bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutually Exclusive Cdk4-Cyclin D1 and Cdk6-Cyclin D2 Pairing Inactivates Rb and Promotes Cell Cycle Dysregulation in Multiple Myeloma.
Authors: Ely Scott , Di Liberto Maurizio , Niesvizky Ruben , Hatada Eunice , Cho Hearn , Knowles Daniel M. , Lane Joseph , Chen-Kiang Selina 
Published: April 2020

Abstract
Multiple myeloma (MM), the second most common hematopoietic cancer, ultimately becomes refractory to treatment when self-renewing MM cells begin unrestrained proliferation by unknown mechanisms. Cell cycle reentry and progression is modulated by the balance between positive cell cycle regulators [cyclins and cyclin-dependent kinases (Cdk)] on the one hand and Cdk inhibitors (CKI) on the other. Here we show that one, but not more than one, of the three early G1 D cyclins is elevated in each case of MM. However, cyclin D1 or D3 overexpression rarely leads to phosphorylation of the retinoblastoma protein Rb and G1 cell cycle progression, unless cyclin-dependent kinase 4 (Cdk4) is correspondingly elevated in the absence of Cdk6. By contrast, cyclin D2 and Cdk6 are coordinately increased, thereby overriding inhibition by Cdk inhibitors, p18INK4c and p27Kip1, and phosphorylating Rb in conjunction with Cdk4. Thus, Cdk4 pairs exclusively with cyclin D1 whereas Cdk6 pairs exclusively with cyclin D2, although Cdk4 can also pair with cyclin D2 in MM cells. The basis for the exclusive Cdk4-cyclin D1 and Cdk6-cyclin D2 pairing is coordinated transcriptional activation. Cyclin D1 or D3 expression is scattered or uniform among bone marrow MM cells and at a constant frequency in the clinical course. By contrast, phosphorylation of Rb by Cdk6-cyclin D2 occurs in discrete foci of bone marrow MM cells early in the clinical course before cell proliferation, then is heightened with proliferation and disease progression. Mutually exclusive Cdk4-cyclin D1 and Cdk4/6-cyclin D2 pairing, therefore, critically controls cell cycle re-entry and G1 progression, which underlies the expansion of self-renewing MM cells in MM progression.
Pax-5 Demonstrates Residual B-Cells in Bone Marrow Trephines Post Anti-CD20 Immunotherapy.
Authors: D’Souza Alwyn , Juneja Surender , Trivett Melanie , Carney Dennis , Westerman David 
Published: April 2020

Abstract
Background: Immunohistochemical stains for CD20 are reliable in both formalin and mercuric-based fixed tissues. Anti-CD20 (rituximab (R)) immunotherapy for B- cell malignancies has negated the usefulness of CD20 immunohistochemistry post-therapy. Many other routine B-cell immunohistochemical stains are unreliable in mercuric-based fixatives. Thus, a reliable B-cell stain is needed post-R treatment.
Pax-5 is a transcription factor specific for B-cells that is required for normal B-cell development. It is expressed from the Pro-B stage through to mature B-cells and is expressed on both normal and malignant B-cells. The Pax-5 immunohistochemical stain has proven to be reliable in formalin-fixed tissue. Its role in mercuric-fixed tissue has yet to be determined.
Aim: To demonstrate residual CD20-negative B-cells, using the Pax-5 immunohistochemical stain, on mercuric-fixed bone marrow trephines following R treatment.
Methods: We performed CD20 and Pax-5 immunostains on bone marrow trephines in patients who had received combined chemoimmunotherapy with R. Patients underwent restaging bone marrows midway through treatment (range 2–4 cycles) and at the end of treatment (range 6–8 cycles). We divided analysis into two groups; 1. Patients with overt residual disease on H&E stains. 2. Patients with morphologic complete remission on trephine.
