bluuebunny/crossref_metadata_2025_split huggingface dataset:
JAK2 Genotyping (Real-Time Allelic Discrimination) Reveals Rare JAK2 V617F-Positive Erythroid Colonies in Pediatric Patients with Essential Thrombocythemia.
Authors: Pospisilova Dagmar , Veselovska Jitka , Pekova Sona , Horvathova Monika , Solna Renata , Cmejlova Jana , Cmejla Radek , Belickova Monika , Stary Jan , Divoky Vladimir 
Published: April 2020

Abstract
Childhood essential thrombocythemia (ET) is a very rare disease belonging to a group of Bcr-Abl negative myeloproliferative disorders. Our study involved 15 pediatric ET patients diagnosed at the age of 6–17 years. Monoclonal hematopoiesis was detected only in one patient, who is recently an adult (diagnosed at the age of 9). JAK2 V617F was detected in whole blood DNA by allele-specific (AS)-PCR and BsaXI restriction analysis. In our hands AS-PCR sensitivity reached the detection limit of one homozygous cell in 2000 normal cells. In addition, more sensitive AS-RT-PCR was performed on RNA isolated from granulocytes and platelets from peripheral blood. Only one patient was JAK2 V617F-positive as detected by these established protocols. In the clonal assay of hematopoietic progenitors, most patients showed hypersensitivity to erythropoietin (Epo) in vitro with the growth of Epo-independent erythroid colonies (EECs) in some of them. Over 300 myeloid colonies were picked and analyzed by real-time allelic discrimination assay for JAK2 V617F mutation run on a RotorGene 3000 instrument (Corbet Research, Australia) using fluorescently labeled LNA-modified probes. We have detected a few JAK2 V617F-positive EECs and CFU-GMs in 4 patients from our cohort. For example in one patient out of 7 analyzed EECs, one colony was homozygous and one heterozygous for the mutation. In the same patient out of 10 analyzed CFU-GMs one was homozygous for the mutation. In another patient out of 27 analyzed EECs only one was heterozygous. Some positive clones were confirmed by direct sequencing. Our data clearly show that some childhood ET patients posses JAK2 V617F-positive hematopoietic colonies derived from in vitro assays of committed hematopoietic progenitors. The rarity of the mutated subclones and the inability to detect them from peripheral blood using standardized protocols suggest either that the culture conditions without addition of Epo led to a great enrichment of the mutated colony growth or that the JAK2 V617F positive clones may be repressed in ET. The presence of JAK2 V617F clone in our cohort was not associated with any severe clinical symptoms. It would be interesting to follow up the patients for possible subsequent acquisition of JAK2 mutation as well as possible evolution of the disease to a clonal one or to polycythemia vera.
This work was supported by Ministry of Health of the Czech Republic (Grant NR9471-3), Ministry of Education, Youth and Sports of Czech Republic (projects MSN 6198959205 and MSN 6198959216).
Role of JAK2V617F during In Vitro PV Erythroid Progenitor Differentiation.
