bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Factors in Localized Hodgkin’s Lymphoma: How To Define Intermediate/Unfavourable Disease?.
Authors: Gisselbrecht Christian , Mounier Nicolas , Casanovas Olivier , Reman O. , Sebban Catherine , Divine Marine , Brice Pauline , Briere Josette , Hennequin Christophe , Feugier Pierre , Ferme Christophe
Published: April 2020

Actually, the prognosis of localized Hodgkin’s lymphoma (HL) patients may be assessed by different scoring systems. Although many similar characteristics have been identified, these scoring systems are not easy to relate to advanced stage HL. The aim of the present study was to refine the assessment of risk using the published scoring systems and to construct a statistical model for predicting risk of death. We report here the results of the EORTC, GHSG and Canadian-ECOG scoring systems obtained in 1156 patients for whom hematological data were available among the 1390 patients with localized HL prospectively treated within GELA centres in H8 (518 pts) and H9 (638 pts) trials. The International prognostic score (IPS) was available only for the H9 subset. All patients have been treated with radio-chemotherapy of different intensity or duration according to their prognostic factors. Median age was 30 yr [14–69] and age≥45yr.: 18%, female 50%; stage 1: 25%; stage 2: 75%; B symptoms with elevated ESR: 40%; number of nodal sites 1–2: 52%; ≥3: 48%; extra nodal involvement: 8%, bulky mediastinum> 0.35, 28%; elevated ESR> 50:33%; Hb< 10.5 g/dl: 7%; Lymphocytes < 600/μl: 6%; WBC > 15000/μl:11 %; albumin< 40g/l: 37%. With the EORTC scoring system 36% of patients had favourable HL, with GHSG 35% and with Canadian-ECOG 38%. The IPS was 0 in 19% and 1 in 45%. With a median follow up of 42 months, 54 patients died. Survival curves according to the different scoring systems significantly discriminated favourable and unfavourable patients outcomes (5 yrs OS 95% vs 92%, p=0.01). By multivariate Cox analysis, age > 45yr (RR=2.0), sex male (RR=2.5), haemoglobin <10.5g/dl (RR=2.3), lymphocytes < 600/μL (RR=3.6), B symptoms with elevated ESR (RR=3.6), extra nodal sites (RR=1.2) retained a significant prognostic value. The 5 yrs OS was 99%, 98%, 92%, 82%, 73% for patients with 0,1, 2, 3, 4–5 factors respectively (p< 0.0001, see figure). 10% of the patients had 3–5 factors. The covariates selection was validated by the bootstrap method. The introduction of albumin< 40g/l in the H9 subset population did not bring more significant information. In conclusion, these factors are similar with those described in the IPS when stages 3–4 are replaced by extra nodal (E) localization. They should be validated in other prospective trials because such a scoring system could unify the assessment of the prognosis for HL patients and facilitate the treatment choice.

Figure Figure
African Americans and Caucasians with Myeloma Have Similar Outcomes in the Current Era: A Tumor Registry Study.
Authors: McClune Brian , Kumar Birendra , Buadi Francis , Womeodu Robin , Wright Kathy , Baskin Reed , Minhas Sohail , Ratliff Thomas W. , Spiers Kathleen , Yunus Furhan , Przepiorka Donna
Published: April 2020

Multiple myeloma is essentially an incurable disease, and SEER data suggests striking differences in survival between caucasians and African Americans. Recent advances in stem cell transplantation, however, can improve survival. To determine whether survivals continue to differ between caucasians and African Americans in the era of stem cell transplantation, we performed a retrospective analysis of 474 patients identified from a hospital tumor registry with a diagnosis of myeloma made consecutively from 1981 to 2000. The study cohort was comprised of 238 African Americans and 236 caucasians. Seven patients were lost in follow-up while still alive, and the remainder have either died or have follow-up to within one year of the analysis. There were 239 females and 235 males, and the distribution by gender did not differ by race (p=0.93). Median age of the cohort was 70 years (range 30–95 years); 6.5% were <50 years old, 67.9% 51–75 years old, and 25.5% >75 years old. The distribution by age differed significantly by race. A higher proportion of African Americans were diagnosed when <50 years old or when >75 years old in comparison to caucasians (p=0.006). Median survival for the entire cohort was 2.07 years, 1.92 years for African Americans and 2.31 years for caucasians (p=0.475). The difference in survival was essentially limited to patients diagnosed prior to 1996 (1.84 years vs 2.33 years, p=0.02). For patients diagnosed 1996–2000, the median survivals were similar (2.27 years vs 2.03 years, p=0.89). In a multivariate analysis, increasing age group was significantly predictive of poorer survival, but race, gender and quartile of year of diagnosis were not independent risk factors. We conclude that race is no longer associated with poorer survival for patients with myeloma.
Severe Gemcitabine-Associated Lung Injury in Hodgkins Disease & Other Cancers: Reporting Quality and Clinical Characteristics of Cases Reported in the Medical Literature and to the FDA.
Authors: Belknap Steven M. , Slimack Nicolas , Kuzel Timothy , Carson Kenneth R. , Yarnold Paul R. , Raisch Dennis W. , Trifilio Steven M. , Bennett Charles L.
Published: April 2020

Background: In view of concern about substantially increased risk of gemcitabine-associated lung injury (ALI), vigilant post-marketing surveillance is necessary to further characterize the frequency, severity, and clinical features of gemcitabine-associated pulmonary injury.

Methods: From 2001–2003, investigators with the Research on Adverse Drug reactions And Reports (RADAR) program compared the clinical characteristics and adverse event reporting quality of gemcitabine-associated lung injury contained in published case reports and adverse event reports submitted in the setting of clinical trials or the non-clinical trial setting.