Results: Patient diagnoses included: CLL/SLL n=20; Follicular lymphoma n=2; Mantle cell lymphoma n=1; Waldenstrom macroglobulinaemia n=3. Patients’ morphologic responses were: complete remission (CR) n=5; partial remission (PR) n=9; nodular partial remission (nPR) n=10; no response (NR) n=2. In the non-CR group (PR, nPR, NR) 4 patients were positive for CD20 and all 21 patients were positive for Pax-5. In the CR group 0 patients were positive for CD20 and 5 patients were positive for Pax-5.
Conclusion: Pax-5 is a robust and reliable immunohistochemical stain that demonstrates B-cells post anti-CD20 immunotherapy. While it stains both normal and malignant B-cells, it may prove to be a useful tool in assessing minimal residual disease following immunotherapy.
IL-21 and CpG ODN Are Synergistic in Their Ability To Induce Apoptosis of Chronic Lymphocytic Leukemia (CLL) Cells and Benign B1 Cells.
Authors: Jahrsdoerfer Bernd , Blackwell Sue E. , Wooldridge James E. , Andreski Melinda W. , Jacobus Laura S. , Taylor Christiana M. , Weiner George J. 
Published: April 2020

Abstract
We previously reported the TLR9 ligand CpG ODN can induce apoptosis of CLL cells. Interleukin 21 (IL-21), a recently discovered cytokine with structural homology to IL-2, IL-4 and IL-15, has pleiotropic effects on lymphocyte populations including NK, T and B cells. IL-21 is known to co-stimulate normal human B cell proliferation induced by CD40 ligation, and to inhibit B cell proliferation induced by anti-IgM antibodies and IL-4. We explored the impact of these two agents on CLL because of the overlapping nature of their signaling pathways. Gene chip array studies demonstrated CLL cells express the receptor for IL-21, and expression of this receptor is upregulated by CpG ODN. IL-21 as a single agent induced apoptosis of CLL cells in most samples studied. The combination of IL-21 and CpG ODN induced a greater degree of apoptosis than either agent alone.
Figure Figure
Dosing studies demonstrated synergy between these two agents in their ability to induce apoptosis of CLL cells.
Figure Figure
The effect of IL-21 and CpG ODN was also evaluated in peripheral blood from normal donors, and in umbilical cord blood. In both types of samples, therapy preferentially eliminated CD5(+) B-cells. Monoclonal antibody against CD5, but not control antibody, was able to inhibit the pro-apoptotic effect of IL-21. Our results suggest treatment with IL-21 and CpG ODN preferentially eliminates CD5(+) B cells in both malignant and benign samples, and may be a useful combination for the treatment of CLL or autoimmune disorders dependent elevated B1 cell levels. Ongoing studies are exploring the underlying signaling pathways which might be responsible for these effects.
Subcutaneous Administration of Alemtuzumab: A Single Institution Experience.
Authors: Bubis Jeffrey A. , Schaal Anna D. , Kimtis Elizbeth A. , Gautier Marc 
Published: April 2020

Abstract
Alemtuzumab is an active drug in the treatment of a number of lymphoid malignancies and is currently indicated for intravenous administration to patients with B-cell chronic lymphocytic leukemia (CLL) who have failed therapy with fludarabine. Unfortunately, despite premedication, grade 3/4 infusion-related reactions (IRR) are common during alemtuzumab IV administration (fever = 19%, rigors = 16%, and hypotension = 5%, amongst others). If grades 1/2 IRR are included, these numbers increase to 86%, 85%, and 32%, respectively. Nausea also occurs in 54% of patients. In addition to complicating therapy, these reactions sometimes make it necessary to prematurely discontinue therapy. These toxicities may be avoided by administering alemtuzumab subcutaneously (SC); a promising modality, but one with limited supporting data. We report the results of our institutional experience with SC alemtuzumab administration. We performed a retrospective chart review examining data points related to demographics, safety, and efficacy. This IRB - approved review looked at 20 patients who were treated with SC alemtuzumab (13 = CLL, 1 = CLL/AML, 3 = CTCL, 3= PTCL); 2 of these were retreated subcutaneously after receiving IV therapy. Treatment was attempted with a dose-escalation scheme of 3mg-10mg-30mg; with the goal of a 12-week regimen. The average age of the patients was 61 (median 62, range 45–76). 