the best treatment for such patients? Is radiotherapy necessary? We report here our experience with protocol HD 98 in 62 patients, with stage I–II HL. Since January 98 we have included 30 individuals without risk factors and 32 with one of the following risk factors: B symptoms (n:11), X (n:9), extensive spleen involvement (n:1) and involvement of more than two lymph node regions (n:11). Other patient characteristics were: age: x 31yrs (15–69), sex: females 31, males :31. Ann Arbor stage IA :11, IB :1, IIA: 36, IIB :14. Histologic subtypes were: LP: 4, NS: 42, MC: 15, lymphocyte rich :1. Patients with favourable features received 4 cycles of ABVD plus IFRT, those with unfavourable factors received 6–8 cycles of ABVD plus RT in areas of bulky or residual disease.

Results: 59/61 evaluable patients obtained CR or CRu. Two patients were considered primary resistant. Three patients relapsed at 7, 13 and 30 months after completion of treatment. Autologus bone marrow transplant was performed in four patients. The two primary resistant patients relapsed after the transplant and died with proggressive disease. Those patients transplanted in a chemosensitive relapse are currently in CR. With a median follow up of 46m (13–84) 96.7% of the patients are alive, in CR.

Conclusions: In our experience patients with unfavourable stages I–II HL are succesfully treated with 6–8 cycles of ABVD. In such patients RT might only be necessary in areas of bulky or residual disease.