RARE DISEASE
B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia
Synonyms: B-PLL
Synonyms: B-PLL
Synonyms: B-PLL
Drug discovery
3
drugs
With orphan designations
Overview
B-cell prolymphocytic leukemia (B-PLL) is a rare, aggressive mature B-cell neoplasm characterized by >55% prolymphocytes in peripheral blood, splenomegaly, and high white blood cell counts (>100×10⁹/L). It primarily affects older adults, with frequent TP53/17p deletions conferring poor prognosis [1][4][16]. Diagnosis requires morphology, immunophenotyping (CD19+/CD20+/CD5±/CD23−), and exclusion of mimics like CLL and mantle cell lymphoma [1][5]. Treatment borrows from CLL regimens but shows limited efficacy, with median survival ~3 years [4][12].
Therapies
First-line: Chemoimmunotherapy (e.g., bendamustine-rituximab, FCR) or targeted agents (ibrutinib) based on TP53 status [3][11][16]
High-risk: Venetoclax, alemtuzumab, or clinical trials for TP53-mutated cases [4][13][18]
Curative intent: Allogeneic HSCT for young/fit responders (5-year survival ~40%) [3][5][12]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
112 drug discovery papers about B-cell prolymphocytic leukemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
112 drug discovery papers about B-cell prolymphocytic leukemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-08-31 | Zanubrutinib as upfront treatment in de-novo B-cell prolymphocytic leukemia: the case of two elderlies.
B-cell prolymphocytic leukemia (B-PLL) is a rare lymphoproliferative disorder characterized by splenomegaly, lymphocytosis, and poor prognosis. Treatment options are limited, with modest responses to chemo-immunotherapy. We present two elderly patients with B-PLL treated with Zanubrutinib, a second-generation BTK inhibitor, achieving good disease response and tolerance. Both had TP53 deletion/mutations and high-risk complex karyotype. They obtained partial remission with normalization of hematologic parameters and spleen size. Given the rarity of the disease, further studies are needed to define treatment strategies, but Zanubrutinib appears to be a promising drug in this rare orphan drug disease.
2024-05-13 | Using Artificial Intelligence to Uncover Novel Therapeutic Targets in Hematology/Oncology
Abstract ID 100128 Poster Board 250 Hematology/Oncology models: We developed 42 machine learning models using Knowledge Graphs (KGML), informed by data from Pharos (1), based on major resources like DepMap (2), Reactome (3), and STRING (4). Focused on 41 blood cancers, we utilized cancer-specific positive genes and 440 shared negative genes, using metapath and XGBoost (5). Analysis of the top 500 genes from each model revealed 3,842 genes strongly linked to cancers, with 519 classified as "Tchem," i.e., small molecule modulators are known (6). We focused on Tchem proteins given the notion that small molecules perturbing these proteins are already known, which accelerates drug discovery. "Druggable" targets: Four separate, 1SVM (one-class support vector machine) and XGBoost KGML models were built using mode-of-action drug targets (6) (also called Tclin; N = 704) as input. This 42nd model evaluates the likelihood that a gene shares the characteristics of Tclin targets ("druggable") using aggregated probabilities across the 4 models. Main Findings: Of the 519 Tchem genes, 132 have "Tclin-like" probability above 50%. The top five "druggable targets" are GAPDH, AKT1, HRAS, TLR4 and TP53, respectively; their role in cancer is well studied. Our focus then shifted to genes that have no known cancer associations, as evaluated by the DISEASES platform (7) - see Table 1. Two G-protein coupled receptor genes, LPAR5 and ADORA3, appear to be uniquely associated with primary bone diffuse large B cell lymphoma, and with acute leukaemic transformation of myeloproliferative neoplasm, respectively. PLD1 (an enzyme) is associated with B cell prolymphocytic leukemia. Additional studies are required to elucidate their role in these malignancies. Our work illustrates how machine learning can be used to uncover overlooked, but potentially promising drug targets for leukemias, lymphomas and myelomas. References 1. Kelleher KJ, Sheils TK, Mathias SL, Yang JJ, Metzger VT, Siramshetty VB, et al. Nucleic Acids Res. 2023; 51:D1405–16. 2. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Cell. 2017; 170:564–76.e16. 3. Gillespie M, Jassal B, Stephan R, Milacic M, Rothfels K, Senff-Ribeiro A, et al. Nucleic Acids Res. 2022; 50:D687–92. 4. Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. Nucleic Acids Res. 2023; 51:D638–46. 5. Binder J, Ursu O, Bologa C, Jiang S, Maphis N, Dadras S, et al. Commun Biol. 2022; 5:125. 6. Oprea TI, Bologa CG, Brunak S, Campbell A, Gan GN, Gaulton A, et al. Nat Rev Drug Discov. 2018; 17:317–32. 7. Grissa D, Junge A, Oprea TI, Jensen LJ. Database. 2022; 2022:baac019.