13 were male and 7 were female. The average number of weeks of subcutaneous therapy received was 7 (median 7, range 1–12 weeks). The average number of prior treatment regimens was 3 (median 2, range 1–7). ORR to therapy with alemtuzumab= 60%. (CR = 4, PR = 8). 9 patients had refractory or progressive disease. Patients tolerated the therapy well. Toxicities were all grades 1/2 and usually resolved with supportive therapy and continued alemtuzumab administration; these included hemolytic anemia (n=1), mild pruritis (n=1), anemia (n=1), neutropenia (n=2), fever (n=3), rigors (n=2) mild skin reactions (n=2). Infectious complications included bacterial pneumonia (n=1), herpes zoster (3 months after the completion of therapy, n=1), CMV reactivation (antiviral therapy with alemtuzumab held for two weeks, n=1). No patients discontinued therapy due to grade 3/4 IRR. Of particular interest are the two patients retreated with SC alemtuzumab after previously receiving the drug IV. (1 = PR after first and second course, 1 = PR after first course and no response to second course.) These patients tolerated the drug well with minimal toxicity. One of the retreated patients who had experienced bronchospasm with IV therapy, had no respiratory issues with subcutaneous administration. Based on this data, we conclude that SC alemtuzumab is a safe, well-tolerated, and effective alternative to IV administration. Final data will be available at presentation.
Treatment Outcomes in Patients (Pts) with Transformed Chronic Lymphocytic Leukemia (CLL) in One Institution.
Authors: Acs Peter , Mavromatis Blanche , Ozdemirli Metin , Hartman Daniel , Cheson Bruce 
Published: April 2020

Abstract
CLL is usually an indolent lymphoproliferative disease; however pts are at risk over time (3-5% yr) of transformation to a more aggressive histology, e.g., prolymphocytic leukemia (PLL), or Richter’s transformation (RT). The outcome of these pts is poor with median overall responses of 5–43%, CR 5–43%, and overall survival of 5–8 months regardless of the chemotherapeutic approach.
We report on 15 pts with CLL transformed to PLL or RT treated at our institution over the last 4 years. The median pt age at transformation was 64 (51–79). 9 had PLL, 4 had RT, one had an anaplastic histology, and another with atypical transformation. 7/14 pts were positive for ZAP-70 expression. 10/14 presented with CLL prior to the transformation with a median time of 7 yrs (range 3–27), and had undergone prior therapy with either fludarabine or chlorambucil. Pts were treated with mainly rituximab chemotherapy combinations. One pt who achieved a CR, was consolidated with a matched related donor transplantation and remains disease free for 3 yrs.
Conclusion. CR and ORR were higher than reported in the literature. Also, pts treated with rituximab-based combinations achieved longer overall survivals. Rituximab based-combinations should be considered in treating such pts. Whether they would benefit from consolidation therapy needs further investigation.
Treatment Based Response and Overall Survival in Patients with Transformed Chronic Lymphocytic Leukemia Treatment # Pts Prev. Tx # Pts CR (%) PR (%) OS after Transformation (Months) Pts, patients; Prev., previously; Tx, treated; CR, complete response; PR, partial response; OS, overall survival; R, rituximab; Flu, fludarabine; Cy, cyclophosphamide PLL R/Flu +/− Cy 2/6 6 67 12 36+, 36+, 36, 24+, 4, 12+ RCHOP or R-EPOCH 2/2 2 0 50 8, 3+ Alemtuzumab 1/1 1 0 100 12+ RT RCHOP or REPOCH 1/4 4 75 25 36+, 30+, 3, 9 Anaplastic RCHOP 1/1 1 100 0 24+ Atypical R/Flu/Cy 1/1 1 100 0 24+ Overall 60 27
Maintenance Alemtuzumab in Refractory B-Cell Chronic Lymphocytic Leukemia Patients: Updated Data.