Results: Completeness of reporting was excellent for published case reports and intermediate to poor for FDA adverse event reports from clinical trials or observational studies, including age (100%, 92%, 91%); time to onset of toxicity (100%, 63%, 58%); dose (97%, 63%, 79%); results of imaging studies (94%, 56%, 59%); presence/absence of hypoxia (97%, 6%, 4%); and cause of death (88%, 82%, 66%). Temporal analyses identified a bimodal pattern for the onset of pulmonary symptoms: 90% occurred before 150 days and 8% after 300 days. The highest rates of severe lung injury were in high dose patients co-administered bleomycin (28%) and in lung cancer patients (16%).

Conclusions: Reporting completeness for severe gemcitabine-ALI to the FDA from the clinical trial and the non-clinical trial setting is poor, limiting the ability of the RADAR group to comprehensively assess this toxicity. Nonetheless, this toxicity is severe and, as shown in published case reports, frequent in the presence of concomitant pulmonary insults such as bleomycin-containing combination chemotherapy regimens for Hodgkin’s disease and taxol-containig combination chemotherapy regimens for lung cancer.

Gemcitabine-associated Acute Lung Injury in Selected Clinical Trials

Author DX Other ChemoRx N ALI % Friedberg JW Hodgkin Doxorubicin, Bleomycin, Vinblastine 12 5 42 Bredenfeld H Hodgkin BA_COPP 27 6 22 Chen YM Non-SCLC Vinorelbine 20 5 25 Popa IE Non-SCLC Docetaxel 32 6 19 Herbst RS Non-SCLC Vinorelbine 36 5 14 Blackstock AW Non-SCLC 16 2 13 Bhatia S Non-SCLC Paclitaxel 34 4 12 Safran H Pancr. Ca Paclitaxel, Radiation 19 2 11 Lobo F Breast Ca Vinorelbine, Anthracyclines 21 2 10
Tracing the Pre-B to Immature B Cell Transition in Human Leukemia Cells Reveals a Coordinated Sequence of Primary and Secondary IGK Gene Rearrangement, IGK Deletion and IGL Gene Rearrangement.
Authors: Klein Florian , Feldhahn Niklas , Mooster Jana L. , Wernet Peter , Müschen Markus
Published: April 2020

The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of pre-B cells in humans and prevents further development. We studied whether inhibition of BCR-ABL1 kinase activity using STI571 can relieve this differentiation block. STI571 treatment of leukemia patients induced expression of the Ig light chain-associated transcription factors IRF4 and SPIB. Upregulation of RAG1 and RAG2, Cκ and Cλ germline transcription and rearrangement of IGK and IGL genes were also observed in cell culture experiments. However, STI571-treated pre-B ALL cells expressed λ- but almost no κ-light chains. This could be explained by STI571-induced rearrangement of the κ-deleting element (KDE), which can delete productively rearranged Vκ-Jκ joints. Amplifying short-lived DNA intermediates from double-strand breaks at recombination signal sequences within the IGK, KDE and IGL loci revealed a coordinated sequence of rearrangement events induced by STI571: Recombination of IGK gene segments is already initiated within one hour after STI571-treatment, followed by KDE-mediated deletion of Vκ-Jκ-joints six hours later and, ultimately, IGL gene rearrangement after 12 hours. Consistently, upregulation of Cκ and Cλ germline transcripts, indicating opening of IGK and IGL loci, was detected after one and six hours for IGK and IGL, respectively. Continued activity of the recombination machinery induced secondary IGK gene rearrangements, which shifted preferential usage of upstream located Jκ- to downstream Jκ- gene segments. Thus, inhibition of BCR-ABL1 in pre-B ALL cells i.) recapitulates early B cell development, ii.) directly shows that IGK, KDE and IGL genes are rearranged in sequential order and iii.) provides a model for Ig light chain gene regulation in the human.

Figure Legend: BCR-ABL1 + BV173, NALM1 and SUP-B15 cells were were cultured in the presence or absence of 10 μmol/l STI571 for the times indicated. Genomic DNA was isolated from 5 x 106 cells. Broken-ended DNA strand breaks were ligated to linker molecules and subjected to two rounds of PCR-amplification using primers specific for breaks at Jκ-RSS, KDE-RSS and Jλ-RSS sites.
Pharmacogenetics of Minimal Residual Disease Response in Children with Acute Lymphoblastic Leukemia (ALL).
Authors: Davies Stella M. , Borowitz Michael , Devidas Meenakshi , Winick Naomi , Martin Paul L. , Bowman Paul , Elliott James , Linda Stephen , Cook Edwin H. , Relling Mary V.
Published: April 2020

The presence of minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not yet known. Specific host germline pharmacogenetic polymorphisms have been linked to event-free survival in ALL in some studies, but their relationship to level of MRD after remission induction therapy has not been clearly elucidated. Herein, we determined whether the presence of MRD in bone marrow, measured by flow cytometry at day 8 and day 28 of remission induction therapy in over 1,000 children enrolled on Pediatric Oncology Group anti-metabolite based therapy protocols 9904, 9905, and 9906 was related to the following germline polymorphisms: MTHFR (A1298G, n=1413 and C677T, n=334), NQO1 (n=334), GSTP1 (n=334), TYMS (n=309), ADRB2 (n=715), RFC 80A/G (n=578), VDR (n=714), MDR1 C3435T (n=333), and MDR1 G2677T/A (n=328). We found that, after adjustment for ploidy, race and TEL-AML1 status (believed to influence blast clearance) the level of MRD at day 28 differed significantly by MTHFR A1298C genotype (p=0.005). MRD was detected in 31%, and 19% of those with A/A or A/C versus CC genotypes, respectively. Similarly, after adjustment for ploidy, race and TEL-AML1 status the level of MRD at day 28 differed by MDR1 2677 genotype (p=0.02). MRD was detected in 39% and 25% of those with GG versus other MDR1 2677 genotypes, respectively. MTHFR C677T, NQO1, GSTP1, TYMS, ADRB2, RFC, and MDR1 G2677T genotypes were not associated with presence of MRD. There was a trend towards an association between VDR genotype and presence of MRD. No significant associations were detected between any pharmacogenetic genotype and MRD at day 8.