2024-03-22 | Abstract 3535: Seeking novel therapeutic targets in oncology using machine learning
Abstract We developed 42 machine learning models using Knowledge Graphs (KGML), informed by data from Pharos (1), based on major resources like DepMap (2), Reactome (3), and STRING (4). Focused on 41 blood cancers, we utilized cancer-specific positive genes and 440 shared negative genes, using metapath and XGBoost (5). Analysis of the top 500 genes from each model revealed 3,842 genes strongly linked to cancers, with 519 classified as “Tchem,”i.e., small molecule modulators are known (6). We focused on Tchem proteins given the notion that small molecules perturbing these proteins are already known, which accelerates drug discovery. A separate, 1SVM (one-class support vector machine) model was built using mode-of-action drug targets (6) (Tclin, N = 704) as input. This 42nd model evaluates the likelihood that a gene shares the characteristics of Tclin targets (“Tclin-like”). Of the 519 Tchem genes, 132 have “Tclin-like” probability above 50%. The top five “Tclin-like” genes are GAPDH, AKT1, HRAS, TLR4 and TP53, respectively; their role in cancer is well studied. Our focus shifted to 19 genes that have limited or no known cancer associations, as evaluated by the DISEASES platform (7) - see Table 1. Three genes (LPAR5, GPR18 and FCER2) are associated with primary bone diffuse large B cell lymphoma, and 2 (ADCY1 and PLD1) with B cell prolymphocytic leukemia. Additional studies may elucidate their role in these malignancies. Five genes (IRAK3, EPHB1, ITPKB, ACVR2B and CAMK2D) are predicted to be relevant in 10 or more blood cancers. Machine learning may uncover overlooked, but potentially promising drug targets for leukemias, lymphomas and myelomas. References 1. Kelleher KJ, et al. Nucl Acids Res. 2023; 51:D1405-16.2. Tsherniak A, et al. Cell. 2017; 170:564-76.e16.3. Gillespie M, et al. Nucl Acids Res. 2022; 50:D687-92.4. Szklarczyk D, et al. Nucl Acids Res. 2023; 51:D638-46.5. Binder J, et al. Commun Biol. 2022; 5:125.6. Oprea TI, et al. Nat Rev Drug Discov. 2018; 17:317-32.7. Grissa D, et al. Database. 2022; 2022:baac019. Table 1: “Tclin-like” targets lacking known cancer associations. Gene 41 Cancer counts Disease names LPAR5 1 primary bone diffuse large B cell lymphoma ADCY1 1 B cell prolymphocytic leukaemia ITPKB 15 PLD1 1 B cell prolymphocytic leukaemia PRKCE 2 hepatosplenic T cell lymphoma; acute leukaemia of ambiguous lineage EPHB1 17 GPR18 1 primary bone diffuse large B cell lymphoma FRK 3 chronic myeloid leukaemia; acute myeloid leukaemia therapy related; NK cell leukaemia CAMK2D 13 IRAK3 20 TRPV4 1 primary central nervous system lymphoma ACVR2B 14 TRPC6 1 Hodgkin lymphoma FCER2 1 primary bone diffuse large B cell lymphoma GRM8 1 acute myeloid leukaemia therapy related CAMK2A 1 hepatosplenic T cell lymphoma BLK 4 ADORA3 1 acute leukaemic transformation of myeloproliferative neoplasm PIM1 8 Citation Format: Mohammed Quazi, Suman Sirimulla, Cristian G. Bologa, Alexei Pushechnikov, Nikolay Savchuk, Tudor Ionel Oprea. Seeking novel therapeutic targets in oncology using machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3535.
2023-05-31 | B-Cell Prolymphocytic Leukemia: Two Case Reports and Review of the Literature
B-cell prolymphocytic leukemia is a very rare mature B-cell leukemia occurring in elderly people diagnosed when prolymphocytes comprise more than 55% of the lymphoid cells in peripheral blood. Its evolution is most often aggressive. We report here the cases of two patients with clinical signs dominated by splenomegaly associated with significant hyperlymphocytosis. Their blood smears revealed extensive prolymphocyte invasion suggesting Prolymphocyte leukemia confirmed by immunophenotyping. Both purine analogues and monoclonal antibodies have shown promoting results, however, allogeneic hematopoietic stem cell transplantation remains the only therapeutic means allowing a lasting response. However, it is reserved for young patients with compatible donors. A good understanding of the pathogenesis and a better integration of the molecular data of this hemopathy open the way to the use of new targeted therapies. Prolymphocyte leukemia is a very rare, complex, and often aggressive, mature lymphoid hemopathy. The mean age of onset is 65 years with a predominance of males. We report here the case of a patient with splenomegaly and severe lymphocytosis in whom the smear showed an invasion of 90% of prolymphocytes suggesting Prolymphocyte leukemia confirmed by immunophenotyping.