Authors: Thieblemont Catherine , Houot Roch , Toure Boubacari Ali , Traulle Catherine , Michallet Anne-Sophie , Bouafia Fadhela , Espinouse Daniel , Salles Gilles , Coiffier Bertrand 
Published: April 2020

Abstract
Alemtuzumab has an impressive clinical activity in B-cell chronic lymphocytic leukemia. The standard regimen (30 mg three times weekly for 12 weeks) results in high rate of early responses but frequent early progression. To prolong TTP, we realized a phase II study with an identical initial scheme: 3, 10, 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly until partial response, and maintenance therapy with 30 mg every one or 2 weeks, then, 30 mg monthly until progression or toxicity. Between January 2001 and August 2005, 16 B-CLL patients have been treated with this regimen and were retrospectively analyzed on an intent-to-treat basis. Eighty-one percent (13/16) of the patients had received 3 or more prior chemotherapy regimens. Response was evaluated at 12 weeks (W12) after the beginning of the treatment by the CLL WG criteria. Survivals were defined from the first day of alemtuzumab. With a median follow-up for alive patients at 26 months, median duration of treatment was 8.5 months (range: 1.5–23.5) corresponding to a median number of 18 injections of alemtuzumab (range 6–36) realized. Nine (56%) patients received more than 6 months of monthly injections. Among them, 3 patients received one injection every 2 or 3 months after these 6 months. Two patients progressed in blood during maintenance. Modulation of the doses was then proposed with more frequent injections during a time period allowing to re-obtain a CR. Maintenance was stopped because of nodal progression in 6 patients, opportunistic infections in 2 patients (1HSV and 1 pulmonary infection), persistent CR in 3 patients, and persistant neutropenia in 1 patient. Objective response at W12 was reached in 13 (81%) of the patients, including 5 (31%) CR and 8 (50%) PR. One patient had a stable disease (disappearance of blood infiltration but stability of lymph nodes involvement) and 2 a progressive disease. Median duration of response was 11.7 months (range: 5–30). Median of TTP and overall survival were 12 months and 38 months, respectively. In this series, patients did not experience more hematological toxicities or opportunistic infections than reported with the standard regimen. Of the 13 patients that progressed at the time of analysis, 7 were re-treated by alemtuzumab (n=4) or alemtuzumab + chemotherapy (n=3). Objective responses were obtained in 6 patients during a median time at 8.7 months. In conclusion, maintenance alemtuzumab with modulation of dose intensity allowed improving time to progression and survival, without adding hematological toxicities and infectious complications.
Figure Figure
Combined Chemotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) for Relapsed or Untreated Progressive Chronic Lymphocytic Leukemia (CLL). A Single Center Experience.
Authors: Pavlovsky Santiago , Pavlovsky Carolina , Pardo Laura , Sapia Sandra , Fernandez Isolda I. , Juni Mariana 
Published: April 2020

Abstract
Introduction: During the last decade, strong prognostic factors and new compounds emerged for the treatment of CLL. The initial experience with the combination of FCR at MDACC as salvage therapy and later in untreated patients (pts) promote us to use these regimen since March 2001.
Purpose: To evaluate the efficacy of FCR in improving the complete remission (CR), disease free survival (DFS) and overall survival (OS) rates in pts previously treated with chlorambucil-prednisone as a single therapy and untreated CLL pts.
Patients and methods: A total of 32 CLL pts, 16 after relapse and 16 untreated with progressive disease completed treatment and evaluation, 3 pts are still on treatment. FCR consisted of Fludarabine 25 mg/m2 iv on days 1 to 3, Cyclophosphamide 250 mg/m2 iv on day 1 to 3 and Rituximab 375 mg/m2 iv on day 1 given at 4 weeks interval up to 4–6 cycles. Response was assessed 4–8 weeks after treatment. CR was defined by CLL/NCI-WG. Minimal residual disease (MRD) negative was defined as &lt;1% CD19, CD5 positive cells in peripheral blood and bone marrow as assessed by three colour flow cytometry. Median age was 63 years (range 34–80). Binet’s clinical stage were A: 9%, B: 31% and C: 60%. The CD38 expression was positive (&gt;7% of cells) in 53% and negative in 47% of the cases.