Comment: These data indicate that presence of minimal residual disease at the end of induction, a known adverse risk factor in ALL, is importantly influenced by pharmacogenetic polymorphism. The strong association with MTHFR genotype, before the use of significant doses of methotrexate, illustrates the key role of folate in ALL blast metabolism. These data also indicate the value of an early endpoint such as MRD in identifying pharmacogenetic variables likely to influence outcome of specific therapeutic regimens, allowing prompt development of relevent mechanistic studies. Additional analyses will determine the impact of these polymorphisms on overall survival when the clinical outcome data from these studies is mature.
Induction Therapy Failures in Down Syndrome Patients with Acute Myelogenous Leukemia.
Authors: Loew Thomas W. , Gamis Alan , Smith Franklin O. , Massey Gita V. , Woods William G. , Hilden Joanne M. , Lange Beverly , Alonzo Todd A. , Chang Myron , Gerbing Robert B.
Published: April 2020

Down Syndrome (DS) is known to increase the risk of acute myelogenous leukemia. Recent cooperative group clinical trials, POG 9421 and CCG 2891, using standard timing and cytarabine/daunomycin based chemotherapy achieved induction rates of 95% and 91%, respectively. In 218 total patients (57 on 9421, 161 on standard timing arm of 2891), 17 induction failures occurred (3/57 on 9421, 14/161 on 2891). Analysis of the 17 induction failures demonstrated 6 died of toxicity/other causes (2 on 9421, 4 on 2891) and 11 failed to achieve complete remission (CR) with initial induction therapy (1 on 9421, 10 on 2891). Overall survival (OS) for patients not achieving CR with induction therapy was 9% (1 of 11). For the 10 who failed to achieve CR and subsequently died, median time to death was 10 months (range 3–59). Available data for these 11 patients indicate 10 underwent at least one attempt to induce a remission using other therapies with cytarabine in combination with asparaginase, anthracycline or etoposide being the most common regimen. The longest survivor was still alive 96 months post on-study after reinduction with mitoxantrone/cytarabine therapy. Three patients received bone marrow transplants (all allogeneic, 1 known matched sibling). One patient was transplanted still in relapse and died of progressive disease 10 months post on-study. One patient died of GvHD 59 months post on-study. While overall induction rates for patients with DS and AML are high (92% versus 78% for non-DS patients), survival rates for induction failures are dismal. Reevaluation of therapeutic approaches to DS patients failing induction chemotherapy is indicated.
Pulsing with Blast Cell Lysate or Blast-Derived Total RNA Reverses the Dendritic Cell-Mediated Increase in Cytotoxic Activity of Cytokine-Induced Killer Cells Against Human Allogeneic Acute Myelogenous Leukemia Cells.
Authors: Schottker Bjorn , Marten Angela , Ziske Carsten , Gorschluter Marcus , Schmidt-Wolf Ingo G.H.
Published: April 2020

Immunotherapeutic strategies may be a treatment option in patients with refractory acute myelogenous leukemia (AML) or, in cases of complete remission after conventional therapy regimens, may help to reduce disease recurrence or delay time to progression. Because evidence suggests a key role of dendritic cells (DCs) in cancer immunotherapy, we examined cytokine induced killer (CIK) cell responses in vitro after coincubation with autologous peripheral blood monocyte-derived DCs against three cell lines and allogeneic blasts from three patients with de novo AML. Although DCs were unable to enhance CIK cell effects against all three cell lines tested, the cytotoxic activity against the AML cells of the patients increased after coculture with mature DCs, which was significant in two of three patients. However, neither prior pulsing of the DCs with blast cell lysates nor with leukaemic cell-derived total RNA further enhanced the lytic capacity of the CIK cells. On the contrary, pulsing reduced the cytotoxic activity of the effector cells in a concentration-dependent manner. Because this decrease of allogeneic cytotoxicity was observed, we conclude that monocyte-derived DCs may be useful in autologous or allogeneic vaccine strategies for the treatment of AML or in priming donor lymphocytes in vitro, but unfractionated antigens as pulsing agents may have inhibitory effects on T cell efficiency and their employment in immunotherapeutic strategies for AML seems questionable.
Syncytial Variant of Nodular Sclerosing Hodgkin’s Disease.
Authors: Darabi Kamran , Tester William , Daskal Ierachmiel , Cohn Jeffrey
Published: April 2020

Background: Syncytial Variant is a subtype of nodular sclerosis Hodgkin’s disease (NSHD), reported to occur in younger patients (median age 25 years) who typically present with advanced disease and systemic symptoms.

Objectives: To evaluate the pretreatment characteristics and outcomes of NSHD patients diagnosed with syncytial variant (SV), compared to other NSHD patients without this histology (non-SV).

Methods: This is a retrospective medical chart review of all cases of NSHD seen at one institution over 2 decades. Pretreatment patient characteristics and outcomes data were analyzed.

Results: Of 63 patients with NSHD, 10 (16%) had SV histology. In contrast to previous reports, a trend for older age was observed for patients with SV (median 35 years), compared to patients with non-SV (median 27 years) (p=0.545). No differences in the distribution of B-symptoms or stage were observed between the two groups. Median recurrence-free survival was 37 months for SV cases, compared to 79 months for non-SV cases (p=0.046). Median overall survival was 38 months for SV, compared to 81 months for non-SV patients (p=0.05).