2022-10-12 | Venetoclax induces deep and durable minimal residual disease-negative remission in high-risk TP53 disrupted B prolymphocytic leukaemia.
B-cell prolymphocytic leukaemia (B-PLL) is an aggressive B-cell lymphoproliferative disease with few clinically proven targeted treatments. Due to the rarity of the condition, there is a paucity of clinical trial data and none that involve targeted inhibitors. We present a unique case of relapsed refractory B-PLL treated to a sustained minimal residual disease-negative remission with venetoclax monotherapy, to add to the current evidence base and rationale for future studies using BCL-2 inhibitors in B-PLL.
cell therapies
2025-03-25 | Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Prolymphocytic Leukemia
T-prolymphocytic leukemia (T-PLL) is a rare lymphoid neoplasm with particularly poor prognosis. B-prolymphocytic leukemia (B-PLL), although no longer recognized as a distinct entity by the World Health Organization (WHO), comprises conditions with unfavorable outcome as well. Both diseases most frequently affect patients in the 7th decade of their lives. Allogeneic hematopoietic stem cell transplantation (alloHSCT) significantly improves outcomes for selected PLL cases as shown by several, mostly retrospective, analyses. In this article, we provide a review of existing PLL analyses, followed by a summary of cases treated at our center. We describe outcomes of six T-PLL and three B-PLL cases receiving alloHSCT at our institution between 2015 and 2022. Despite a post-transplant 4-year cumulative relapse incidence of 61% in our T-PLL series, median OS was 78 months, because relapse therapy was remarkably successful. All B-PLL patients are alive and relapse-free with a median follow-up of 54 (range, 11 – 74) months. A poor pre-transplant Karnofsky performance score (<= 80) and an HCT Comorbidity Index (HCT-CI) of >= 3 were significantly associated with post-transplant mortality. The comparatively favorable outcomes in our case series underline the increasing value of alloHSCT in PLL in the current era, as it offers a prospect of cure in selected patients with otherwise very poor prognosis.
2018-03-01 | Reduced Intensity Conditioning with Pentostatin and Low-Dose TBI in Patients with Relapsed Hematologic Malignancies
Reduced intensity conditioning regimens have resulted in successful engraftment of allogeneic stem cells with low regimen-related toxicities. We previously demonstrated in a Phase II study that a regimen of extracorporeal photopheresis (ECP), pentostatin (4 mg/m2 CIVI days −5 and −4) and 600 cGy of total body irradiation (TBI) in 3 fractions was associated with stable engraftment, NRM of 11% and a low incidence of acute and chronic GVHD. We now report long-term results from 98 pts with lymphoid malignancies treated with pentostatin and TBI 600 cGy (days −3 and −2) followed by allogeneic peripheral blood stem cell (PBSC) infusion. Five pts with T-cell lymphomas who received ECP as part of the regimen are included. Median age was 59 yrs (range, 20-73). Indications for transplant were B-NHL (27 pts), PTCL (24), CTCL (7), B-ALL (21), T-ALL (4), CLL (4), CLL-RT (3), B-PLL (1), T-PLL (5), HD (2). Eighteen pts had prior autologous transplant and 1 had prior alloBMT for ALL. CIBMTR disease risk index was low (39%), intermediate (45%), and high (16%). Donors were 45% matched related (MRD), 38% matched unrelated (MUD), and 17% mismatched unrelated (MMUD). In pts with MRD or MUD, 62% received Tac/MMF for GVHD prophylaxis, whereas 23% received Tac/Siro. Tac/Siro/Mtx were used in MMUD. Filgrastim was used from day +7 to engraftment. There were no graft rejections. The 100-day TRM was 5%. With median follow-up of 55 months (range, 1-144) in surviving pts, the median overall survival (OS) was not reached. The 2-year OS and progression-free survival (PFS) were 60% and 64%, respectively. Median OS was not reached in B–NHL and T–NHL pts and was 19 months in B-ALL pts. For B-NHL and T–NHL pts combined, the 2-year OS and PFS were 71% and 72%, respectively. There was no difference in OS or PFS between B–NHL and T–NHL groups (P-value .97 and .75). There was no difference in OS or PFS between CIBMTR low/int and high-risk groups (P-value .89 and .87). Incidence of acute GVHD grade 3-4 was 19% (36% gr 2-4). Extensive chronic GVHD occurred in 32 pts (35%). The 1-year GVHD–free relapse–free survival (GRFS) was 39%. Early infectious complications included bacterial (20 pts), CMV reactivation (27 pts), and HHV–6 reactivation in 6 febrile pts (HHV–6 encephalitis 2 pts). Regimen related toxicities included mild renal insufficiency (14 pts), mostly in combination with Tac/Rapa. Early deaths were related to relapse (1 pt), acute GVHD (3), SOS (1), and TMA (1). Late infectious complications included invasive aspergillosis (1 pt), nocardiosis (2), mucormycosis (1) and toxoplasmosis (1). These results demonstrate that this regimen of infusional pentostatin and low-dose TBI was well tolerated and associated with significant disease control in both low and high-risk patients with lymphoid malignancies. Disease control was superior in the subgroups with either B–cell or T–cell nodal disease. A high proportion of patients are alive and free of morbidity.