Authors: Nussenzveig Roberto , Gaikwad Amos , Manshouri Taghi , Dwyer Karen , Zhang Ying , Kantarjian Hagop , Verstovsek Srdan 
Published: April 2020

Abstract
The dominant gain-of-function mutation in the tyrosine kinase JAK2 (1849 G to T) has been detected in over 80% PV patients and in approximately half of ET or PMF patients. The mutation results in a non-synonymous amino acid substitution at position 617 (valine to phenylalanine) in the JH2 pseudo-kinase auto-inhibitory domain. Current models predict that expression of mutant JAK2V617F in patient hematopoietic stem cells leads to activation of signaling pathways important for proliferation and survival. Furthermore, experimental evidence using murine models, in which JAK2V617F is retrovirally over-expressed, display a phenotype that closely resembles PV, including progression to myelofibrosis. Previous reports have indicated that “in vitro” expansion of PV progenitors favors erythroid precursors with decreased JAK2V617F mutational burden (Exp. Hematol. (2007) 35(4): 587–95). Investigators in these studies, however, did not report changes in JAK2V617F frequency in sorted live erythroid progenitors after “in vitro” expansion. Furthermore, CD34+cells from PV patients cultured in the presence of 20% serum indicated an inverse relationship between JAK2V617F frequency and Epo dose (Blood (2006) 108(9):3128–34). However, these reports failed to correlate Epo dose, and JAK2V617F frequency, with live “in vitro” expanded purified erythroid progenitor cells. Using our published procedure (Exp. Hematol. (2007) 35(4): 587–95), we expanded erythroid progenitors from healthy volunteers and JAK2V617F positive PV patients (mutational burden ranging from 20–90%) in serum-free media supplemented with SCF, Tpo, and Flt3L (100 ng/mL each - week 1) followed by SCF (50 ng/mL), IGF1 (50 ng/mL), and Epo (0, 0.003, 0.03, 0.3, and 3 Units/mL - week 2). Progression of progenitor expansion, erythroid lineage commitment, live/dead cells, and JAK2 mutation frequency was followed by flow cytometry and real-time PCR. At the end of week 2, cells were harvested, stained with anti-CD71 (transferrin receptor), anti-CD235A (glycophorin A), and the Aqua Live/Dead cell reagent. Stained cells were fixed in 2% paraformaldehyde, analyzed, and sorted on a FACSAria flow cytometer. Live, expanded progenitor cells were sorted into CD235A positive and negative populations, and subsequently used for estimation of JAK2 frequency by quantitative real-time PCR (Exp. Hematol. (2007) 35(1): 32–38). Our results indicate expansion and erythroid commitment of PV progenitor cells in the absence of Epo correlates with the patients’ intrinsic JAK2V617F burden. Furthermore, irrespective of JAK2V617F frequency in purified peripheral blood granulocytes, an inverse correlation between Epo dose and mutation frequency in “in vitro” expanded purified erythroid progenitors was not observed in all patients examined.
Results from a Phase II Study of Lenalidomide Oral Monotherapy in Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma.
Authors: Witzig Thomas E. , Vose Julie M. , Moore Timothy D. , Reeder Craig B. , Cole Craig E. , Justice Glen , Kaplan Henry P. , Voralia Michael , Pietronigro Dennis , Takeshita Kenichi , Ervin-Haynes Annette , Zeldis Jerome B. , Wiernik Peter H. 
Published: April 2020

Abstract
Background: Indolent non-Hodgkin’s lymphoma (NHL) has a median survival as long as 10 years but is rarely cured. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved in the US for treatment of myelodysplastic syndromes associated with a del[q5] cytogenetic abnormality and is approved both in the US and the EU for the treatment of relapsed/refractory multiple myeloma. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma.
Aim: This study was designed to assess the safety and efficacy of lenalidomide monotherapy in patients with relapsed/refractory indolent NHL.
Methods: Patients with relapsed/refractory indolent NHL with measurable disease ≥ 2cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology.
Results: Forty-three patients were enrolled in the study and included in this analysis. The median age was 63 (43–89) and 17 were female. Histology was small lymphocytic lymphoma [SLL] (n=18), follicular center lymphoma grades 1, 2 [FCL] (n=22), nodal marginal B-cell lymphoma (n=2) and extranodal marginal zone B-cell lymphoma of MALT type (n=1). Median time from diagnosis to lenalidomide treatment was 4.5 (0.4–24) years and median number of prior treatment regimens was 3 (1–15). Eleven of the 43 patients (26%) exhibited an objective response (2 complete responses (CR), 1 complete response unconfirmed (CRu), 8 partial responses (PR)), 15 had stable disease (SD), 13 had progressive disease (PD) and 4 were not evaluated. Responses included 4/18 SLL (22%) and 7/22 FCL (32%). Median time to response was 3.6 months (range 1.7–4.1). Progression free survival is 4.6 months for all patients, &gt; 7.7 months (range 4.4 - &gt; 13.5) for responding patients and ongoing. Sixteen patients (37%) required at least one dose reduction with a median time to first dose reduction of 2 months (0.5–9.6). The most common Grade 4 adverse event was neutropenia (14%) and the most common Grade 3 adverse events were neutropenia (21%) and thrombocytopenia (12%).
Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory indolent NHL.
