bluuebunny/crossref_metadata_2025 huggingface dataset:
Important Role of Routine Cerebrospinal Fluid Examination in Diagnosing Central Nervous System Relapse during Maintenance Therapy in Pediatric Acute Lymphoblastic Leukemia.
Authors: Lieberman Lani , Grant Ronald , Hitzler Johann K. , Gassas Adam
Published: April 2020

Despite the success of central nervous system (CNS) preventive therapy in reducing the incidence of CNS recurrence in pediatric acute lymphoblastic leukemia (ALL) on therapy, CNS relapse continues to be a significant cause of treatment failure and is observed in 5–10% of patients. While most pediatric ALL treatment protocols mandate periodic lumbar puncture (LP) surveillance for the length of therapy, some centers have stopped collecting routine CSF samples unless there are suggestive signs or symptoms of CNS involvement. Our objective herein was to assess the value of routine cerebrospinal fluid (CSF) obtained while performing routine LPs for administration of intrathecal chemotherapy in diagnosing CNS relapse in children with ALL in the maintenance phase.

Patients and Methods: All children (0–18 years) with ALL, diagnosed and treated at the Hospital for Sick Children, Toronto, Canada between 1994–2004 were subjected to a retrospective analysis. Original reports for CNS relapse during maintenance therapy were examined to determine whether CNS relapse was diagnosed based on routine CSF sample obtained while administering intrathecal chemotherpy or a CSF sample obtained based on signs and symptoms or after a diagnosis of a bone marrow relapse.

Results: Four hundred and ninety four children were diagnosed and treated in our institution during the study period. Children were treated based on the children oncology group (COG), pediatric oncology group (POG) and local protocols where applicable. Thirty-one children (6.3%) suffered CNS relapse while on maintenance therapy. Twenty-one had an isolated CNS relapse and ten had a combined bone marrow and CNS relapse. Seventy-six percent (16/21) isolated CNS relapses were diagnosed base on routine CSF samples obtained from asymptomatic children while administering intratheacal chemotherapy. Conversely, all patients with combined bone marrow and CNS relapse presented with symptoms and signs that warranted CSF examination.

Conclusion: Routine CSF examinations are important in detecting CNS relapse in children with ALL during maintenance therapy. Furthermore, routine CSF sampling may detect isolated CNS relapse in asymptomatic children with ALL prior to extension into combined relapse where prognosis is less favorable.
A Report of the Event Free Survival (EFS) for Children with Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL) Treated on Pediatric Oncology Group (POG) Protocol 9605.
Authors: Bell Beverly A. , Abish Sharon B. , Chauvenet Allen , Kurtzberg Joanne , Pullen Jeanette , Devidas Meenakshi , Shuster Jonathan , Camitta Bruce M.
Published: April 2020

POG 9605 opened in 1996, as a randomized 2x2 factorial design for children with standard risk ALL to determine: 1) whether the addition of 6 months of delayed intensification with divided dose oral methotrexate (ddMTX) improves the event free survival (EFS) and 2) the effect on EFS of delivering oral 6-mercaptopurine (MP) on a divided (twice daily) vs. once daily schedule, during delayed intensification and continuation. A total of 1063 eligible patients were randomized to the post induction therapy. Following remission induction, consolidation was defined as weeks (wk) 5–24 from diagnosis, and all patient received MTX 1 g/m2 IV over 24 hours q3 wks x 6 courses, with leucovorin rescue 10 mg/m2 p.o./IV q6h for 5 doses beginning 42 hours after the start of MTX infusion, oral MP 50 mg/m2/day, prednisone/vincristine (VCR) pulses, (prednisone 40 mg/m2/day x 7 days, with VCR 1.5mg/m2/dose (max 2 mg) IV days 1 and 8, on wks 8.17 and 25. Late intensification was defined as wks 25–52. Patients were randomized to the following regimens: 1) MTX 20 mg/m2 IM q wk, MP 75 mg/m2 p.o. qhs, 2)ddMTX 25 mg/m2 p.o. q6h x 4 doses q2wks, leucovorin 5 mg/m2 p.o. q12h x 2 doses, (beginning 48 h after the start of ddMTX), MP 75 mg/m2 po qhs, 3)MTX 20 mg/m2 IM q wk, MP 37.5mg/m2 p.o. BID 4)ddMTX (as in regimen 2) MP 37.5 mg/m2 p.o. BID. All regimens received prednisone/VCR pulses wks 25, 41, 57, 73 89 and 105. Continuation therapy was defined as wks 53 to 130. All patients received MTX 20mg/m2 IM weekly. Reg 1&2: MP 75 mg/m2 qhs; Reg 3&4: MP 37.5 mg/m2/dose BID. CNS prophylaxis was age adjusted, initially with triple intrathecal chemotherapy (TIT), amended in 1999 to deliver IT MTX alone, and leucovorin rescue was subsequently added because of projected excessive neurotoxicity. The overall EFS for this study is 77%±1.6 %(s.e.) at 6 years. This study had a 2x2 factorial design to answer the two questions related to MTX and MP delivery, respectively. However, the results showed statistically significant interaction between the MTX and MP questions (P=0.0081). There were significant differences in EFS between the four arms (stdMTX-stdMP 70.7%±3.6%, ddMTX-stdMP 82.7%±2.9%, stdMTX-ddMP 80.7%±3.2%, ddMTX-ddMP 76.4%±3.2%), P=0.0141. Although ddMTX-stdMP and stdMTX-ddMP had significantly better EFS compared to the stdMTX-stdMP arm (P=0.005 and P=0.01, respectively), this was not designed as a four arm study and has insufficient power to determine which arm was superior.
Therapy-Related Myelodysplastic Syndrome (sMDS) /Acute Myelogenous Leukemia (sAML) in Acute Promyelocytic Leukemia (APL) Patients with Long-Lasting Molecular Remission: The GIMEMA Experience.
Authors: Latagliata R. , Breccia M. , Fazi P. , Gubbiotti S. , Di Bona E. , Specchia G. , Chiarenza A. , Murru R. , Carella A.M. , Ferrara F. , Rossi G. , Melillo L. , Sica S. , Invernizzi R. , Cimino G. , Petti M.C. , Avvisati G. , Lo-Coco F. , Mandelli F.
Published: April 2020