2015-04-13 | Successful allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning for B-cell prolymphocytic leukemia in partial remission.
B-cell prolymphocytic leukemia (B-PLL) is a rare, chemotherapy-resistant lymphoid neoplasm. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potentially curative treatment for B-PLL, the number of B-PLL patients who have been treated with allo-HSCT is small and its efficacy has not been established. We report the case of a 59-year-old woman with B-PLL in partial remission, who was successfully treated with allo-HSCT following reduced-intensity conditioning (RIC). She was initially treated with four courses of combination chemotherapy consisting of rituximab, fludarabine, cyclophosphamide, and mitoxantrone, which resulted in partial remission with residual tumor cells comprising 7 % of bone marrow nucleated cells. Although the residual B-PLL cells appeared to be indolent, as the disease progressed slowly during partial remission, these cells lost CD20 expression, and the prognosis of the patient was considered to be poor with conventional chemotherapy. She was therefore given RIC, followed by allo-HSCT from an HLA-matched sibling donor. Her clinical course following allo-HSCT was uneventful, and she remained in complete remission at 32 months post-transplantation. Although the therapeutic strategy for B-PLL should be determined based on the severity of the disease, RIC with allo-HSCT may be a therapeutic option for indolent B-PLL when the long-term prognosis of patients is markedly poor.
2012-10-02 | How I treat prolymphocytic leukemia.
T- and B-cell subtypes of prolymphocytic leukemia (PLL) are rare, aggressive lymphoid malignancies with characteristic morphologic, immunophenotypic, cytogenetic, and molecular features. Recent studies have highlighted the role of specific oncogenes, such as TCL-1, MTCP-1, and ATM in the case of T-cell and TP53 mutations in the case of B-cell prolymphocytic leukemia. Despite the advances in the understanding of the biology of these conditions, the prognosis for these patients remains poor with short survival and no curative therapy. The advent of monoclonal antibodies has improved treatment options. Currently, the best treatment for T-PLL is intravenous alemtuzumab, which has resulted in very high response rates of more than 90% when given as first-line treatment and a significant improvement in survival. Consolidation of remissions with autologous or allogeneic stem cell transplantation further prolongs survival, and the latter may offer potential cure. In B-PLL, rituximab-based combination chemo-immunotherapy is effective in fitter patients. TP53 abnormalities are common and, as for chronic lymphocytic leukemia, these patients should be managed using an alemtuzumab-based therapy. The role of allogeneic transplant with nonmyeloablative conditioning needs to be explored further in both T- and B-cell PLL to broaden the patient eligibility for what may be a curative treatment.
2012-02-16 | Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901.
Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.
antibodies
2023-05-23 | Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies
B cells are central to the adaptive immune response, providing long lasting immunity after infection. B cell activation is mediated by a cell surface B cell receptor (BCR) following recognition of an antigen. BCR signaling is modulated by several co-receptors including CD22 and a complex that contains CD19 and CD81. Aberrant signaling through the BCR and co-receptors promotes the pathogenesis of several B cell malignancies and autoimmune diseases. Treatment of these diseases has been revolutionized by the development of monoclonal antibodies that bind to B cell surface antigens, including the BCR and its co-receptors. However, malignant B cells can escape targeting by several mechanisms and until recently, rational design of antibodies has been limited by the lack of high-resolution structures of the BCR and its co-receptors. Herein we review recently determined cryo-electron microscopy (cryo-EM) and crystal structures of the BCR, CD22, CD19 and CD81 molecules. These structures provide further understanding of the mechanisms of current antibody therapies and provide scaffolds for development of engineered antibodies for treatment of B cell malignancies and autoimmune diseases.
2021-12-23 | Zanubrutinib, rituximab and lenalidomide induces deep and durable remission in TP53-mutated B-cell prolymphocytic leukemia: a case report and literature review
Not available.
2021-02-22 | Systemic capillary leak syndrome: a rare but potentially life-threatening cause of protein loss and oedema in B cell prolymphocytic leukaemia.