Conclusion: No significant differences were observed in pretreatment patient characteristics between SV and non-SV cases. However, we did observe a significantly worse recurrence-free and overall survival for SV patients, compared to non-SV cases. This is a limited retrospective study at a single institution and not all patients had received the same treatment. Therefore, further studies are needed to confirm these findings.
Analysis of Lymphocyte Monoclonality in Patients with Sjögren’s Syndrome Associated with Lymphoproliferative Disorder or Lymphoma.
Authors: Masaki Yasufumi , Dong Lingli , Kawabata Hiroshi , Hirose Yuko , Sugai Susumu
Published: April 2020

Purpose: Among 450 Sjögren’s syndrome (SS) patients in our hospital, we investigated 27 cases of malignant lymphoma (ML). In many reports, the risk of developing ML is higher, for example 43.8 times greater in patients with SS than in a comparable normal population in Kassan, et al, and 47.8 times greater in our Cases. Besides MALT lymphoma, other types of nodal lymphomas have been observed in patients with SS. To clarify the relationship between lymphocyte monoclonality and the development of the lymphomas in SS, we performed a clonality analysis of the tissues from salivary glands and lymphoproliferative organs.

Method. Clonality analysis was applied to lymphocytes in SS-related lymphoproliferative tissues from 3 patients who had lymphoproliferative disorder and were observed sequentially. We also compared the clonality between minor salivary gland and lymphoma tissues from 6 SS patients with nodal lymphoma. PCR amplification, cloning and sequencing were performed to identify immunoglobulin heavy chain complementarity-determining region 3 (IgH-CDR3) and T cell receptor-gamma (TCR-γ) gene rearrangement.

Results. In the 3 patients with sequential observation, B cell proliferation progressed from polyclonal or oligoclonal into monoclonal expansion in the salivary gland or extraglandular tissues. In one of these patients, lymphoma development was seen in the salivary gland. In all of the 6 SS patients with nodal lymphomas, the B cell clone in the salivary glands were different from those in the lymphoma tissues.

Conclusion. In patients with SS, there were two patterns of lymphoma progression. One was the multi-step process in which polyclonal B cell expansion evolves into monoclonal disease in extra-nodal lymphomas in salivary or lacrimal glands. The other was the independent clonality between salivary glands and lymphomas in patients with nodal lymphomas, and SS may play a role in the development of nodal lymphoma. Considering that the microenvironments of lymph nodes and salivary glands are different, the mechanism of the development of the extra-nodal lymphomas and the nodal lymphomas may be different.
Immunohistochemical Detection of CD95L (Fas Ligand) in Mantle Cell Lymphoma: A Prognostic Factor for Clinical Outcome.
Authors: Schrader Carsten , Meusers Peter , Brittinger Guenter , Janssen Dirk , Parwaresch Reza , Kneba Michael , Tiemann Markus
Published: April 2020

Mantle cell lymphoma is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. Proliferation indices are important prognostic factors in the clinical outcome. We investigated immunohistochemically the expression of the apoptotic marker CD95L (Fas Ligand) in relation to the clinical course. Biopsy specimen from 69 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, CD95L. The CD95L expression was analyzed into three groups: negative, weak positive and strong positive. The expression was compared with the overall survival data analysed according to Kaplan and Meier. Patients with mantle cell lymphoma that had negative and weak positive CD95L expression had a median overall survival time of 32.0 months compared to 18.3 months for patients with a strong CD95L expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time between the patients with strong CD95L expression and the group of patients with negative or weak positive tumor cells (p<0.0038). Based on these findings, the immunohistochemical detection of CD95L in mantle cell lymphoma is a prognostic factor.
Primary Cutaneous CD30+ Anaplastic Large Cell Lymphoma: Analysis of the Stanford Series Reveals Two Clinical Subsets of Patients.
Authors: Reddy Sunil A. , Liu Howard , Kohler Sabine , Hoppe Richard T. , Kim Youn H.
Published: April 2020

Primary cutaneous CD30+ anaplastic large cell lymphoma (PCALCL) represents the malignant end of the spectrum of CD30+ lymphoproliferative disorders. The management of PCALCL is markedly different than that of its primary nodal counterpart. The basis of this difference is due to the less aggressive nature of PCALCL. There is no evidence that chemotherapy is necessary or superior to the excellent results of local therapies such as radiation and/or excision for unilesional or local disease. Even patients with generalized disease have done well in some series. Here we review the characteristics and management of 40 cases of this rare cutaneous lymphoma. We have excluded Lymphomatoid Papulosis (LyP), the benign counterpart of PCALCL. In our series PCALCL was defined as CD30+ ALCL with disease limited to the skin as defined by a negative CT scan. Bone marrow biopsy was not necessary although it was always negative when done. Unilesional, local and extensive regional patients were generally treated with radiotherapy and/or excision, while chemotherapy and biologics were reserved for extensive regional and multifocal patients. The study included 30 men and 10 women with a mean age of 57.5 years (range 24–86). The estimated Kaplan-Meier disease specific survival (DSS) at 4 years for the entire group is 75.6%, with a median follow-up of 27.5 months (1–213). Twenty-six patients presented with unilesional or local disease, while there were 8 multifocal and 6 extensive regional patients (defined as 2 or more lesions beyond a 15 cm2 area apart but limited to 1 or 2 contiguous body regions). The unilesional/local patients had an estimated 4 year DSS of 93%. All but 2 of these patients are alive. The estimated Kaplan-Meier 4 year DSS of patients with either multifocal or extensive regional disease is 30%.

