Prolymphocytic Leukaemia: an Update on Biology and Treatment.

PURPOSE OF REVIEW: This review summarises the recent advances in knowledge regarding the biology and treatment of prolymphocytic leukaemias. RECENT FINDINGS: Both B-PLL and T-PLL are genetically complex, and the molecular landscape of these diseases has been well characterised recently. Diagnostic criteria for T-PLL have been refined with the publication of the first international consensus criteria, whereas the diagnosis of B-PLL has been thrown into question by the most recent WHO classification. Treatment advances in B-PLL have relied heavily on the advances seen in CLL that have then been extrapolated to B-PLL with just a few case reports to support the use of these targeted inhibitors. Despite increased knowledge of the biology of T-PLL and some elegant pre-clinical models to identify potential treatments, unfortunately, no improvements have been made in the treatment of T-PLL. Unmet need is a term oft used for many diseases, but this is particularly true for patients with prolymphocytic leukaemias. Ongoing improvements in our understanding of these diseases will hopefully lead to improved therapies in the future.

CircBCAR3 sponges miR-27a-3p and mediates ferroptosis in human B-prolymphocytic leukaemia cells via SLC7A11.

B-lymphocytic leukaemia is one of the most commonly diagnosed blood malignancies, and our knowledge of B-prolymphocytic leukaemia remained barely comprehensive. CircRNAs and miRNAs were identified of important regulatory roles in tumours. This study focused on the possibly existing interaction of circBCAR3 and miR-27a-3p, and downstream molecules thereafter in B-prolymphocytic leukaemia cells. CircBCAR3 and miR-27a-3p expression was evaluated in JVM-2 cell line and normal lymphocytes. Dual-luciferase luminescence assay was conducted for validation of circBCAR3 and miR-27a-3p interaction, as well as western blot and flow cytometry for evaluation and validation of their association with SLC7A11, reactive-oxygen species and Fe2+ regarding ferroptosis. CircBCAR3 were upregulated in JVM-2 cells and were reversely correlated with the expression of miR-27a-3p. CircBCAR3 targeted at miR-27a-3p and was consequently associated with SLC7A11 expression positively, inhibiting ferroptosis and peroxidative damage in JVM-2 cells. This study identified a circBCAR3-miR-27a-3p-SLC7A11 axis regulating ferroptosis and peroxidation of B-prolymphocytic leukaemia cells which might be a key mechanism facilitating the survival of tumour cells. However, further validation based on more diverse cell lines and animal models might be required.

Long-Smoldering T-prolymphocytic Leukemia: A Case Report and a Review of the Literature.

T-prolymphocytic leukemia (T-PLL) is a rare malignancy of mature T-cells with distinct clinical, cytomorphological, and molecular genetic features. The disease typically presents at an advanced stage, with marked leukocytosis, B symptoms, hepatosplenomegaly, and bone marrow failure. It usually follows an aggressive course from presentation, and the prognosis is often considered dismal; the median overall survival is less than one year with conventional chemotherapy. This case report describes a patient with T-PLL who, after an unusually protracted inactive phase, ultimately progressed to a highly invasive, organ-involving disease. After initial treatments failed, a novel treatment approach resulted in a significant response.

Partial response to venetoclax and ruxolitinib combination in a case of refractory T-prolymphocytic leukemia.

Background: T-prolymphocytic leukemia (T-PLL) is an aggressive hematologic malignancy. A portion of patients can be cured with alemtuzumab induction followed by allogeneic hematopoietic stem cell transplant, but patients who relapse after transplant have a poor prognosis, and there is no standard of care.Methods: We report a case of a 64-year-old man with relapsed JAK3-mutant T-PLL following allogeneic transplant who was treated with ruxolitinib and venetoclax.Results: Treatment with ruxolitinib and venetoclax resulted in a partial response including stabilization of the peripheral lymphocyte count, improvement in thrombocytopenia, decrease in splenomegaly, and a numerical reduction in the percentage of bone marrow involved by T-PLL. The combination was well tolerated with the exception of neutropenic infections.Conclusion: This case adds to the growing body of literature supporting venetoclax and rituximab as a viable treatment option for relapsed/refractory T-PLL with JAK-STAT alterations.