A 64-year-old man had a several year history of B prolymphocytic leukaemia (PLL) which behaved indolently and had not required any treatment. Five years after diagnosis, he developed hypoalbuminaemia associated with severe lower-limb oedema, consistent with systemic capillary leak syndrome (SCLS). He recovered spontaneously but went on to have three further increasingly severe and protracted episodes over the subsequent 18 months. There was no identifiable precipitating factor for these episodes, but his peripheral lymphocyte count continued to increase slowly. The start of treatment for his PLL with chemoimmunotherapy was followed by a rapid resolution of residual oedema and normalisation of serum albumin. He has had no further attacks of SCLS in the 14 months since he started therapy for PLL. SCLS is a rare consequence of haematological malignancy which may show an excellent response to treatment of the haematological disease.
small molecules
2025-08-31 | Zanubrutinib as upfront treatment in de-novo B-cell prolymphocytic leukemia: the case of two elderlies.
B-cell prolymphocytic leukemia (B-PLL) is a rare lymphoproliferative disorder characterized by splenomegaly, lymphocytosis, and poor prognosis. Treatment options are limited, with modest responses to chemo-immunotherapy. We present two elderly patients with B-PLL treated with Zanubrutinib, a second-generation BTK inhibitor, achieving good disease response and tolerance. Both had TP53 deletion/mutations and high-risk complex karyotype. They obtained partial remission with normalization of hematologic parameters and spleen size. Given the rarity of the disease, further studies are needed to define treatment strategies, but Zanubrutinib appears to be a promising drug in this rare orphan drug disease.
2024-05-13 | Using Artificial Intelligence to Uncover Novel Therapeutic Targets in Hematology/Oncology
Abstract ID 100128 Poster Board 250 Hematology/Oncology models: We developed 42 machine learning models using Knowledge Graphs (KGML), informed by data from Pharos (1), based on major resources like DepMap (2), Reactome (3), and STRING (4). Focused on 41 blood cancers, we utilized cancer-specific positive genes and 440 shared negative genes, using metapath and XGBoost (5). Analysis of the top 500 genes from each model revealed 3,842 genes strongly linked to cancers, with 519 classified as "Tchem," i.e., small molecule modulators are known (6). We focused on Tchem proteins given the notion that small molecules perturbing these proteins are already known, which accelerates drug discovery. "Druggable" targets: Four separate, 1SVM (one-class support vector machine) and XGBoost KGML models were built using mode-of-action drug targets (6) (also called Tclin; N = 704) as input. This 42nd model evaluates the likelihood that a gene shares the characteristics of Tclin targets ("druggable") using aggregated probabilities across the 4 models. Main Findings: Of the 519 Tchem genes, 132 have "Tclin-like" probability above 50%. The top five "druggable targets" are GAPDH, AKT1, HRAS, TLR4 and TP53, respectively; their role in cancer is well studied. Our focus then shifted to genes that have no known cancer associations, as evaluated by the DISEASES platform (7) - see Table 1. Two G-protein coupled receptor genes, LPAR5 and ADORA3, appear to be uniquely associated with primary bone diffuse large B cell lymphoma, and with acute leukaemic transformation of myeloproliferative neoplasm, respectively. PLD1 (an enzyme) is associated with B cell prolymphocytic leukemia. Additional studies are required to elucidate their role in these malignancies. Our work illustrates how machine learning can be used to uncover overlooked, but potentially promising drug targets for leukemias, lymphomas and myelomas. References 1. Kelleher KJ, Sheils TK, Mathias SL, Yang JJ, Metzger VT, Siramshetty VB, et al. Nucleic Acids Res. 2023; 51:D1405–16. 2. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Cell. 2017; 170:564–76.e16. 3. Gillespie M, Jassal B, Stephan R, Milacic M, Rothfels K, Senff-Ribeiro A, et al. Nucleic Acids Res. 2022; 50:D687–92. 4. Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. Nucleic Acids Res. 2023; 51:D638–46. 5. Binder J, Ursu O, Bologa C, Jiang S, Maphis N, Dadras S, et al. Commun Biol. 2022; 5:125. 6. Oprea TI, Bologa CG, Brunak S, Campbell A, Gan GN, Gaulton A, et al. Nat Rev Drug Discov. 2018; 17:317–32. 7. Grissa D, Junge A, Oprea TI, Jensen LJ. Database. 2022; 2022:baac019.