The occurrence of a sMDS in patients potentially cured from a previous APL has been recently reported. To evaluate the real incidence and the clinical characteristics of sMDS/sAML post APL, the follow-up of 336 patients with newly diagnosed APL enrolled by 22 GIMEMA Centers in the LAP AIDA 0493 protocol has been revised. After the induction, 314 patients (93.4%) achieved complete remission (CR): of them, 225 (71.6%) are still alive in 1st CR, 12 (3.8%) died in CR and 71 (22.7%) relapsed. The remaining 6 patients (1.9%) developed a sMDS while in 1st morphological CR, after a median time from CR achievement of 42 months (range 27 - 75). Among the 71 relapsed patients, 15 had no further data and 41/56 (73.2%) achieved a 2nd CR after salvage treatments: 2 of them (4.8%) developed a sMDS while in 2nd morphological CR, after 48 and 27 months from 1st CR, respectively. Furthermore, another patient showed a sMDS while in 3rd CR. As to clinical and biological characteristics of these 9 sMDS patients, there were 3 male and 6 female with a median age at sMDS diagnosis of 57 years (range 31 – 71): cytogenetic analysis failed in 2 patients, was normal in 1 patient and revealed abnormalities of chromosomes 5 or 7 in the remaining 6 patients, with a complex karyotype in 4 of them. One patient underwent allogeneic BMT soon after sMDS and is still alive after 57 months, 2 patients are in stable myelodysplastic phase after 25 and 63 months respectively. An evolution in sAML occurred in the remaining 6 patients, after a median sMDS duration of 7.6 months (range 2 – 45): 5 sAML patients received only supportive care +/− palliative chemotherapy, 1 patient underwent intensive chemotherapy but was resistant. All sAML patients died after a median time from AML evolution of 4 months (range 0.8 – 5) In conclusion, the incidence of sMDS post APL seems low in 1st molecular CR, but increases in patients achieving 2nd or subsequent CR: clinical characteristics and prognosis are similar to those observed in other sMDS. A longer follow-up will help us to define the late occurrence (> 5 years from CR) of this severe complication. In addition, the availability of prognostic score systems at initial diagnosis and residual disease monitoring by PCR might allow better tailoring of treatment intensity in APL, in an attempt to spare unnecessary toxicity and minimise the risk of sMDS/sAML development for patients who have low risk disease.
A 3-Year Follow-Up of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (As2O3) as Front Line Therapy for Newly Diagnosed Acute Promyelocytic Leukemia (APL).
Authors: Hu Jiong , Liu Yuan-Fang , Zhu Yong-Mei , Shi Zhan-Zhong , Li Jun-Min , Wang Li , Chen Yu , Shen Zhi-Xiang
Published: April 2020

PURPOSE: To confirm the potential benefit of front-line use of all-trans retinoic acid (ATRA) combined with arsenic trioxide (As2O3) in patients with newly diagnosed acute promyelocytic leukemia (APL) with prolonged follow-up to median of 3-year and compared with historical control.

PATIENTS AND METHODS: Two groups of newly diagnosed patients with APL were included in the analysis. The study group received combination therapy of ATRA and As2O3 includes 56 patients since April 2001. The historical control groups included 56 patients from May 1998 to March 2001. No statistically significant differences of clinical characteristics such as sex, age and hematological data were documented between two groups. For the study group groups, all patients received 25mg/m2 ATRA orally and 0.16mg/kg As2O3 intravenously per day till CR. Once CR achieved, they were given 3 courses of consolidation chemotherapy and then 5 cycles of sequential treatment of ATRA, As2O3 and 6-MP/MTX. For the historical group, the induction therapy was ATRA given at 25mg/m2 daily till CR and chemotherapy was added in case of leukocytosis. The post-remission therapy consists of chemotherapy with ATRA.

RESULT: In study group, 52 (92.9%) patients achieved CR and the time to CR was 26.4±4.5 days. At last follow-up at February 2005, only two patients underwent extramedullary relapse and one died from CNS leukemia while all other patients were alive and remained in hematological remission. With a median follow-up of 34 months (21 to 46 months), the 3-year OS and EFS were estimated as 97.4% and 93.5%. For the historical control groups, the median follow-up was 56 months (12 to 79 months). The 3-year estimated OS and EFS was 83.2% and 57.7% (P=0.069 and 0.00001 respectively). Of notice, in the last follow-up, all evaluable patients in clinical remission maintained a complete molecular response (undetectable PML-RARa via both regular and real-time RT-PCR).

CONCLUSION: Our 3-year follow-up data demonstrate a solid clinical benefit of front-line combination of ATRA and As2O3 in terms of EFS. There was also a trend toward improvement in OS which might translate into better chance of curing the disease.
Tolerability of Chemotherapy for AML or MDS in Children with Fanconi Anemia.
Authors: Mehta Parinda A. , Ileri Talia , Harris Richard E. , Williams David A. , Auerbach Arleen D. , Smith Franklin O. , Mo Jun , Smolarek Teresa , Kelly Patrick , Davies Stella M.
Published: April 2020

Fanconi anemia (FA) patients have a 33% cumulative incidence of AML by 40 years of age (Kutler et al, 2003). Chemotherapy treatment of FA patients with MDS or AML is challenging because of constitutional sensitivity to DNA-damaging agents. Severe toxicity and marrow aplasia without hematological recovery have been described, largely in case reports of children given chemotherapy prior to diagnosis of FA. The definitive treatment for hematological malignancy in FA is stem cell transplant (SCT). However, transplant in patients with overt AML has a poor prognosis and also a donor may not be immediately available. Relapse post-SCT is usually fatal. Between 2002 and 2005 we treated 6 children with FA and AML or hypercellular MDS with monosomy 7, referred to the Fanconi Anemia Comprehensive Care Clinic at Cincinnati Children’s Hospital, with a uniform chemotherapy protocol (“mini-FLAG”).