Estimated 4 year Kaplan-Meir survival of PCALCL by extent of skin involvement

unilesional/local 93% multifocal/extensive regional 30% P-value<0.001

Seven deaths occurred in this series of which 6 were either directly or indirectly attributable to PCALCL. Of the deaths 3 were among the 6 patients with extensive regional disease and 2 were among the 8 patients with multifocal disease. Furthermore, 4 multifocal and 2 extensive regional patients have active disease at the time of last follow-up. Further followup will determine their eventual outcome. The 2 patients with unilesional disease who died, both developed rapid progression to extensive regional disease. Although most patients with PCALCL present with local disease and do quite well with local therapy, it appears that some PCALCL patients with multifocal disease, extensive regional disease, and rapidly progressive unilesional disease behave as high grade lymphomas refractory to standard chemotherapy.
Phase II Study of Arsenic Trioxide Plus Ascorbic Acid for Relapsed and Refractory Lymphoid Malignancies: A Wisconsin Oncology Network Study.
Authors: Kahl Brad S. , Ahuja Harish G. , Sanchez Federico A. , Rodrigues Gilberto A. , Voorhees Peter M. , Stevens Emily A. , Smith Jamie , Turman Nancy , Kim KyungMann , Bailey Howard H.
Published: April 2020

Introduction: Arsenic trioxide (AT) has impressive single agent activity in relapsed acute promyelocytic leukemia. It also has activity in myelodysplastic syndromes and multiple myeloma. In vitro data has suggested increased cytotoxicity when combined with agents that deplete intracellular glutathione, forming the rationale for combination studies. Ascorbic acid (AA) can deplete intracellular glutathione and may potentiate the cytotoxicity of AT. Upon this basis, we initiated a phase II study of arsenic trioxide plus ascorbic acid for relapsed/refracory lymphoid malignancies. Arsenic trioxide was administered at a dose of 0.25 mg/kg IV over one hour M-F for one week and then 2X/week for 5 weeks. Each arsenic infusion was followed by an infusion of 1000 mg ascorbic acid over 15 minutes. Each 6-week cycle was followed by a two-week rest period before repeating the cycle. Treatment was continued until best response plus two cycles or progressive disease.

Patient characteristics: Median age 70.5 (37–88). Gender 10M, 6F. Histologies CLL/SLL (4), Follicular (3), Mantle Cell (3), DLBCL (2), Burkitt (2), Marginal Zone (1), Hairy Cell (1). Median # Prior therapies 4 (2–13). Refractory to prior treatment 13/16. Median ECOG PS 1 (0–2). B symptoms 3/16. Elevated LDH 8/16. Elevated B2M 13/16.

Results: Median number of completed cycles 1 (0–4). Eight patients did not complete cycle #1, six due to progressive disease (PD) and 2 due to toxicity. Of the 2 patients coming off for toxicity, one patient with known coronary artery disease suffered a myocardial infarction on the 4th day of treatment and expired from congestive heart failure and the other experienced repeated grade 4 hyperglycemia. Six patients completed one cycle of therapy and were removed for PD. One patient completed 3 cycles of therapy before experiencing PD. One patient with mantle cell lymphoma received 4 cycles of therapy and achieved a CRu. The overall response rate was 6% (1/16). The responding patient’s treatment was stopped after 4 cycles for MD/patient preference and she experienced PD 5 months after completion of therapy. Grade 3 toxicities included thrombocytopenia (2 patients), anemia (3), neutropenia (1), stomatitis (1), anorexia (1), and elevated LFTs (1). Grade 4 toxicities included neutropenia (2) and hyperglycemia (1).

Conclusions: AT plus AA in this dosing schedule had modest toxicity but limited antitumor activity. The data should be interpreted in the context of our heavily treated, essentially refractory patient population. Our trial had a two-stage design, and was closed due to lack of activity at the first stage analysis. Other doses and schedules may prove to be more efficacious.
The MYOCAN Study. A Phase II Study of Cyclophosphamide, Oncovin, Myocet™, and Prednisone Plus Rituximab (R-COMP) in the Treatment of Elderly Patients with Diffuse Large B-Cell Non-Hodgkin Lymphoma (DLBCL).
Authors: Federico Massimo , Dyer Martin J.S. , Caballero Maria Dolores , Reilly Claire , Thiel Eckhard
Published: April 2020

BACKGROUND: For more than 20 years, CHOP has been the gold standard treatment for patients with aggressive NHL. The addition of rituximab to this regimen has been shown to improve outcomes in elderly patients with advanced (Coiffier et al NEJM2002; 346:235–42). However, CHOP is often poorly tolerated by elderly patients resulting in dose reductions and consequently lower response and cure rates compared to younger patients. Myocet™ (non-pegylated liposomal doxorubicin) has an improved pharmacokinetic profile with less myelosuppression and GI toxicity and has a reduced risk of cardiotoxicity at dose levels equivalent to standard formulations of doxorubicin.

METHODS: In this phase II, open label, 2-stage study, we replaced the conventional doxorubicin with Myocet™ to evaluate the response rate and safety of the R-COMP regimen (rituximab, cyclophosphamide, vincristine, Myocet™, prednisone). Previously untreated, elderly patients (≥60 yrs) with CD20+ newly diagnosed, advanced DLBCL were treated every 3 weeks with: Myocet™ 50mg/m2, cyclophosphamide 750mg/m2, vincristine 1.4 mg/m2 (max. 2mg), rituximab 375 mg/m2 (day 3 on cycle 1, day 1 thereafter) and prednisone 100mg/d d1–5 for 8 cycles. Response was assessed after 3 and 8 cycles.