From the archives of MD Anderson Cancer Center: Aleukemic T-prolymphocytic leukemia, a rare presentation and review of the literature.

T-prolymphocytic leukemia (T-PLL) is a rare, aggressive T-cell leukemia, and patients typically present with marked peripheral blood lymphocytosis. Approximately 15-20 % of patients may present with moderate and relative stable lymphocytosis and an indolent clinical course that can persist for a few years. However, eventually these patients go on to develop marked lymphocytosis and rapidly progressive disease. We report a 72-year-old man who presented with multicompartmental lymphadenopathy and a normal complete blood count. Excision of left and right cervical lymph nodes showed replacement of the lymph node architecture by a small T-cell neoplasm positive for CD3, CD4, CD5, CD7 and TCL-1, and negative for CD8, CD20, CD30 and ALK. Subsequent bone marrow evaluation showed minimal bone marrow involvement by a T-cell neoplasm associated with TCL1A rearrangement in 11 % of cells supporting the diagnosis of T-PLL. Despite treatment, he showed progressive lymphadenopathy while remarkably maintaining normal white blood cell counts until he eventually developed leukocytosis of 110.9 × 103/uL 26 months later. Review of the literature identified only a single abstract reporting a patient with a similar lymphoma-like presentation and normal white blood cell count; however, that case showed significant bone marrow involvement in stark contrast to the current case. In summary, we report a highly unusual case of T-PLL can initially presenting with an aleukemic or lymphoma-like clinical picture, which can make establishing the diagnosis challenging.

Computational gene expression analysis reveals distinct molecular subgroups of T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare blood cancer with poor prognosis. Overexpression of the proto-oncogene TCL1A and missense mutations of the tumor suppressor ATM are putative main drivers of T-PLL development, but so far only little is known about the existence of T-PLL gene expression subtypes. We performed an in-depth computational reanalysis of 68 gene expression profiles of one of the largest currently existing T-PLL patient cohorts. Hierarchical clustering combined with bootstrapping revealed three robust T-PLL gene expression subgroups. Additional comparative analyses revealed similarities and differences of these subgroups at the level of individual genes, signaling and metabolic pathways, and associated gene regulatory networks. Differences were mainly reflected at the transcriptomic level, whereas gene copy number profiles of the three subgroups were much more similar to each other, except for few characteristic differences like duplications of parts of the chromosomes 7, 8, 14, and 22. At the network level, most of the 41 predicted potential major regulators showed subgroup-specific expression levels that differed at least in comparison to one other subgroup. Functional annotations suggest that these regulators contribute to differences between the subgroups by altering processes like immune responses, angiogenesis, cellular respiration, cell proliferation, apoptosis, or migration. Most of these regulators are known from other cancers and several of them have been reported in relation to leukemia (e.g. AHSP, CXCL8, CXCR2, ELANE, FFAR2, G0S2, GIMAP2, IL1RN, LCN2, MBTD1, PPP1R15A). The existence of the three revealed T-PLL subgroups was further validated by a classification of T-PLL patients from two other smaller cohorts. Overall, our study contributes to an improved stratification of T-PLL and the observed subgroup-specific molecular characteristics could help to develop urgently needed targeted treatment strategies.

Molecular characterization of Novel ATM fusions in chronic lymphocytic leukemia and T-cell prolymphocytic leukemia.