Figure Figure

Clinical characteristics of patients, toxicity and efficacy of mini-FLAG are shown below: 3 patients belonged to complementation group A and one each to group D1, J and F. Overall, mini-FLAG was well tolerated with no mucositis or organ toxicity. Two of the three patients with leukemia achieved clearance of blasts and cytoreduction was attained in those with MDS. In all cases, patients proceeded to SCT once cytoreduction was achieved so reconstitution of normal hematopoiesis and durability of response could not be assessed.

Table 1 Pt # Age / Gender Marrow cytogenetics Toxicity of mini-FLAG Marrow morphology pre-mini-FLAG Marrow morphology after mini-FLAG 1 16.3yrs/M 45,XY, t(2;3) No organ toxicity AML; 51% blasts No residual blasts; markedly hypocellular marrow 2 14.2yrs/F 47,XX, t(6;11) No organ toxicity AML; 80% blasts Hypoplastic; <5% blasts 3 2yrs/M Complex karyotype including add(1)(q21),add No organ toxicity; reversible skin rash with Ara-C AML; 75% blasts Blasts reduced to 36%; marrow blasts cleared with daunomycin + Ara-C 4 13.7yrs/F 46,XX,del(7) No organ toxicity CMMoL; hypercellular Normocellular marrow; morphology still CMMoL 5 8.5yrs/M 46,XY,der(2)t(2;3)(q3?6;q?),der (7)del(7)(p11.2) No organ toxicity MDS; hypercellular; prominent abnormal monoblasts Hypocellular; minimal dysplasia 6 10.6yrs/F 45,XX,-7 No organ toxicity Mild dysplastic changes Hypocellular; Monosomy 7 in 13% of cells

Three children survive; one died of relapsed leukemia 4 months post-SCT and 2 of complications of SCT. These data show that mini-FLAG can be used with minimal toxicity and significant but heterogeneous responses in children with FA. A future prospective multi-center study is needed to optimize use of chemotherapy in FA and determine the effect of pre-transplant chemotherapy on outcomes of SCT.
Estimated Annual Number of US Acute-Care Hospital Inpatients Meeting ACCP Criteria for Venous Thromboembolism (VTE) Prophylaxis.
Authors: Anderson Frederick A. , Zayaruzny Max , Heit John A. , Cohen Alexander T. ,   On Behalf of the VTE Impact Assessment Group
Published: April 2020

Background While consensus guidelines regarding VTE prophylaxis for hospital inpatients have been available for more than 15 years, the number of US inpatients who are potentially eligible for prophylaxis is unknown. Such data are required for estimating the potential costs and benefits of prophylaxis in reducing VTE incidence. Objective To estimate the number of Y2002 US acute-care hospital inpatients who are potentially eligible for VTE prophylaxis.

Methods We applied the 7th (2004) American College of Chest Physician (ACCP) Consensus Conference VTE prophylaxis guidelines (Geerts et al. Chest2004;126:338S–400S) to inpatients with hospital discharge International Classification of Disease (ICD-9) codes for major surgery or medical illness identified from the Healthcare Utilization and Cost Database (HCUP), a national acute-care hospital database supported by the US Agency for Health Care Quality Research.

Results Of a total of 37.8 million inpatients discharged from US acute-care hospitals in Y2002, 13.4 million (35%) met ACCP guideline criteria for VTE prophylaxis (Table).

Table. Inpatients Discharged from US Acute-Care Hospitals with ACCP Guideline Defined Risk of VTE in Y2002 Surgical VTE Risk N Highest risk surgery 744,465 High risk surgery 3,031,318 Moderate risk surgery 2,019,696 Surgical subtotal 5,795,479 Medical VTE Risk N Heart failure 1,867,576 Cancer 1,017,356 Stroke 515,370 Other medical conditions 4,196,343 Medical subtotal 7,596,645 Grand Total 13,392,124

Among the 37.8 million Y2002 discharged inpatinets, 7.7 million were defined by HCUP criteria as having had a major operative procedure. When ACCP surgical risk criteria were applied to this population, 1.9 (25%) were at low VTE risk, while 5.8 million (75%) were at moderate (26%), high (39%) or highest (10%) VTE risk. Among the patients without a major operative procedure, 7.6 million met the ACCP criteria for VTE prophylaxis based on medical illness risk factors.

Conclusions In total, 13.4 million US residents meet ACCP criteria for VTE prophylaxis annually due to hospitalization for either major surgery or medical illness. Given that almost 60% of all VTE events occurring in the community are related to recent acute-care hospitalization, providing universal, safe and effective VTE prophylaxis to this population affords an important opportunity to significantly reduce the incidence of VTE. These data provide support for developing and monitoring compliance with hospital-wide guidelines for VTE prevention.
Low Dose Warfarin Is Effective Prophylaxis Against Deep Vein Thrombosis Following Total Hip Arthroplasty.
Authors: Bern Murray M. , Deshmukh Rahul V. , Nelson Russell , Bierbaum Benjamin , Losina Elena , Katz Jeffrey N. , Sevier Nancy , Howie Noreen
Published: April 2020