2024-03-22 | Abstract 3535: Seeking novel therapeutic targets in oncology using machine learning
Abstract We developed 42 machine learning models using Knowledge Graphs (KGML), informed by data from Pharos (1), based on major resources like DepMap (2), Reactome (3), and STRING (4). Focused on 41 blood cancers, we utilized cancer-specific positive genes and 440 shared negative genes, using metapath and XGBoost (5). Analysis of the top 500 genes from each model revealed 3,842 genes strongly linked to cancers, with 519 classified as “Tchem,”i.e., small molecule modulators are known (6). We focused on Tchem proteins given the notion that small molecules perturbing these proteins are already known, which accelerates drug discovery. A separate, 1SVM (one-class support vector machine) model was built using mode-of-action drug targets (6) (Tclin, N = 704) as input. This 42nd model evaluates the likelihood that a gene shares the characteristics of Tclin targets (“Tclin-like”). Of the 519 Tchem genes, 132 have “Tclin-like” probability above 50%. The top five “Tclin-like” genes are GAPDH, AKT1, HRAS, TLR4 and TP53, respectively; their role in cancer is well studied. Our focus shifted to 19 genes that have limited or no known cancer associations, as evaluated by the DISEASES platform (7) - see Table 1. Three genes (LPAR5, GPR18 and FCER2) are associated with primary bone diffuse large B cell lymphoma, and 2 (ADCY1 and PLD1) with B cell prolymphocytic leukemia. Additional studies may elucidate their role in these malignancies. Five genes (IRAK3, EPHB1, ITPKB, ACVR2B and CAMK2D) are predicted to be relevant in 10 or more blood cancers. Machine learning may uncover overlooked, but potentially promising drug targets for leukemias, lymphomas and myelomas. References 1. Kelleher KJ, et al. Nucl Acids Res. 2023; 51:D1405-16.2. Tsherniak A, et al. Cell. 2017; 170:564-76.e16.3. Gillespie M, et al. Nucl Acids Res. 2022; 50:D687-92.4. Szklarczyk D, et al. Nucl Acids Res. 2023; 51:D638-46.5. Binder J, et al. Commun Biol. 2022; 5:125.6. Oprea TI, et al. Nat Rev Drug Discov. 2018; 17:317-32.7. Grissa D, et al. Database. 2022; 2022:baac019. Table 1: “Tclin-like” targets lacking known cancer associations. Gene 41 Cancer counts Disease names LPAR5 1 primary bone diffuse large B cell lymphoma ADCY1 1 B cell prolymphocytic leukaemia ITPKB 15 PLD1 1 B cell prolymphocytic leukaemia PRKCE 2 hepatosplenic T cell lymphoma; acute leukaemia of ambiguous lineage EPHB1 17 GPR18 1 primary bone diffuse large B cell lymphoma FRK 3 chronic myeloid leukaemia; acute myeloid leukaemia therapy related; NK cell leukaemia CAMK2D 13 IRAK3 20 TRPV4 1 primary central nervous system lymphoma ACVR2B 14 TRPC6 1 Hodgkin lymphoma FCER2 1 primary bone diffuse large B cell lymphoma GRM8 1 acute myeloid leukaemia therapy related CAMK2A 1 hepatosplenic T cell lymphoma BLK 4 ADORA3 1 acute leukaemic transformation of myeloproliferative neoplasm PIM1 8 Citation Format: Mohammed Quazi, Suman Sirimulla, Cristian G. Bologa, Alexei Pushechnikov, Nikolay Savchuk, Tudor Ionel Oprea. Seeking novel therapeutic targets in oncology using machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3535.
2023-05-31 | B-Cell Prolymphocytic Leukemia: Two Case Reports and Review of the Literature
B-cell prolymphocytic leukemia is a very rare mature B-cell leukemia occurring in elderly people diagnosed when prolymphocytes comprise more than 55% of the lymphoid cells in peripheral blood. Its evolution is most often aggressive. We report here the cases of two patients with clinical signs dominated by splenomegaly associated with significant hyperlymphocytosis. Their blood smears revealed extensive prolymphocyte invasion suggesting Prolymphocyte leukemia confirmed by immunophenotyping. Both purine analogues and monoclonal antibodies have shown promoting results, however, allogeneic hematopoietic stem cell transplantation remains the only therapeutic means allowing a lasting response. However, it is reserved for young patients with compatible donors. A good understanding of the pathogenesis and a better integration of the molecular data of this hemopathy open the way to the use of new targeted therapies. Prolymphocyte leukemia is a very rare, complex, and often aggressive, mature lymphoid hemopathy. The mean age of onset is 65 years with a predominance of males. We report here the case of a patient with splenomegaly and severe lymphocytosis in whom the smear showed an invasion of 90% of prolymphocytes suggesting Prolymphocyte leukemia confirmed by immunophenotyping.
2022-10-12 | Venetoclax induces deep and durable minimal residual disease-negative remission in high-risk TP53 disrupted B prolymphocytic leukaemia.