ATM deletions and/or mutations are recurrent in lymphoid neoplasms while rearrangements are rare. In this study, we used mate pair sequencing (MPseq) technology to characterize two novel ATM rearrangements in one patient with chronic lymphocytic leukemia (CLL) and one patient with T-prolymphocytic leukemia (T-PLL). Both patients showed chromosome 11q22 aberrations encompassing ATM by conventional karyotype and fluorescence in situ hybridization: isolated t(11;13)(q22;q14) in CLL and a complex karyotype with apparent 11q deletion and unbalanced der(14)t(11;14)(q22;p11.2) in T-PLL. MPseq identified ATM-LINC00371 fusion in CLL and ATM-USP28 in T-PLL, both of which led to ATM inactivation, confirmed by loss of immunohistochemical protein expression. Next-generation sequencing mutation analysis detected concurrent ATM mutation(s) CLL patient, while T-PLL lacked ATM mutation. ATM rearrangements, not apparently detectable using standard laboratory technologies, represent another mechanism of loss-of-function. Recent high-throughput technologies such as MPseq can uncover novel pathogenic gene fusions and resolve complex chromosomal rearrangements in hematologic malignancies.

An Unusual Case of Prolymphocytic Leukemia Transformation in a Patient With Chronic Lymphocytic Leukemia.

B-cell prolymphocytic leukemia (B-PLL) is a rare leukemia characterized by rapidly increasing leukocytosis with splenomegaly and lymphadenopathy. Treatment strategies are largely based on studies of chronic lymphocytic leukemia (CLL). Antibodies against the cell surface protein CD20 are considered to be first-line therapy. A 76-year-old male with known CLL presented 2 weeks after starting chemoimmunotherapy for newly refractory CLL after failing ibrutinib therapy. White blood cell count was elevated at 226.7 × 103/µL. Fluorescent in situ hybridization analysis of a bone marrow specimen showed new development of complex cytogenetics. Flow cytometry revealed B cells appearing slightly dimmer on CD45 and brighter on CD20 compared with typical B-CLL suggestive of less mature lymphocyte forms. The patient was diagnosed with B-PLL and started on obinutuzumab and venetoclax with rapid normalization of white blood cells. This case recapitulates the challenges in diagnosing and treating B-PLL. Ibrutinib resistance is a growing area of study with several proposed mechanisms of acquired resistance. The pathogenesis of B-PLL is not completely understood, although mutations in MYC are presumed to play a role.

Ibrutinib-induced acute kidney injury via interstitial nephritis.

The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 µmol/L to 125 µmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.

De novo chronic lymphocytic leukemia/prolymphocytic leukemia or B-cell prolymphocytic leukemia? The importance of integrating clinico-morphological and immunophenotypic findings in distinguishing chronic lymphoproliferative diseases with circulating phase

B-cell prolymphocytic leukemia (B-PLL) is an extremely rare disease, accounting for approximately 1% of the lymphocytic leukemias. B-PLL generally occurs in older people. It is characterized by the presence of more than 55% prolymphocytes in the peripheral blood (PB), no or minimal lymphadenopathy, massive splenomegaly, and very high white blood cell counts. The prognosis of B-PLL patients is generally poor, with a median survival of 3 years, although a subset of patients may show a prolonged survival. Herein, we report a case of a 70-year-old male with weakness, generalized lymphadenopathy, and moderate splenomegaly at the initial presentation. Hematologic examination revealed lymphocytic leukocytosis, favoring a chronic lymphoproliferative disorder (CLPD). The key to decoding the precise CLPD was a combination of the clinical profile, morphologic findings on the peripheral blood and the bone marrow, immunophenotypic analysis, and cytogenetic study. The best diagnosis proffered was a de novo chronic lymphocytic leukemia/prolymphocytic leukemia. There was no prior history of lymphoproliferative disorder or lymphocytic leukocytosis. Discriminating this entity from other lymphoproliferative disorders is crucial as the treatment and prognosis are varied compared to the other lymphoproliferative disorders. The diagnostic conundrum encountered and the incredible utility of ancillary studies in such a scenario are highlighted in this study.