Thromboembolic disease (TED) including deep vein thrombosis (DVT) and pulmonary embolus (PE) remain major complications following total hip arthoplasty. Warfarin is an important pharmacologic prophylaxis against these complications. How to optimally use warfarin remains a sourse of debate. This retrospective patient report extends eariler observations that low dose warfarin is effective prophylaxis against symptomatic thromboembolic disease. Patients planned for elective unilateral total hip replacement were given 1 mg of warfarin for 7 days prior to surgery. Patients were excluded from this regimen if they had a coagulopathy, platelet count less than 140,000/mm3, previous TED, cancer, or were in need of long term anticogulation for other reasons. Prothrombin times were measured on the morning of surgery. The night following surgery they were prescribed variable dose warfarin which was continued while in hospital, with target INR 1.5–2.0. They were discharged to rehabilitation centers or home taking 1 mg daily until their 4–6 week followup visit. All patients received post-operative pneumatic compression stockings, followed by elastic compression stockings when ambulatory. Patients were encouraged to begin isometric exercises immediately after surgery and were mobilized on day 1 or 2 following surgery. Hospital and clinic charts for 13 months of consecutive patients were reviewed for any evidence of TED. Auxiliary data basis were probed for any additional evidence of TED, including the hospital logs of Radiology Department, Orthopedic Department Morbidity and Mortality rounds, Adverse Events, Medical Records Department, and Case Management. There were 833 primary and 170 revision total hip athroplasties. Of the 1003 patients studied, 3 had TED (0.3%, 95% CI 0.0–0.6), including 2 with DVT and l with nonfatel PE. The followup rate was 98.9%, with 11 patients lost to follow-up. Complications from the warfarin were minimal. The prothrombin times on the morning of surgery were below INR 1.4 for 98.9% of the patients. Two patients with INR greater than 1.49 on day of surgery received fresh frozen plasma. Seven patients had post-operative wound hematomas, one of which had INR greater than 1.5. Very low warfarin when started preopartively, continued as variable dose in the immediate postoperative period, and continued at 1 mg until the patient is fully ambulatory, combined with the mechanical tools listed, is effective and safe prophylaxis against TED.
A Variant of Congenital Neutropenia Is Caused by a 3′-UTR Mutation in the Gene Encoding the Endosomal Adaptor Protein p14 (MAPBPIP).
Authors: Bohn Georg , Allroth Anna , Thiel Jens , Schäffer Alejandro A. , Brandes Gudrun , Glocker Erik , Teis David , Taub Nicole , Zeidler Cornelia , Geffers Robert , Buer Jan , Huber Lukas A. , Welte Karl , Grimbacher Bodo , Klein Christoph
Published: April 2020

We have investigated the molecular etiology of autosomal recessive congenital neutropenia in a pedigree of 15 members with four affected children. Combining genome wide linkage analysis and a transcriptional profiling approach, we identified a homozygous mutation in the 3′-UTR of p14 (MAPBPIP), a recently identified adaptor molecule controlling late endosomal signaling by the MP1-MAPK complex. The mutation segregated with the disease, and neutrophils from all patients showed decreased RNA and protein levels of p14. To further assess the significance of this point mutation, we designed firefly luciferase reporter plasmids carrying either wildtype or mutated 3′-UTRs and cotransfected these constructs together with renilla luciferase expression plasmids into CHO cells. The specific luciferase activity was consistently decreased in the mutated constructs, suggesting that the mutated 3′-UTR is associated with decreased RNA levels in a heterologous system. Mechanistically, we excluded aberrant splicing and aberrant polyadenylation as a cause for decreased RNA levels. However, an increased ratio of unprocessed to processed nuclear RNA in transfected cells suggests a defect in RNA processing. Decreased levels of p14 lead to an abnormal configuration of lysosomes in granulocytes as shown by transmission electron microscopy. Whereas phagocytosis capacity is normal, killing of pathogenic bacteria is reduced in p14-deficient granulocytes. This defect is reversed upon retroviral p14 gene transfer into hematopoietic stem cells and subsequent differentiation into neutrophils in vitro. In summary, we provide evidence that decreased levels of p14 cause neutropenia. Furthermore, our report extends the small list of hereditary diseases associated with 3′-UTR mutations.
Rituximab Maintenance Prolongs Response Duration after Salvage Therapy with R-FCM in Patients with Relapsed Follicular Lymphomas and Mantle Cell Lymphomas: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Hiddemann Wolfgang , Forstpointner Roswitha , Dreyling Martin , Gramatzki Martin , Böck Hans-Peter , Hänel Mathias , Seymour John , Planker Manfred , Dührsen Ulrich , Wilms Klaus , Clemens Martin , Ludwig Wolf-Dieter , Wandt Hannes , Pasold Rita , Unterhalt Michael
Published: April 2020

Preceding studies have shown that Rituximab prolongs the time to treatment failure (TTF) and response duration (RD) in follicular lymphoma (FL) when given either together with chemotherapy or as maintenance after a no R containing therapy. In the current study the impact of R maintenance on RD was evaluated after remission induction by an R-chemo combination. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized a first randomization between 4 courses of chemotherapy with Fludarabine (25mg/m2/d days 1–3), Cyclophosphamide (200mg/m2/d days 1–3) and Mitoxantrone (8mg/m2/d day 1) (FCM) versus FCM plus Rituximab (375mg/m2/d on day 0) (R-FCM). Patients entering a complete (CR) or partial remission (PR) underwent a second randomzation for observation only versus R maintenance with 4 weekly doses of R (375mg/m2/d) to be given at three and nine month after end of therapy. Both randomizations were stratified for histology and preceding therapy. The first randomization was stopped after 147 patients demonstrating a significant improvement for the R-FCM therapy in initial response, progression free survival and even overall survival (OS). So all subsequent patients received R-FCM.