High Response Rate to Lenalidomide in Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma with Prior Stem Cell Transplant.
Authors: Vose Julie M. , Tuscano Joseph M. , Justice Glen , Lossos Izidore S. , Ervin-Haynes Annette , Takeshita Kenichi , Pietronigro Dennis , Zeldis Jerome B. , Habermann Thomas M. 
Published: April 2020

Abstract
Background: High dose chemotherapy with stem cell transplant is currently employed in relapsed/refractory aggressive Non-Hodgkin’s Lymphoma (NHL). Lenalidomide (Revlimid®), an immunomodulatory drug, has shown activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma.
Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory aggressive NHL following stem cell transplant (SCT).
Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology.
Results: Fourteen (29%) of the 49 patients enrolled into the study had a prior SCT. Median age was 61 (23–76) and 5 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=5), follicular center lymphoma grade 3 [FL] (n=2), mantle cell lymphoma [MCL] (n=5) and transformed [TSF] (n=2). Median time from diagnosis to lenalidomide was 3.9 (1.1–31.4) years and median time from SCT to study entry was 1.9 (0.5–11.7) years. The median number of prior treatment regimens was 5 (2–8). Seven patients (50%) exhibited an objective response (1 complete response unconfirmed (CRu), and 6 partial responses (PR)), 5 had stable disease (SD) and 2 patients had progressive disease (PD). Six responses were in eight patients having a tumor burden &lt; 50 cm2 and a time since last rituximab therapy of ≥ 230 days. One response was achieved in six patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of &lt; 230 days. Four of 6 (67%) patients who had SCT as their last treatment prior to lenalidomide [median time from SCT to lenalidomide = 0.8 (0.5–4.8) years] responded. Progression free survival [PFS] is 4.5 months and ongoing. Six patients (43%) required at least one dose reduction with a median time to first dose reduction of 1.6 months (0.4–4.9). Two patients each (14%) had Grade 4 adverse events of neutropenia and thrombocytopenia. The most common Grade 3 adverse events were neutropenia (36%), thrombocytopenia (21%), and leukopenia (14%).
Conclusion: Lenalidomide produced a 50% response rate with manageable side effects in relapsed/refractory aggressive NHL following stem cell transplant.
Initial Results from an International Study in Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma To Confirm the Activity, Safety and Criteria for Predicting Response to Lenalidomide Monotherapy.
Authors: Witzig Thomas E. , Reeder Craig B. , Polikoff Jonathan , Chowhan Naveed M. , Esseessee Isaac , Greenberg Richard , Patel Hermant , Vafai Davood , Wiernik Peter H. , Ervin-Haynes Annette , Pietronigro Dennis , Zeldis Jerome B. , Czuczman Myron 
Published: April 2020

Abstract
Background: Lenalidomide (Revlimid®) has demonstrated activity with manageable side effects in relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL). In the initial pilot study, response to lenalidomide was associated with low tumor burden, long duration from prior rituximab and high absolute lymphocyte count.
Aims:
To confirm the activity and safety of lenalidomide monotherapy in patients with relapsed/refractory aggressive NHL in an international setting and Determine whether predictors of response identified in the previous study were valid.
Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test were conducted to investigate and characterize associations of prognostic variables with response.
Results: Eighteen patients who received lenalidomide were eligible for response assessment as of May 15, 2007. The median age was 66 (43–81) and 17 were male. Histology was diffuse large B-cell lymphoma [DLBCL] (n=11), mantle cell lymphoma [MCL] (n=5) and transformed (n=2). Median time from diagnosis was 2 (0.4–12) years and median number of prior treatment regimens was 3 (1–13). Four patients (22%) exhibited an objective partial response including 2/11(18%) DLBCL and 2/5 (40%) MCL. Five patients had stable disease. Lenalidomide response was associated with low disease burden (29% for &lt; 50 cm2v 0% for ≥ 50 cm2), time from last rituximab to lenalidomide treatment (36% for ≥ 230 days v 0% for &lt; 230 days) and absolute lymphocyte count [ALC] (33% for ≥ 0.6×109/L v 0% &lt; 0.6×109/L). Patients with favorable values for these three prognostic factors (N = 7) had a 57% response rate (compared with a 0% response rate for patients with unfavorable values (N = 11; P = 0.01). Grade 4 adverse events were neutropenia (22%) and thrombocytopenia (11%). Most common Grade 3 adverse events were fatigue (17%), thrombocytopenia (11%) and leukopenia (11%).