RESULTS: Thirty patients were enrolled in stage 1 of the study with a median age of 72 (range 61–82). At baseline 17 (56%) patients had stage III–IV disease; 60% had an intermediate or high risk (2+) International Prognostic Index score and the median LVEF was 59% (range 50–75). A total of 198 cycles of chemotherapy were given, with a median of 8 cycles (range 1–8). Of the 198 cycles administered 15 (8%) were delayed by haematological or hepatic toxicity for a median of 7 days (range 0 to 25). The relative dose intensity for the regimen was 87%, for Myocet™ it was 84%. Toxicity was mainly haematological with grade 3 or 4 neutropenia in 29% of cycles and febrile neutropenia in 4%. There was no grade 3 or 4 vomiting and a low incidence of grade 1 or 2 vomiting (3%). At the last observation the median LVEF was 55% (range 40–76), 16 patients had no change or an improved LVEF and 13 patients had a reduced LVEF. In the cohort of 24 patients evaluable for response, 15 (63%) had a complete response and an additional 7 (29%) achieved a partial response.

CONCLUSIONS: These interim results suggest R-COMP is a well tolerated regimen with promising response rates in elderly patients with advanced DLBCL. Patient recruitment continues in stage 2 of the study with the aim of enrolling a total of 75 patients with a 2-year follow-up.
Long Term Results for Cladribine Induction and Interferon Maintenance Treatment in Previous Untreated Indolent Lymphoma.
Authors: Fridrik Michael A. ,   for the AGMT
Published: April 2020

Indolent lymphoma in advanced stage is an incurable disease. The main treatment goal is palliation with low treatment related toxicity. In a multicenter setting we prospectively treated 91 previous untreated indolent lymphomas with intravenous cladribine 0.12 mg/kg body weight for 4 or 5 consecutive days every 4 weeks for 4 cycles. Following the cladribine induction treatment an interferon-2c maintenance therapy was started until progression. Median age was 59 years (range 25–79). All patients had stage 3 or 4 disease. Overall remission rate was 70% with 23% complete remissions. We found no significant difference in remission rate between the 4 or 5 day regimen. The remission rate was not different between follicular lymphoma, mantel-cell lymphoma, or Waldenstrom’s disease. Neither did the international prognostic index influence the rate of remission. Median observation was 60 months for living patients. Median time to progression and survival was 22 and 69 months respectively. At 5 years 23% and 57% were progression free and alive respectively. Transformation in a high-grade lymphoma occurred in 11/91 patients. A secondary cancer was observed in 4/91 patients. Toxicity was mainly hematologic for cladribine. Interferon maintenance was poorly tolerated, 27% of patients did not complete the therapy. Four months of cladribine seems to have similar results as conventional therapy with chlorambucil for 6 to 12 months.
L-Asparaginase in the Treatment of Relapsing Nasal/Nasal Type NK-T-Cell Lymphoma.
Authors: Jaccard Arnaud , Suarez Felipe , Zini Jean-Marc , Turlure Pascal , Trimoreau Franck , Petit Barbara , Bordessoule Dominique , Hermine Olivier
Published: April 2020

Nasal/nasal type NK-T-cell lymphoma is a rare and severe type of non Hodgkin’s lymphoma (NHL) more frequent in asia than in western countries. When localised, radiotherapy seems to be the best treatment. When radiotherapy cannot be used because of dissemination or relapse, chemotherapy protocols used for other types of NHL give poor results. Recently some papers from China and Japan, (Yong W et al: L-asparaginase-based regimen in the treatment of refractory midline nasal/nasal-type T/NK-cell lymphoma. Int J Hematol. 2003 Aug;78(2):163–7), reported the efficacy of a drug: L-asparaginase, usually used to treat acute lymphoblastic leukemia. Few patients have been treated in Asia and no patient from western countries have been reported.

We used this drug in 3 french centers to treat 7 patients with relapsed nasal/nasal type NK-T-cell lymphoma.

There were 4 men and 3 women, median age was 52 (39 to 81), the primary site of disease was the nasal cavity in 3 patients, the nasopharynx in 2, the gastrointestinal tract in 1 and the bone marrow in 1. Pathological diagnosis was confirmed by biopsy, showing typical aspect of necrosis and angioinvasion. Tumoral cells were usually CD20 negative, SCD3 positive, CD56 positive. EBV was found by in situ hybridisation in all but one case.

When L-asparaginase was given 5 patients were refractory to CHOP and/or DHAP regimen, 5 patients were in stage IV with bone marrow involvment (n=2), cerebral involvment (n=2), gastrointestinal tract involvment (n=1). Hemophagocytosis was seen in 3 patients with typical biological anomalies.

L-asparaginase 6000 UI / m2 (1 to 3 courses) was given for 5 to 10 days associated with Dexamethasone 40 mg for 4 days (n=4), methotrexate 3 gr/m2 (n=1) or velbe 6 mg (n=1). 2 patients who had a severe anaphylactic reaction with L-asparaginase received further courses of PEG-asparaginase.

Treatment efficacy was evident in all patients with 4 patients in complete remission (CR) and 3 patients in partial remission (PR) after treatment with L-asparaginase. 2 patients died, one of acute GVH after allotransplantation and a second 1 month after the second course of L-asparaginase, probably of pulmonary embolism. Apart from this case toxicity related to L-asparaginase was mild, mainly brief leucopenia and elevation of alanine aminotransferase. With antithrombine III transfusions when its level was below 60% no other thrombotic event was noted.

5 patients are still alive with a median follow-up of 7 months (3 to 13), 4 patients are in persistent CR, 2 had received high dose therapy with autologous stem cell transplant.