174 cases are currently evaluable for the second randomization, 136 of whom had received R-FCM for remission induction. In these patients the median RD has not been reached in the R-maintenance arm whereas it is 17 months in patients with no further treatment after R-FCM (p=0.0024). This improvement was seen both in FL and MCL. This study demonstrates that R maintenance after R-FCM salvage therapy is highly effective and improves the outcome of patients with relapsed FL and MCL.
The Addition of Rituximab to Dose-Adjusted EPOCH with HAART Suspension Is Highly Effective and Tolerable in AIDS-Related Lymphoma (ARL) and Allows the Delivery of Abbreviated Chemotherapy.
Authors: Dunleavy Kieron , Wayne Alan , Little Richard , Grant Nicole , Steinberg Seth , Jaffe Elaine S. , Pittaluga Stefania , Yarchoan Robert , Carrasquillo Jorge , Janik John , Wilson Wyndham H.
Published: April 2020

In ARL, the addition of Rituximab ® to CHOP chemotherapy may improve tumor response but the benefit appears offset by increased infectious deaths (Kaplan et al. Blood 2005; May 24: Epub). We hypothesized R with DA-EPOCH may enhance tumor kill, enabling fewer treatment cycles and lowering toxicity compared to DA-EPOCH alone. Pts received DA-EPOCH-R (in mg/m2/d etoposide 50, vincristine 0.4 and doxorubicin 10 all CIV d 1–4; and in mg/m2 cyclophosphamide 750 IV day 5, prednisone 60 po days 1–4 and rituximab 375 IV d 1, 5; and G-CSF sc d 6–15). Prophylactic IT MTX x 6 was administered and HAART was discontinued on all cycles. Cyclophosphamide was adjusted based on ANC nadir. Response was assessed by CT and PET and pts received 1 cycle beyond CR for a minimum of 3 cycles. Characteristics of 27 pts include median (range) age 41 (9–61) years; IPI 3 (0–4); ECOG PS 1 (1–4), CD-4 212 (0–674) cells/mm3; HIV viral load 58,700 (0–6,080,000) RNA copies/mL; male sex 22 (81%); LDH > N 19 (70%); stage IV 18 (67%) and histology DLBCL 25 (93%) and Burkitt lymphoma 2 (7%). Of 24 evaluable pts (2 NE, 1 TE), median (range) cycles is 3 (3–5) with CR/Cru in 21 (88%) and PR 1 (4%) pts. At 25 mos median follow-up, PFS and OS are 77% and 72%, respectively. Shown below are PFS and OS for the entire group and PFS in pts with CD4 > and < 100 cells/mm3. In pts with CD4 > and < 100 cells/mm3, OS was 92% and 48%, respectively, indicating a relatively low probability of non-tumor related deaths at 2 yrs among pts in remission. IPI did not impact OS or PFS. The predictive value of early PET (after cycle 2 or 3) for progression was evaluated in 21 pts in remission. None of 11 pts with a negative PET progressed (100% negative predictive value) whereas only 2 of 10 pts with a positive PET progressed (20% positive predictive value). Toxicity on 81 cycles included ANC < 500/mm3 on 33 (41%); platelets < 50000/mm3 on 20 (25%) and; fever/neutropenia on 27 (33%). No treatment related deaths occurred. Short course DA-EPOCH-R is highly effective and tolerable in all subgroups of ARL with significantly fewer treatment cycles (median 3 versus 6 cycles) compared to DA-EPOCH alone. CD4 cells decreased a median of 42 cells/mm3 (range +271 to − 320) by end of therapy with DA-EPOCH-R compared to 189 cells/mm3 (range +19 to −973) with DA-EPOCH alone. While a negative PET scan reliably predicted a disease-free state, a positive PET scan only predicted treatment failure in 20% of pts in remission. Although this study was not designed to assess the benefit of rituximab, a comparison to DA-EPOCH (Blood101:4653, 2003) suggests rituximab may enhance tumor kill and reduce immune suppression. Accrual continues.

Figure Figure Figure Figure
Results of a Pilot Trial of Fludarabine, Mitoxantrone and Rituxan in Mantle Cell Lymphoma.
Authors: Levine Alexandra M. , Tulpule Anil , Smith Lynne , Espina Byron M. , Mohrbacher Ann F. , Feinstein Donald I.
Published: April 2020

Mantle cell lymphoma is an aggressive B cell tumor, with a median survival of approximately 3 years, despite treatment. While intensive therapy may be curative in some patients, the median age at diagnosis is in the 60’s, and such therapy is not always feasible. We developed a regimen of fludarabine, mitoxantrone and rituximab, comprised of fludarabine, 25 mg/m2, IV on days 1–3; mitoxantrone, 10mg/m2, IV on day 1, every 28 days for 6 cycles, along with rituximab, 375 mg/m2 given on day 1, of cycles 2 through 6, and then given alone for 3 weekly doses as cycle 7. To date, 14 male and 7 female patients with a median age of 60 years (range 41–87) have been accrued. Five patients (24 %) relapsed from prior systemic chemotherapy including stem cell transplantation in 1. All but 1 patient had either stage III (n=2) or stage IV disease (n=20). Sites of extranodal disease included bone marrow in 15 (71%), pleural effusions in 5 (24 %), and GI tract involvement in 3 (14 %) patients. Eight patients (38 %) had an intermediate or high IPI score. B symptoms were present in 7. On pathologic assessment, no patient had blastoid morphology. Cyclin D1 was expressed in 19 of 21 tissues tested. Treatment has been well tolerated; the most common side effect was transient grade 3 or 4 neutropenia reported in 17 (81 %) patients; transient grade 3 or 4 thrombocytopenia in 3 patients; and anemia observed in 6 patients. No grade 3 or 4 non-hematologic toxicity has been reported. Of 20 evaluable patients, complete remissions (CR) have been documented in 18 (90 %). The median duration of complete remission is 17.4 months (range 1.1–29.9). Thirteen patients have relapsed after 1.1 to 29.9 months in CR. All 20 of the evaluable patients remain alive after a median follow-up of 16.4+ mos (range 1.0–39.6+). Combination therapy with fludarabine, mitoxantrone, and rituxan is a well tolerated regimen and is highly active in patients with both newly diagnosed and relapsed mantle cell lymphoma. While relapse is seen in the majority, the regimen is capable of inducing CR in 90 % and can be used safely in elderly patients and those who have relapsed or are not eligible for stem cell transplant.
Validation Studies in European Blood Centers To Evaluate Processing Whole-Blood-Derived or Apheresis Plasma Using the INTERCEPT Blood System Intended for Commercialization.
Authors: Singh Y. , Hervig T. , Schlenke P. , Cazenave J.P. , Pinkoski L. , Corash L.
Published: April 2020

Introduction: INTERCEPT plasma (I-FFP) for transfusion is prepared with a photochemical treatment (PCT) system using amotosalen (S-59) and long-wavelength UVA light to inactivate a broad spectrum of blood-borne pathogens. For Phase 3 clinical trials, 6 US blood centers prepared an inventory of ~10,000 I-FFP units by processing ~250 mL whole blood-derived (WB) or apheresis (APH) plasma units using a prototype PCT system. In these trials, I-FFP effectively supported patients with congenital and acquired coagulopathies or TTP. The prototype PCT system has been modified to treat up to 635 mL of plasma in a single PCT process, yielding up to three ~200 mL doses while maintaining pathogen inactivation efficacy. This modified PCT system intended for commercialization was evaluated in process validation studies in 3 European blood centers under routine operating conditions. After processing with the commercial PCT system, the effect on coagulation factor activity and retention was assessed in APH plasma (Blood2004;104:746a) and, as reported here, in WB plasma.