Conclusion: Lenalidomide has activity in relapsed/refractory aggressive NHL with a favorable safety profile. Initial results from this ongoing study are confirming that patients with low tumor burden, long duration from prior rituximab, and high ALC are more likely to respond.
Bortezomib, Rituximab, and Dexamethason (BORID) as Salvage Treatment in Relapsed/Refractory Mantle Cell Lymphoma: Sustained Disease Control in Patients Achieving a Complete Remission.
Authors: Drach Johannes , Kaufmann Hannes , Pichelmayer Oskar , Sagaster Verena , Holzer Sonja , Odelga Viktoria , Zielinski Christoph , Raderer Markus 
Published: April 2020

Abstract
Background: Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. We therefore evaluated the activity and safety of B in combination with R and dexamethasone (BORID) in patients with relapsed and refractory MCL (phase II trial).
Methods: A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) achieving a response received 4 additional doses of R as maintenance (every 8 weeks). Pts with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) were eligible.
Results: We have completed enrollment of 16 pts (median age, 67 years; range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6, prior rituximab in 88%; thalidomide in 50%; high-dose therapy in 31%; a fludarabine-containing regimen in 31%). Median time between start of frontline therapy and study inclusion was 42 months (range, 11 to 98 months). Severe adverse events (&gt; grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts) and vasculitic skin infiltrates in 3 pts. Thrombopenia (&lt; 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Overall response rate was 69% (11 of 16 pts), with 6 pts achieving a CR (38%; confirmed by PET-scan in 5 pts) and 5 pts reaching a PR. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. Remission status appeared to be associated with progression-free survival (PFS): Patients in CR had longer PFS (29+, 24+, 21+, 12+, 12, and 10+ months) compared to patients in PR (median 8.5 months, range 6 – 15).
Conclusions: BORID has promising activitiy (69% overall response rate; CR rate 38%) and managable toxicity in this patient population with predominantly heavily pretreated MCL. Achievement of a CR emerged as an important factor for sustained disease control. Further evaluation of this regimen, in particular in pts at an earlier phase of the disease, is warranted.
First Report of a Phase II Clinical Trial of Lenalidomide Oral Therapy for Peripheral T-Cell Lymphoma.
Authors: Reiman Tony , Finch Daygen , Chua Neil , White Darrell , Stewart Douglas A. , van der Jagt Richard , Johnston James , Prasad Angeli , Schwarz Henry , Zeldis Jerome , Belch Andrew R. 
Published: April 2020

Abstract
BACKGROUND: Lenalidomide has immunomodulatory and anti-neoplastic properties, with demonstrated activity in myelodysplastic syndrome and multiple myeloma. Preliminary reports indicate that lenalidomide has activity against cutaneous T-cell lymphoma (mycosis fungoides) and chronic lymphocytic leukemia. We hypothesized that lenalidomide should be studied as a non chemotherapy approach for Peripheral T- Cell Lymphoma (PTCL).
STUDY DESIGN AND METHODS: In this Canadian multi-center, open label, single-arm, phase II clinical trial, patients with PTCL were treated with lenalidomide 25 mg po qd × 21 days on a 28-day cycle until disease progression, death or unacceptable toxicity. Patients with ECOG 0-2 and relapsed/refractory disease were eligible, as well as patients who had not previously had systemic therapy but who were ineligible for standard curative chemotherapy regimens due to comorbid illness. We report on the first ten patients enrolled. The primary endpoint is response rate defined according to the 1999 Cheson criteria.