B-cell prolymphocytic leukaemia (B-PLL) is an aggressive B-cell lymphoproliferative disease with few clinically proven targeted treatments. Due to the rarity of the condition, there is a paucity of clinical trial data and none that involve targeted inhibitors. We present a unique case of relapsed refractory B-PLL treated to a sustained minimal residual disease-negative remission with venetoclax monotherapy, to add to the current evidence base and rationale for future studies using BCL-2 inhibitors in B-PLL.
cell therapies
2025-03-25 | Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Prolymphocytic Leukemia
T-prolymphocytic leukemia (T-PLL) is a rare lymphoid neoplasm with particularly poor prognosis. B-prolymphocytic leukemia (B-PLL), although no longer recognized as a distinct entity by the World Health Organization (WHO), comprises conditions with unfavorable outcome as well. Both diseases most frequently affect patients in the 7th decade of their lives. Allogeneic hematopoietic stem cell transplantation (alloHSCT) significantly improves outcomes for selected PLL cases as shown by several, mostly retrospective, analyses. In this article, we provide a review of existing PLL analyses, followed by a summary of cases treated at our center. We describe outcomes of six T-PLL and three B-PLL cases receiving alloHSCT at our institution between 2015 and 2022. Despite a post-transplant 4-year cumulative relapse incidence of 61% in our T-PLL series, median OS was 78 months, because relapse therapy was remarkably successful. All B-PLL patients are alive and relapse-free with a median follow-up of 54 (range, 11 – 74) months. A poor pre-transplant Karnofsky performance score (<= 80) and an HCT Comorbidity Index (HCT-CI) of >= 3 were significantly associated with post-transplant mortality. The comparatively favorable outcomes in our case series underline the increasing value of alloHSCT in PLL in the current era, as it offers a prospect of cure in selected patients with otherwise very poor prognosis.
2018-03-01 | Reduced Intensity Conditioning with Pentostatin and Low-Dose TBI in Patients with Relapsed Hematologic Malignancies
Reduced intensity conditioning regimens have resulted in successful engraftment of allogeneic stem cells with low regimen-related toxicities. We previously demonstrated in a Phase II study that a regimen of extracorporeal photopheresis (ECP), pentostatin (4 mg/m2 CIVI days −5 and −4) and 600 cGy of total body irradiation (TBI) in 3 fractions was associated with stable engraftment, NRM of 11% and a low incidence of acute and chronic GVHD. We now report long-term results from 98 pts with lymphoid malignancies treated with pentostatin and TBI 600 cGy (days −3 and −2) followed by allogeneic peripheral blood stem cell (PBSC) infusion. Five pts with T-cell lymphomas who received ECP as part of the regimen are included. Median age was 59 yrs (range, 20-73). Indications for transplant were B-NHL (27 pts), PTCL (24), CTCL (7), B-ALL (21), T-ALL (4), CLL (4), CLL-RT (3), B-PLL (1), T-PLL (5), HD (2). Eighteen pts had prior autologous transplant and 1 had prior alloBMT for ALL. CIBMTR disease risk index was low (39%), intermediate (45%), and high (16%). Donors were 45% matched related (MRD), 38% matched unrelated (MUD), and 17% mismatched unrelated (MMUD). In pts with MRD or MUD, 62% received Tac/MMF for GVHD prophylaxis, whereas 23% received Tac/Siro. Tac/Siro/Mtx were used in MMUD. Filgrastim was used from day +7 to engraftment. There were no graft rejections. The 100-day TRM was 5%. With median follow-up of 55 months (range, 1-144) in surviving pts, the median overall survival (OS) was not reached. The 2-year OS and progression-free survival (PFS) were 60% and 64%, respectively. Median OS was not reached in B–NHL and T–NHL pts and was 19 months in B-ALL pts. For B-NHL and T–NHL pts combined, the 2-year OS and PFS were 71% and 72%, respectively. There was no difference in OS or PFS between B–NHL and T–NHL groups (P-value .97 and .75). There was no difference in OS or PFS between CIBMTR low/int and high-risk groups (P-value .89 and .87). Incidence of acute GVHD grade 3-4 was 19% (36% gr 2-4). Extensive chronic GVHD occurred in 32 pts (35%). The 1-year GVHD–free relapse–free survival (GRFS) was 39%. Early infectious complications included bacterial (20 pts), CMV reactivation (27 pts), and HHV–6 reactivation in 6 febrile pts (HHV–6 encephalitis 2 pts). Regimen related toxicities included mild renal insufficiency (14 pts), mostly in combination with Tac/Rapa. Early deaths were related to relapse (1 pt), acute GVHD (3), SOS (1), and TMA (1). Late infectious complications included invasive aspergillosis (1 pt), nocardiosis (2), mucormycosis (1) and toxoplasmosis (1). These results demonstrate that this regimen of infusional pentostatin and low-dose TBI was well tolerated and associated with significant disease control in both low and high-risk patients with lymphoid malignancies. Disease control was superior in the subgroups with either B–cell or T–cell nodal disease. A high proportion of patients are alive and free of morbidity.
2015-04-13 | Successful allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning for B-cell prolymphocytic leukemia in partial remission.