Methods: Whole blood and/or APH plasma units were collected at 3 European blood centers. Three-unit pools (~600 mL) of WB plasma were prepared. APH plasma (~600 mL) was collected using Autopheresis C (Baxter) or MCS+(Haemonetics) devices. Blood bank personnel processed a total of 60 WB plasma pools and 90 APH plasma units using the commercial PCT system. Baseline and I-FFP plasma samples were collected, frozen below -60°C, and sent to Cerus for assay of factors I (fibrinogen), II, V, VII, VIII, IX, X, XI, and XIII, proteins C (PC) and S (PS), and antithrombin III (AT). Alpha-2 antiplasmin (AP) was assayed by a reference laboratory. Comparative data from a representative subset of I-FFP units prepared for the Phase 3 trials using the prototype PCT system were obtained from samples collected during PCT processing and stored at ≤−70°C. Retention of activity is expressed as the proportion (%) of pre-treatment (baseline) activity remaining after PCT.

Results: Retention of coagulation factor activity in WB and APH I-FFP prepared with the commercial PCT system (Comm) was 73–76% of baseline fibrinogen and FVIII activity, and 80–97% of baseline for factors II, V, VII, IX, X, XI, XIII, PC, PS, AT, and AP (Table). Retention of activity in I-FFP prepared with the commercial PCT system was similar to that of I-FFP prepared with the clinical prototype.

Conclusion: The PCT system intended for commercialization provides multiple I-FFP doses with a single PCT process. Retention of coagulation factor activity in WB and APH plasma processed with the commercial PCT system was similar to that of I-FFP used in Phase 3 trials to effectively support patients with congenital and acquired coagulopathies or TTP.

Retention of Coagulation Factor Activity in I-FFP
A Fully-Automated Screening Method for Anti-HLA Antibodies: Implications for Screening Plasma Donations To Prevent Transfusion-Related Acute Lung Injury (TRALI).
Authors: Culler Elizabeth , Barclay Sheilagh B. , Bray Robert A. , Gebel Howard M. , Hillyer Christopher D. , Roback John D.
Published: April 2020

Background: TRALI is a potentially fatal complication of transfusion. Although the pathogenesis is not completely understood, and may involve a “multi-hit” mechanism, transfusion of donor plasma containing anti-HLA and/or anti-neutrophil antibodies appears to play an important role. In previous studies, up to 22% of all blood components were found to contain HLA antibodies (Bray et al, Human Immunology, 65, 240–4, 2004). Based on the possible involvement of HLA antibodies in TRALI, some blood services no longer provide plasma from female donors for transfusion, since these donors are more likely to have these antibodies due to pregnancy. An alternative, more specific approach to prevent transfusion of HLA antibody-containing plasma, and possibly reduce the risk of TRALI, is to screen plasma prior transfusion. However, no automated method is yet available with sufficient throughput to screen blood donors for HLA antibodies.

Methods: The 3Ti Aegis is a novel open-architecture automated blood typing platform that uses fluorescence cytometry. The Aegis was readily configured for detecting anti-HLA Class I antibodies in donor plasma by modifying the commercially-available FlowPRA Class I Screening Test (One Lambda, Canoga Park, CA) to include a phycoerythrin (PE)-labeled secondary antibody. Positive and negative control samples, as well as patient specimens previously demonstrated to contain HLA antibodies, were evaluated to determine the accuracy of the automated Aegis method.

Results: Positive and negative controls were readily distinguished from one another whether testing was performed manually (according to manufacturer’s instructions) and acquired on a BD FACScan cytometer, or performed using the fully-automated method on the 3Ti Aegis. For the Aegis, the mean fluorescence intensities for positive and negative controls were 156.2 and 14.4, respectively. For the manual method, the signal to noise separation was comparable (692.5 and 28.9, respectively). Six additional patient samples, which had previously identified anti-Class I antibodies, also tested positive with the Aegis system. Estimated staining and acquisition times on the Aegis for 96 samples are 2 hours and 1.5 hours, respectively, which is comparable to the times for manual testing

Conclusions: The Aegis can perform accurate, high throughput, completely automated screening of plasma donations for HLA Class I antibodies prior to transfusion. Future work will focus on developing combined Class I and II screening beads, as well as beads for detecting common anti-neutrophil antibodies, to produce a comprehensive TRALI antibody detection package for the Aegis platform. The Aegis is the first device to make pretransfusion HLA antibody testing practical, and may reduce the incidence of TRALI and accompanying transfusion fatalities.
Analyses of Pokemon Protein Expression in Lymphoma Reveals Elevated Expression in Nodular Lymphocyte Predominant Hodgkin Lymphoma Compared to Classical Hodgkin Lymphoma.
Authors: Teruya-Feldstein Julie , Maeda Takahiro , Filatov Alexander , Pandolfi P.P.
Published: April 2020

Background: POKEMON (for POK, Erythroid, Myeloid ONtogenic factor) has recently been shown to be a novel proto-oncogene, playing a key role in cellular transformation and repression of ARF. Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Because these transgenic mice developed T-cell lymphoma we sought to expand our original screening analyses. We intially showed POKEMON expression in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and co-expression of BCL6 and POKMEON showed higher proliferation and predicted for better overall survival in DLBCL (Nature 433, 278–285). Nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) is another tumor that expresses BCL6 and shows localization to L&H tumor cells. We therefore sought to compare POKEMON protein expression in NLPHL and Classical Hodgkin Lymphoma (cHL) cases.