RESULTS: Median age of participants was 56y (range, 42–76y), 9M, 1F. Histologies included PTCL not otherwise specified (n=4), angioimmunoblastic (n=4), cutaneous anaplastic large cell (n=1), hepatosplenic gamma/delta (n=1). 8 were relapsed, 2 previously untreated. 2 were refractory to their previous regimen. Median number of prior lines of systemic therapy is 1 (range, 0–3). Median number of cycles delivered to date, 2 (range: 1–8). Therapy has generally been well tolerated. 3 patients experienced grade 3–4 hematological toxicity, 3 experienced grade 3+ infectious complications and 1 had grade 3 rash. No thrombotic events have been seen to date. Best responses to date include 0 CR, 4 PR (2 angioimmunoblastic, 2 PTCL NOS), 1 SD (PTCL NOS), 2 PD (1 angioimmunoblastic, 1 PTCL NOS). Three deaths have occurred on study, due to disease progression (n=2) and pneumonia during cycle 1 (n=1, angioimmunoblastic). One patient has withdrawn from study post cycle 1 due to treatment related asthenia. One previously untreated patient still awaits the first response assessment; the overall response rate (CR+PR) to date in the remaining patients on an intent-to-treat basis is 4/9 (44%). 5 of 9 (56%) patients have achieved stable disease or better, for 2+, 3+, 5, 6 and 8+ months. For the two patients with previously refractory disease, best response was 1 PR for 6 months and 1 PD.
CONCLUSION: Lenalidomide appears to be an active agent in the treatment of relapsed PTCL with an acceptable tolerability profile. Further recruitment and follow-up will allow us to better define the response rate, tolerability, TTP and OS with this regimen.
Phase I Trial of Fenretinide (4-HPR) Intravenous Emulsion for Hematologic Malignancies.
Authors: Mohrbacher Ann , Gutierrez Martin , Murgo Anthony J. , Kummar Shivaani , Reynolds C. Patrick , Maurer Barry J. , Groshen Susan , Vergara Lori , Kang Min H. , Yang Allen S. 
Published: April 2020

Abstract
Background: 4-HPR is a cytotoxic retinoid with broad anti-cancer activity in preclinical studies, but oral capsule 4-HPR had limited bioavailability and activity in clinical trials. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase 4-HPR systemic exposure.
Methods: ILE 4-HPR was administered as a continuous intravenous infusion for 5 of every 21 days and systemic toxicities, clinical response, and pharmacokinetics (PK) assessed. Simon design dose escalation proceeded with a 100% increase per dose level until moderate toxicity in 2 patients or 1 dose-limiting toxicity (DLT). Ten dose levels were planned starting at 80 mg/m2/day, increasing until 1810 mg/m2. Plasma 4-HPR levels were measured by high performance liquid chromatography.
Results: To date, 17 patients have been enrolled. At dose level 10 (1810 mg/m2/day), 2 patients experienced a DLT of grade 4 hypertriglyceridemia, 1 patient with transient grade 2 pancreatitis. A de-escalation to dose level 9 (1280 mg/m2/day) enrolled 5 patients: 1 had asymptomatic Grade 4 hypertriglyceridemia, 1 patient experienced pleural effusions that resolved after pleurocentesis. A de-escalation to dose level 8 (905 mg/m2/day) enrolled 5 pts: two patients experienced asymptomatic Grade 4 hypertriglyceridemias that resolved after stopping the infusion; enrollment is ongoing. PK showed a linear relationship of dose to plasma level, with steady-state 4-HPR levels of 25 μM (640 mg/m2, level 7); 54 μM (1280 mg/m2, level 9) and 62 μM (1810 mg/m2, level 10). Responses to date include a transient response in a non-Hodgkins lymphoma at 320 mg/m2, in two angioimmunoblastic T-cell lymphomas, an 8-month partial response at 1810 mg/m2/day and a 4+ month unconfirmed complete response at 905 mg/m2/day, and in a histone deacetylase inhibitor-refractory cutaneous T cell lymphoma, a 10+ month molecular complete response at 1280 mg/m2. All patients were heavily pretreated. The DLT of hypertriglyceridemia is likely related to the intralipid formulation vehicle accounting for 5/6 DLTs observed, all reversible.
Conclusions: ILE 4-HPR can be safely administered and obtained 4-HPR plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR. Durable clinical activity was observed in T cell lymphomas in the dose range 905–1810 mg/m2.
Supported in part by NCI U01CA62505 and the NCI RAID program.