Results: The CR was obtained in 66% of the pts, nodular partial remission (NPR) in 19%, PR in 9% and stable disease in 6%.
Characteristics Pts. # % CR % MRD negative % DFS 24 mo P= # OS 24 mo P= Untreated Pts 16 81 100 81 0.64 90 0.81 Treated Pts 16 50 81 76 87 CD38 Positive 17 65 82 65 0.01 80 0.28 CD38 Negative 15 67 87 100 100 Total 32 66 84 78 89
Neutropenia grade 3–4 was observed in 31% of the courses, 5% of the pts required hospitalisation due to infeccious episodes.
Conclusion: In patients with CLL, FCR induce a high CR, MRD negative and DFS rate. Patients with CD38 negative expression correlated with a better DFS.
High Dose of Rituximab in B-Cell Malignancies.
Authors: Hugec Vladimir , Alexandrescu Doru T. , Oe Yukiko , Paietta Elisabeth M. , Wiernik Peter H. 
Published: April 2020

Abstract
Background: Rituximab is currently used as a standard agent in many B cell malignancies. High doses of rituximab may be more efficacious in the treatment of chronic lymphocytic leukemia and mantle cell lymphoma, because CD20 antigenic sites occur in low density per cell, and soluble CD20 in the plasma binds with infused rituximab. We describe our results with escalated high doses of single agent rituximab given as weekly induction doses followed by monthly maintenance doses.
Methods: 18 patients (10 males, 8 females) with median age 58 years (range 42 – 80); 4 patients with MCL and 14 patients with CLL were enrolled. Rai stages were: Stage 0–1, Stage I–2, Stage II–5, Stage III–8, Stage IV–2. 9 patients had at least one prior treatment (range, 1–8 treatments): fludarabine-7 patients, chlorambucil-6 patients, chlorambucil and fludarabine-4 patients. Median duration of disease prior to rituximab administration was 23 months (1–143 months). 9 patients had bulky disease (mass largest diameter &gt; 5 cm). All patients received the standard single agent rituximab dose 375 mg/m2 with weekly escalation up to 2,250 mg/m2, followed by the highest escalated dose of rituximab as a monthly maintenance dose. The median monthly dose 1000 mg/m2 (range 500 – 2,250 mg/m2), and the median number of monthly doses was 18 (4–76 doses).
Results: The overall response rate (CR + PR) was 88% (CR 50%, PR 38%). CR median duration is 17 + months (6 – 46 + months). CD20 intensity of staining (range of mean fluorescense intensity ratio 162–4766) and CD38 expression (range 5–99%) did not correlate with responses. The median time to progression was not reached. 8 patients progressed and their median time to progression is 25 months (14–48). None of the patients with bulky disease reached CR. 2 CR and 4 PR were observed in previous fludarabine failures. 3 of 4 patients with MCL reached CR and one continues in CR 46+ months off treatment. Rituximab was very well tolerated and only 2 episodes of grade 3 infusion related toxicity were observed. Both patients completed infusion with appropriate supportive care.
Conclusion: Single agent rituximab in high doses can induce durable clinical response in non-bulky early stage CLL/MCL. Higher than standard doses improve responses possibly by saturating CD20 binding sites and overcoming the obstacle of circulating CD 20 antigen.
Applying of Fludarabine in One Patient with CLL/PL Prolymphocytic Transformation - One Case Report.