Design: Stains for POKEMON were performed with the anti-POKEMON hamster monoclonal antibody (clone 13E9). Sections of reactive human tonsil were stained as controls showing localization to squamous epithelium and reactive germinal centers as well as paracortical regions. For NLPHL, the cohort comprised of 19 males, 2 females; for cHL 16 males, 14 females. 20 NLPHL and 30 cHL tissue biopsies were stained using whole sections. Intensity and percent positivity of malignant L&H cells and Reed-Sternberg (RS) cells as well as surrounding reactive lymphocytes was scored. Expression in T-cell lymphomas was expanded to include a total of 84 cases analyzed by tissue microarray (TMA) that included: 8 ALCL (Anaplastic Large Cell Lymphoma), 11 AILT (Angioimmunoblastic T-cell Lymphoma), 17 T-ALL (T Lymphoblastic Lymphoma), 43 PTCL (Peripheral T-cell Lymphoma), 3 T/NK (Nasal type T/NK cell Lymphoma), and 2 PTCL, NOS (Not Otherwise Subclassified). Tumor cells in T-cell lymphomas and HL were scored and defined as 0 (negative), 1 (scattered <50%, weak positive), and 2 (diffuse >50%, strong positive) with a nuclear localization pattern.

Results: For NLPHL, 18/20 (90%) cases showed diffuse strong positivity in >50% of malignant L&H tumor cells whereas in cHL cases, 6/30 (20%) cases showed diffuse strong positivity in >50% of malignant RS tumor cells for POKEMON protein expression. In T-cell lymphomas, POKEMON expression was strongest in ALCL (6/8, 75%) and AILD (7/11, 74%) compared to the other subtypes. In contrast, BCL6 protein expression was positive in 12/20 (60%) cases which showed weak, scattered to diffuse strong positivity in L&H tumor cells and 1/30 (3%) with scattered weak reactivity in cHL malignant RS cells

Conclusion: POKEMON is co-expressed with BCL6 in malignant L&H tumor cells in NLPHL but not in cHL. Pokemon’s critical role in cellular transformation makes it an attractive target for therapeutic intervention in NLPHL.
Haplotype-Based Sequencing To Delineate the Associated HLA Class I Region for EBV Positive Hodgkin Lymphoma.
Authors: Niens Marijke , van den Berg Anke , Diepstra Arjan , Nolte Ilja M. , van der Steege Gerrit , Jarrett Ruth F. , Poppema Siebrand , te Meerman Gerard J.
Published: April 2020

Various studies have indicated that the human leukocyte antigen (HLA) region is associated with Hodgkin Lymphoma (HL). We recently demonstrated a specific association of the HLA class I region with Epstein-Barr virus (EBV) positive HL cases. The positively associated haplotype was characterized by alleles 126 and 284 of the consecutive microsatellite markers D6S265 and D6S510 while the negatively associated haplotype was characterized by alleles 130 and 302. Further fine mapping of this region is necessary to find the causative SNP(s). To select the most promising candidate SNPs for screening the total study population, known SNPs were sequenced in an individual homozygous for the positively associated haplotype and an individual homozygous for the negatively associated haplotype. Five SNPs (rs2530388, rs2523972, rs4713276, rs2256543, and rs6457110) that were selected on the basis of displaying different alleles in these two individuals were analysed in the total study population. The five SNPs showed significant association with the EBV-positive patient group, three of them revealed a stronger association than the previously identified associations (−log p difference = 1). These five SNPs were also analysed in a Scottish population, and four of them showed association in that population as well. The associated region was narrowed down from 310 kb in the original study to a region comprising less than 60 kb in the present study. Of the genes mapping to this candidate region, HLA-A represents the most interesting target because of its consistent expression in EBV positive HL cases and its ability to present EBV derived peptides to cytotoxic T cells.
Ocular Adnexal Lymphoma: A Clinicopathological Study of a Large Cohort of Patients with No Evidence for an Association with Chlamydia psittaci.
Authors: Rosado Manuel F. , Byrne Gerald E. , Ding Feying , Fields Keneth A. , Ruiz Phillip A. , Dubovy Sander R. , Walker Gale R. , Markoe Arnold , Izidore Lossos S.
Published: April 2020