B-cell prolymphocytic leukemia (B-PLL) is a rare, chemotherapy-resistant lymphoid neoplasm. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potentially curative treatment for B-PLL, the number of B-PLL patients who have been treated with allo-HSCT is small and its efficacy has not been established. We report the case of a 59-year-old woman with B-PLL in partial remission, who was successfully treated with allo-HSCT following reduced-intensity conditioning (RIC). She was initially treated with four courses of combination chemotherapy consisting of rituximab, fludarabine, cyclophosphamide, and mitoxantrone, which resulted in partial remission with residual tumor cells comprising 7 % of bone marrow nucleated cells. Although the residual B-PLL cells appeared to be indolent, as the disease progressed slowly during partial remission, these cells lost CD20 expression, and the prognosis of the patient was considered to be poor with conventional chemotherapy. She was therefore given RIC, followed by allo-HSCT from an HLA-matched sibling donor. Her clinical course following allo-HSCT was uneventful, and she remained in complete remission at 32 months post-transplantation. Although the therapeutic strategy for B-PLL should be determined based on the severity of the disease, RIC with allo-HSCT may be a therapeutic option for indolent B-PLL when the long-term prognosis of patients is markedly poor.
2012-10-02 | How I treat prolymphocytic leukemia.
T- and B-cell subtypes of prolymphocytic leukemia (PLL) are rare, aggressive lymphoid malignancies with characteristic morphologic, immunophenotypic, cytogenetic, and molecular features. Recent studies have highlighted the role of specific oncogenes, such as TCL-1, MTCP-1, and ATM in the case of T-cell and TP53 mutations in the case of B-cell prolymphocytic leukemia. Despite the advances in the understanding of the biology of these conditions, the prognosis for these patients remains poor with short survival and no curative therapy. The advent of monoclonal antibodies has improved treatment options. Currently, the best treatment for T-PLL is intravenous alemtuzumab, which has resulted in very high response rates of more than 90% when given as first-line treatment and a significant improvement in survival. Consolidation of remissions with autologous or allogeneic stem cell transplantation further prolongs survival, and the latter may offer potential cure. In B-PLL, rituximab-based combination chemo-immunotherapy is effective in fitter patients. TP53 abnormalities are common and, as for chronic lymphocytic leukemia, these patients should be managed using an alemtuzumab-based therapy. The role of allogeneic transplant with nonmyeloablative conditioning needs to be explored further in both T- and B-cell PLL to broaden the patient eligibility for what may be a curative treatment.
2012-02-16 | Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901.
Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.
antibodies
2023-05-23 | Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies
B cells are central to the adaptive immune response, providing long lasting immunity after infection. B cell activation is mediated by a cell surface B cell receptor (BCR) following recognition of an antigen. BCR signaling is modulated by several co-receptors including CD22 and a complex that contains CD19 and CD81. Aberrant signaling through the BCR and co-receptors promotes the pathogenesis of several B cell malignancies and autoimmune diseases. Treatment of these diseases has been revolutionized by the development of monoclonal antibodies that bind to B cell surface antigens, including the BCR and its co-receptors. However, malignant B cells can escape targeting by several mechanisms and until recently, rational design of antibodies has been limited by the lack of high-resolution structures of the BCR and its co-receptors. Herein we review recently determined cryo-electron microscopy (cryo-EM) and crystal structures of the BCR, CD22, CD19 and CD81 molecules. These structures provide further understanding of the mechanisms of current antibody therapies and provide scaffolds for development of engineered antibodies for treatment of B cell malignancies and autoimmune diseases.
2021-12-23 | Zanubrutinib, rituximab and lenalidomide induces deep and durable remission in TP53-mutated B-cell prolymphocytic leukemia: a case report and literature review
Not available.
2021-02-22 | Systemic capillary leak syndrome: a rare but potentially life-threatening cause of protein loss and oedema in B cell prolymphocytic leukaemia.
A 64-year-old man had a several year history of B prolymphocytic leukaemia (PLL) which behaved indolently and had not required any treatment. Five years after diagnosis, he developed hypoalbuminaemia associated with severe lower-limb oedema, consistent with systemic capillary leak syndrome (SCLS). He recovered spontaneously but went on to have three further increasingly severe and protracted episodes over the subsequent 18 months. There was no identifiable precipitating factor for these episodes, but his peripheral lymphocyte count continued to increase slowly. The start of treatment for his PLL with chemoimmunotherapy was followed by a rapid resolution of residual oedema and normalisation of serum albumin. He has had no further attacks of SCLS in the 14 months since he started therapy for PLL. SCLS is a rare consequence of haematological malignancy which may show an excellent response to treatment of the haematological disease.
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Drug Discovery Landscape
3 orphan drug designations for B-cell prolymphocytic leukemia.
3 orphan drug designations for B-cell prolymphocytic leukemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
blinatumomab | antibodies | FDA | 2008-05-16 | — | Amgen, Inc. |
Iodine I 131 murine monoclonal antibody IgG2a to B cell | antibodies | FDA | 1989-09-18 | — | Immunomedics, Inc. |
Ricin (blocked) conjugated murine MCA (anti-B4) | antibodies | FDA | 1988-11-17 | — | ImmunoGen, Inc. |
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