Authors: He XueFeng , Zhang Ri , Ma QinFen , Tao RuiFang , Wu DePei 
Published: April 2020

Abstract
We reported one case of CLL/PL with prolymphocytic transformation and observed the effect of fludarabine on it. The patient was first admitted for nonspecific hematological symptoms. Her bone marrow showed a mixture leukemia cell’s group consisted of 30% prolymphocytes and 50% mature small lymphocytes. Datas of MIC assay were analyzed. Phenotype indicated some prolymphocytic features. The patient was diagnosed as CLL/PL and a traditional chemotherapy regimen mainly consisted of CHOP and leukeran was applied but showed very limited effect. One month later she was admitted once more for aggravating anemia. MIC was examined again and showed a high proportion of 60% prolymphocytes in marrow. Phenotype by FCM indicated a double positive expression of FMC7 and SmIg. The patient was diagnosed as prolymphocytic leukemia transformed from CLL/PL. Chemotherapy based on CVP and leukeran received no good response. So a single-agent regimen of fludarabine (30 mg*m−2*d−1 IV for 5 days as one cycle) was tried. After two cycles’ chemotherapy, bone marrow was reevaluated. Proportion of prolymphocytes descended to a level of 1% and a mild bone marrow suppression was accompanied. Nearly half a year’s follow-up showed a sustained blood tri-linage low level and the patient still led an acceptable quality life with packed red cell support once a month.
Combination of Fludarabine (FAMP) Cyclophosphamide (CTX) and Alemtuzumab for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL).
Authors: Tedeschi Alessandra , Montillo Marco , Miqueleiz Sara , Draisci Michela , Ricci Francesca , Scarpati Barbara , Mura Mariangela , Crugnola Monica , Morra Enrica 
Published: April 2020

Abstract
Previous studies have shown that FAMP in combination with CTX seems to have a significant advantage over single-agent FAMP in patients with relapsed CLL who had previously received alkylators or alkylators plus fludarabine, but are still fludarabine-sensitive. Despite the improved response rates, patients who achieve CR eventually relapse and require alternate therapies. The high rate of relapse in CLL affirms the need for improved treatments, which reduce or eliminate residual disease (MRD) to induce “better quality,” more durable responses. The monoclonal antibody alemtuzumab (Campath®), which is directed towards the CD52 antigen expressed on the surface of B-CLL cells, acts synergistically with fludarabine in vitro and appears to have synergistic activity in vivo. Alemtuzumab is one of a few single agents that has demonstrated the ability to eliminate minimal residual disease in CLL. Therefore, we designed a phase II study to determine the efficacy and safety of a 4-week combination regimen consisting of FAMP, CTX, and alemtuzumab (FCC) in relapsed patients with CLL. Objectives of this study also included the evaluation of the overall response rate (ORR), duration of response (DR), and the presence of MRD following treatment with FCC. Patients received FCC after a short period of alemtuzumab dose escalation, from 1 mg to 3 mg to 10 mg on consecutive days. The FCC regimen consisted of FAMP 40 mg/m2/day PO (Days 1–3), CTX 250 mg/m2/day PO (Days 1–3), followed by alemtuzumab 10 mg SC (Days 1–3). This combination was repeated on Day 29 for up to 6 cycles. MRD was measured by 4-color flow cytometry and consensus primer PCR. Nine patients (7 male and 2 female), have been enrolled in this trial. The median age of patients was 60.3 years (range, 43–78 years); 2 patients (22%) were in Binet stage C, 3 patients were in stage A and 4 patients were in stage B. Median number of prior treatment regimens was 2 (range, 1–3). Currently, 3 patients completed treatment, and 2 patients received 3 courses while the remaining 4 patients completed the first course. Among the 3 patients who completed treatment, 1 achieved a complete response (CR) and 2 patients a partial response (PR). MRD negativity was achieved in the peripheral blood in 1 patient. No CMV reactivation has been observed. No opportunistic infections have been recorded. Hematologic toxicity was manageable: 2 patients required G-CSF support. No nonhematologic toxicity was documented. This preliminary data on safety and efficacy of this regimen are encouraging and warrant further study.