Ocular adnexal lymphomas (OALs) represent 6% of all primary extranodal NHL. However, they are among the most common primary tumors occurring in the ocular adnexa (26%). The etiology of OALs and the reason for the predominance of extranodal marginal zone lymphoma (EMZL) in this anatomical location are unknown. Ferreri et. al (J Natl Cancer Inst2004; 96:586) recently reported the presence of C psittaci DNA in 80% of the analyzed Italian ocular adnexa EMZL cases. Herein, we reviewed our 14-year single institution experience in a large cohort of patients with primary OALs and examined the association with C psittaci infection in South Florida. Clinicopathological characteristics, response to therapy, systemic dissemination and patients’ survival were analyzed in 62 patients with primary OALs treated and followed-up at the Sylvester Comprehensive Cancer Center. EMZL was the most frequent histological subtype (89% of OALs). Majority of EMZL patients (84%) presented with stage IE, however only 16% had an advanced stage. All stage IE patients were treated with local radiotherapy, while patients with disseminated disease received systemic therapy with or without local irradiation. All but one EMZL patient achieved CR. During a median follow up of 52 months (range 3–153), the estimated 5-year OS and FFP were 96% (95% CI: 90 to 100%) and 79% (95% CI: 65 to 92%), respectively. During the follow-up, 22% of patients relapsed, mainly in extranodal sites and 4% transformed to diffuse large B-cell lymphoma. None of the patients exhibited local orbital failure in the radiation field. To analyze the association between C psittaci infection and OALs in our patient population, C psittaci touchdown enzyme time release-PCR was used in 57 tumor specimens. DNA was extracted from 49 specimens of EMZL of ocular adnexa, 8 specimens of non- EMZL of ocular adnexa and 2 specimens from patients with reactive ocular lymphoid hyperplasia. C psittaci DNA was not detected in any of the 57 tumor DNA samples positive for either beta-globin or ApoE DNA quality control amplicons, while control reactions using DNA prepared form C psittaci strain 6 BC yielded amplicon of expected size. It is thus possible that there is a regional variation in EMZL etiology and association with infection pathogens. Additional studies evaluating the association between C psittaci and EMZL of ocular adnexa in other geographical regions are granted.
Establishment of a Waldenstrom’s Macroglobulinemia Cell Line (BCWM.1) with Productive In Vivo Engraftment in SCID-hu Mice.
Authors: Santos Daniel Ditzel , Ho Allen W. , Tournilhac Olivier , Leleu Xavier , Hatjiharrisi Evdoxia , Xu Lian , Tassone Pierfrancesco , Neri Paola , Hunter Zachary , Chemaly Mariana A.Z. , Branagan Andrew , Manning Robert , Patterson Christopher , Adamia Sophia , Kriangkum Jitra , Kutok Jeffery L. , Pilarski Linda , Anderson Kenneth C. , Munshi Nikhil , Treon Steven P.
Published: April 2020

Waldenstrom’s Macroglobulinemia (WM) is incurable B-cell malignancy characterized by the infiltration of the bone marrow infiltration with lymphoplasmacytic cells (LPC) and the presence of an IgM monoclonal gammopathy. A significant impairment in understanding the biology and advancing therapeutics for WM has been the lack of a representative cell line and animal model. We therefore report on work accomplished in our laboratories in establishing the BWMC.1 cell line, which was derived from long term culture of CD19+ selected lymphoplasmacytic cells isolated from the bone marrow (BM) aspirate of a previously untreated 55-year-old female patient with IgMk secreting WM. BCWM.1 cells morphologically resembled LPC and had prominent nucleoli and ample cytoplasm by Wright-Giemsa staining, and were propagated in RPMI 1640 medium supplemented with 10% FBS. Phenotypic characterization by flow cytometric analysis demonstrated typical WM LPC characteristics: CD5−, CD10−, CD19+, CD20+, CD23+, CD27−, CD38+, CD138+, CD40+, CD52+, CD70+, CD117+, cIgM+, cIgG−, cIgA−, ck+, cl−. BCWM.1 cells also expressed the survival proteins APRIL and B-Lymphocyte Stimulator (B-LYS), and their receptors TACI, BCMA and BAFF-R. ELISA studies demonstrated secretion of IgMk in culture. Karyotypic and M-FISH studies did not demonstrate cytogenetic abnormalities. Molecular analysis of BCWM.1 cells confirmed clonality by determination of IgH rearrangements through FR1c/JHc amplification of genomic DNA. BCWM.1 cells were positive for LMP1 expression by histochemical staining and PCR analysis. Importantly, inoculation of BCWM.1 cells directly into the human BM milieu of SCID-hu mice resulted in engraftment of tumor cells and serum detection of human IgMk in four of five SCID-hu mice within two weeks. In contrast, subcutaneous injection of BCWM.1 cells in SCID mice did not lead to engraftment, suggesting a role for the human BM microenvironment in supporting the expansion of BCWM.1 cells. These studies therefore support the use of BCWM.1 cells as an appropriate model for the study of WM, which in conjunction with the SCID-hu mouse model may be used as a convenient model for studies focused on both the pathogenesis and development of targeted therapies for WM.
Strong BCL10 Nuclear Expression Identifies Gastric MALT Lymphomas That Do Not Respond to H. pylori Eradication.
Authors: Ye Hongtao , Gong Liping , Liu Hongxiang , Ruskone-Fourmestraux Agnes , de Jong Daphne , Pileri Stefano , Thiede Christian , Lavergne Anne , Boot Henk , Caletti Giancarlo , Wundisch Thomas , Molina Thierry , Taal Babs G. , Elena Sabattini , Neubauer Andreas , MacLennan Kenneth A. , Siebert Reiner , Remstein Ellen D. , Dogan Ahmet , Du Ming-Qing
Published: April 2020

Purpose: In a previous retrospective study, we have shown that 75% of gastric MALT lymphomas that did not respond to H. pylori eradication could be identified by detection of t(11;18)(q21;q21). The present study examined the value of t(1;14)(p22;q32) in prediction of the response of gastric MALT lymphomas to H. pylori eradication.

Patients and Methods: A total of 111 patients with H. pylori-positive gastric MALT lymphoma, who were treated by H. pylori eradication, were screened for BCL10 involved chromosome translocation by BCL10 immunohistochemistry, followed by interphase FISH and real-time quantitative reverse transcription PCR (qRT-PCR). The clinical presentation of 11 cases of MALT lymphoma including 6 from the stomach with known BCL10 involved chromosome translocation was reviewed.

Results: Of the 111 cases of gastric MALT lymphoma treated by H. pylori eradication, 75 including 35 from the complete regression group and 40 from the non-responsive group, had adequate specimens for BCL10 immunohistochemistry. Two cases showed strong BCL10 nuclear staining in virtually all tumor cells, similar to that seen in those with t(1;14)(p22;q32). Both were from the H. pylori eradication non-responsive group. Although interphase FISH failed to show evidence of BCL10 gene break or amplification, one case showed an IGH break. This case also showed a high level of BCL10 mRNA expression, compatible to that seen in MALT lymphoma with t(1;14)(p22;q32). 9 of the 11 cases with known BCL10 involved translocation were at stage IIE or above, with three showing agressive clinical presentations.

Conclusion: Gastric MALT lymphomas with strong BCL10 nuclear expression or t(1;14)(p22;q32) are mostly likely resistant to H. pylori eradication.