The efficacy of L-asparaginase to treat nasal and nasal type NK-T-cell lymphoma must be known because of the very poor prognosis of relapsing patients with conventionnal chemotherapy. Prospective studies using L-asparaginase for de novo patients are warranted.
Extreme Effectiveness of Operative Resection with or without Radiotherapy as a First Line Treatment for Localized Orbital Malt Lymphoma.
Authors: Yakushijin Yoshihiro , Kodama Toshio , Takaoka Ikue , Otsuka Masaki , Hato Takaaki , Yasukawa Masaki , Fujita Shigeru
Published: April 2020

Localized orbital extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are predominately low-grade, small B cell types and are associated with systemic occurrence either sequentially or concurrently in some cases. The risk of future relapse and the original lymphomas’ transformation to diffuse large B-cell lymphomas are great concerns for the treatment of patients with MALT lymphoma. Several groups have reported on the efficacy and complications related to radiotherapy with orbital MALT lymphoma, however, the efficacy of surgical operation for local control has not been well documented. We have studied series of orbital MALT lymphoma cases treated using operative resection, and analyzed the procedure’s efficacy as a first line treatment. We treated a total of twenty-three patients with orbital MALT lymphoma (median follow-up was 3.0 years). Pathological diagnoses of all cases were reviewed by hematopathologists, and the B cell monoclonality of twenty-two cases was confirmed by immunoglobulin heavy chain (IgH) rearrangement using Southern blot. There were three cases which occurred on both sides (right and left) of the ocular adnexa. In the surgically removed sections, a large component of pathological cells which seemed to be transforming into large cell lymphomas was found in two cases. All patients were treated using surgical operations as a first line therapy, and six (26%) cases needed additional adjuvant treatments such as radiotherapy and/or chemotherapy because of incomplete tumor resection. There was 100% freedom from local relapse or relapse in any sites among seventeen patients treated only with surgical operations. Two patients (12%) out of seventeen had xerophthalmia or strabismus as complications after the operations. Two patients (33%) among the six cases who needed adjuvant treatment had radiation-induced cataracts within three years. We conclude that operative resection as a treatment for orbital MALT lymphoma is very effective and well tolerated as a first line treatment. In addition, if the tumor resection is not complete, additional radiotherapy should be considered.
BL22, a Recombinant Anti-CD22 Immunotoxin, Induces Cell Cycle Arrest and Apoptosis in B-Cell Lymphoma.
Authors: Decker Thomas , Wagner Michaela , Oelsner Madlene , Kreitman Robert J. , Pastan Ira , Peschel Christian , Licht Thomas
Published: April 2020

A recombinant immunotoxin, BL22 has shown clinical efficacy against hairy cell leukemia and other B-cell non-Hodgkin’s lymphomas. BL22 contains an antibody-derived domain that recognizes CD22, and PE38, a truncated Pseudomonas exotoxin A domain, for inhibition of protein synthesis. Previous studies have shown that Pseudomonas exotoxin A-based immunotoxins exert their cytotoxicity by apoptosis and additional, yet uncharacterized mechanisms. We investigated the cytotoxicity of BL22 in two mantle cell lymphoma lines, NCEB-1 and Granta-519, and in the diffuse, large-cell lymphoma line SU-DHL-4. Presence of the CD22 target was confirmed by flow cytometry. Treatment of NCEB-1 cells to 1 μg/ml BL22 for 24-32h reduced the numbers of viable cells in comparison to cells exposed to a non-binding immunotoxin. Induction of apoptosis, determined by activation of caspase-3 and exposure of phosphatidylserine, was not detected before 48h of exposure. Incorporation of bromo-deoxyuridine into DNA was, however, almost completely inhibited after 24h. Correspondingly, the numbers of G1 phase cells were increased upon treatment with BL22 as determined by flow cytometry. G1-arrest resulted from decreased enzyme activities of cyclin-dependent kinases (cdk)-2 and 4 as assessed in vitro with respective substrates, histone H1 and the retinoblastoma susceptibility (RB) protein. Immunoblotting revealed markedly reduced amounts of cyclins A, E, D1 and D3 whereas cdk2 and cdk4 protein expression levels remained unchanged. Expression of the RB protein was decreased, and the protein was hypophosphorylated in immunotoxin-treated cells. Pulse-labeling with [35S]-labeled amino acids, followed by immunoprecitation of cyclins E and D1 confirmed that BL22 inhibited synthesis of these cyclins. Thus, immunotoxin-induced cell cycle arrest results from insufficient synthesis of regulatory cyclins required for progression through G1 into S-phase. Similar results were obtained in Granta-519 cells. SU-DHL-4 diffuse, large-cell lymphoma cells were highly sensitive to BL22, and G1 arrest was observed as early as after 8–24h in these cells. Expression of cyclins A, D3 and E was decreased while cyclin D1 was not expressed in SU-DHL-4 cells. Interestingly, cell cycle arrest did not prevent from subsequent induction of apoptosis in lymphoma cells continuously exposed to the immunotoxin. In conclusion, we have characterized cell cycle arrest as a previously unknown mechanism that contributes to the cytotoxicity of Pseudomonas exotoxin-based immunotoxins.
Refractory Autoimmune Cytopenias, Either Associated with Lymphoproliferative Diseases or Idiopathic in Adult Patients, Treated with Anti-CD20 Monoclonal Antibody (Rituximab).
Authors: Garay Guy , Riveros Dardo , Milone Jorge , Fernandez Jose , Duarte Patricio , Cacchione Roberto , Dupont Juan
Published: April 2020

Immune cytopenias (IC) frequently require prolongued administration of immunosupressors, especially when associated with lymphoproliferative disorders (LPD). Rituximab causes in vivo selective destruction of B lymphocytes and supresses the production of antibodies. Three mechanisms are involved; complement dependent cytotoxicity, antibody dependent cellular citotoxicity and the induction of apoptosis. We present 10 patients with IC: 8 autoimmune hemolytic anemia (AIHA), and 2 AIHA plus immune thombocytopenia (Evans’ syndrome). Seven patients had IC associated with LPD, and 3 were idiopathic. LPD were: 3 follicular lymphoma (1 Grade 1, 1 Grade 2, 1 Grade 3), 1 small lymphocytic lymphoma, 3 chronic lymphocytic leukemia. Three patients with idiopathic cytopenias had a long history of recurrent AIHA (2) and Evans’ syndrome (1). Ages ranged between 43 and 81 (median 63 yrs); 6 were female gender and 4 male. All AIHA cases, except 1 pts with cryogrobulins, presented with warm IgG antibodies. Previous evolution included splenectomy in 2 pts and all pts received multiple courses of immunosupression with steroids and others, like azathioprine and cyclophosphamide. All patients with LPD received one or more chemotherapeutic regimens with alkylating agents, fludarabine or CHOP combination. Median time to IC in 7 pts with LPD was 75 months (2–228). Idiopathic cases had 12, 132 and 204 months of previous evolution. Rituximab was administered at 375 mg/m2 every 1 to 3 weeks for 3 to 8 doses (median 4). Six pts received rituximab as monotherapy and 4 pts in combination with chemotherapy. Toxicity was mainly related to the first cycle of rituximab and consisted in chills and fever grade I-II in three pts. Clinical resolution of cytopenia occured in 9/10 pts (90%). 4 of them (44%) resolved with negative direct antiglobuline test. Median time to response was 4 weeks (2–8). One AHIA died with hemolysis progression, six months after rituximab, and 1 pts with AHIA and follicular lymphoma died 8 months after rituximab treatment with progression of LPD without evidence of hemolysis. The rest of the patients remained without IC for 2–42 months (median 18). Rituximab, originally designed to treat B-cell neoplasms, is an active immunosupressive agent in either lymphoproliferative associated or idiopathic autoimmune cytopenias even in non splectomized pts. Its use may avoid the secondary effects of long term administration of steroids, alkylating agents or transfusions.
All-Trans Retinoic Acid Can Reduce Proviral DNA of Human T-Cell Leukemia Virus as a Reverse Transcriptase Inhibitor.
Authors: Yamaguchi Terufumi , Maeda Yasuhiro , Ueda Satomi , Hijikata Yasuki , Matsuda Mitsuhiro , Kanamaru Akihisa
Published: April 2020

We previously reported that all-trans retinoic acid (ATRA) inhibits growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed the NF-κB transcriptional activity as well as cell growth in HTLV-1-positive T-cell lines decreased significantly in these cells in the presence of ATRA. However, no significant growth inhibition was observed after treatment with IFN-γ, TNF-α, and TGF-β of growth inhibitory cytokines induced by ATRA. Thereafter, we observed that ATRA reduced HTLV-1 proviral DNA, gag and tax mRNA load using a real time quantitative polymerase chain reaction and soluble IL-2 receptor in the culture supernatant using ELISA in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited reverse transcriptase activity similar to azidothymidine in HTLV-1-positive T-cell lines. These results suggested that ATRA could inhibit reverse transcriptase activity in the growth inhibition of ATL cells. Additionally, an effect of ATRA on replication of the human immunodeficiency virus (HIV) was also observed. ATRA significantly reduced the HIV proviral DNA load of both a HIV-1-positive cell line and HIV-1-infected patients. These results indicated that ATRA may be useful for HIV treatment in a clinical setting.
The Change of Vascular Endothelial Growth Factor and Microvessel Density Following Imatinib Mesylate Therapy and Allogeneic Bone Marrow Transplantation in Chronic Myeolid Leukemia.
Authors: Kwak Jae-Yong , Lee Na-Ri , Song Eun-Gi , Yim Chang-Yeol , Chung Myoung-Ja , Jo Yong-Gon , Choi Sam-Im
Published: April 2020

Chronic myeloid leukemia(CML) is a clonal myeloproliferative disorder and increased angiogenesis in bone marrow is a feature of CML. Vascular endothelial growth factor(VEGF) is a potent angiogenic peptide and microvessel density(MVD) is increased in bone marrow of CML. In this study, the effect of imatinib mesylate therapy on angiogeneisis was investigated and compared with allogeneic bone marrow transplantation(BMT) with philadelphia chromosome positive/BCR-ABL+ CML in first chronic phase. Immunohistochemical staining for detecting VEGF protein was performed by labeled avidin-biotin method on the formalin-fixed and paraffin embedded bone marrow biopsy samples of 10patients of allogeneic BMT, 20patients of imatinib mesylate therapy and 10normal control. Initial and sequential, after at least 12 months of therapy, bone marrow biopsy examed and all patients achieved complete cytogenetic remission. Microvessel was scored in at least 3 areas(*200 fields) of the highest MVD in representative sections of each bone marrow biopsy specimen using immunohistochemistry for CD32 antigen. Patients with Imatinib mesylate therapy and allogeneic BMT induced a significant reduction of MVD (normalization in comparison with controls). MVD was no significant difference between the patients with imatinib therapy and allogeneic BMT. VEGF was mainly expressed myeloid progenitors and less abundantly megakaryocytes and mature granulomonocytic cells. Expression of VEGF, it was significantly decreased in patients with Imatinib mesylate therapy and allogeneic BMT(normalization in comparison with controls). VEGF expression was no significant difference between the patients with imatinib therapy and allogeneic BMT. First line therapy with imatinib mesylate was normalization of bone marrow vascularity compared with allogeneic bone marrow transplantation of CML in first chronic phase.