How to manage waldenström's macroglobulinemia in 2024.

Clinical management of Waldenström's Macroglobulinemia has seen major progress in the recent years, triggered by our improved understanding of the biology of the disease and the development of new therapies. Based on this there are multiple treatment options available for patients with WM ranging from classical immunochemotherapy to targeted approaches blocking key enzymes involved in lymphoma growth. This review summarizes our current knowledge about diagnostics and treatment of this rare but recurrent lymphoma subtype, which often presents a major clinical challenge in daily clinical life.

Bortezomib-Dexamethasone, Rituximab, and Cyclophosphamide as First-Line Treatment for Waldenström's Macroglobulinemia: A Prospectively Randomized Trial of the European Consortium for Waldenström's Macroglobulinemia.

PURPOSE: Rituximab/chemotherapy is a cornerstone of treatment for Waldenström's macroglobulinemia (WM). In addition, bortezomib has shown significant activity in WM. This study evaluated the efficacy and safety of dexamethasone, rituximab, and cyclophosphamide (DRC) as first-line treatment in WM. METHODS: In this European study, treatment-naïve patients were randomly assigned to DRC or bortezomib-DRC B-DRC for six cycles. The primary end point was progression-free survival. Secondary end points included response rates, overall survival, and safety. RESULTS: Two hundred four patients were registered. After a median follow-up of 27.5 months, the estimated 24-month progression-free survival was 80.6% (95% CI, 69.5 to 88.0) for B-DRC and 72.8% (95% CI, 61.3 to 81.3) for DRC (P = .32). At the end of treatment, B-DRC and DRC induced major responses in 80.6% versus 69.9% and a complete response/very good partial response in 17.2% versus 9.6% of patients, respectively. The median time to first response was shorter for B-DRC with 3.0 (95% CI, 2.8 to 3.2) versus 5.5 (95% CI, 2.9 to 5.8) months for DRC. This resulted in higher major response rates (57.0% v 32.5%; P < .01) after three cycles of B-DRC compared with DRC. At best response, the complete response/very good partial response increased to 32.6% for B-DRC. Both treatments were well tolerated: grade ≥ 3 adverse events occurred in 49.2% of all patients (B-DRC, 49.5%; DRC, 49.0%). Peripheral sensory neuropathy grade 3 occurred in two patients treated with B-DRC and in none with DRC. CONCLUSION: This large randomized study illustrates that B-DRC is highly effective and well tolerated in WM. The data demonstrate that fixed duration immunochemotherapy remains an important pillar in the clinical management of WM.

Pharmacotherapeutic management of T-cell acute lymphoblastic leukemia in adults: an update of the literature.

INTRODUCTION: T-cell acute lymphoblastic leukemia (T-ALL) is a rare but potentially life-threatening heterogeneous hematologic malignancy that requires prompt diagnosis and treatment by hematologists. So far, therapeutic advances have been achieved in the management of this disease mainly by adopting pediatric-like regimens, and cure rates are significantly worse than in childhood. In T-ALL, less than 70% of adults achieve long-term survival. The prognosis after relapse is still very poor. Hence, there is urgent need to improve therapy of T-ALL by testing new compounds and combinations for the treatment of this disease. AREAS COVERED: This review provides a comprehensive update on the most recent treatment approaches in adults with de novo and relapsed/refractory adult T-ALL. EXPERT OPINION: Intensifying chemotherapy may reduce the incidence of recurrent disease in adult patients, but it has not come without a cost. Novel agents with selective T-ALL activity (e.g. nelarabine) may improve survival in some patient subsets. Due to modern genomic and transcriptomic techniques, various novel potential targets might change the treatment landscape in the next few years and will, hopefully alongside with cellular therapies, augment the therapeutic armamentarium in the near future.

A phase II study of the PI3K inhibitor copanlisib in combination with the anti-CD20 monoclonal antibody rituximab for patients with marginal zone lymphoma: treatment rationale and protocol design of the COUP-1 trial.

BACKGROUND: Advanced stage marginal zone lymphoma (MZL) is an incurable indolent B-cell lymphoma, for which a wide variety of treatments ranging from single agent rituximab to more dose intense immunochemotherapy exists. One of the major goals in this palliative setting is to develop chemotherapy-free treatments, which approach the efficacy of immunochemotherapies, but avoid chemotherapy associated toxicity in this often elderly patient population. The PI3K inhibitor copanlisib has recently shown remarkable clinical activity in refractory or relapsed indolent B-cell lymphomas, among them MZL. Based on these data, copanlisib monotherapy was granted breakthrough designation by the FDA for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least two prior therapies. However, data are still limited in particular for MZL. Based on this, the COUP-1 trial aims at testing the toxicity and efficacy of copanlisib in combination with rituximab in treatment naive and relapsed MZL. METHODS: COUP-1 is a prospective, multicenter, single-arm, open-label, non-randomized phase II trial of 6 cycles (28 days cycle) of copanlisib (60 mg intravenous day 1, 8, 15) and rituximab (375 mg/m2 intravenous day 1) in the induction phase followed by a maintenance phase of copanlisib (d1, d15 every 4 weeks for a maximum of 12 cycles) and rituximab (d1 every 8 weeks for a maximum of 12 cycles) in patients aged ≥18 years with previously untreated or relapsed MZL in need of treatment. A total of 56 patients are to be enrolled. Primary endpoint is the complete response (CR) rate determined 12 months after start of induction therapy. Secondary endpoints include the overall response (OR) rate, progression free survival (PFS), overall survival (OS), safety and patient related outcome with quality of life. The study includes a translational bio-sampling program with the prospect to measure minimal residual disease. The study was initiated in November 2019. DISCUSSION: The COUP-1 trial evaluates the efficacy and toxicity of the treatment of copanlisib in combination with rituximab in patients with MZL and additionally offers the chance for translational research in this heterogenous type of lymphoma. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03474744 . Registration date: 03/23/2018.

Phase II trial evaluating the efficacy and safety of the anti-CD20 monoclonal antibody obinutuzumab in patients with marginal zone lymphoma.

Marginal zone lymphoma (MZL) belongs to the group of indolent B-cell non-Hodgkin's lymphomas, which is characterized by an indolent course. In this mostly elderly patient population, the development of chemotherapy-free approaches is of particular interest. In this situation, single-agent treatment with the next-generation anti-CD20 antibody obinutuzumab is an attractive approach, which promises high efficacy without major toxicity. We describe here an open-label, multicentric Phase II trial evaluating the efficacy and safety of obinutuzumab in de novo MZL patients, who are treatment naive for systemic therapy and not eligible for or failed local treatment. ClinicalTrials.gov identifier NCT03322865.

Rituximab and ibrutinib in the treatment of Waldenström's macroglobulinemia.

The Bruton's tyrosine kinase inhibitor ibrutinib represents a highly effective single substance in the treatment of Waldenström's macroglobulinemia. Ibrutinib monotherapy is a valid therapeutic option either in the relapsed or refractory setting or in patients first line, particulary when they are ineligible for chemotherapy. However, the treatment success depends on the genotype. Recent data suggest that ibrutinib in combination with rituximab may partially overcome this genotype dependency.

Monoclonal IgM Gammopathy and Waldenström's Macroglobulinemia.

BACKGROUND: 3.2-3.5% of persons over age 50 have a monoclonal gammopathy. Monoclonal gammopathies have many causes, including cancer. 10-20% of monoclonal gammopathies are of isotype IgM. A systematic approach to the differential diagnosis of IgM gammopathies is essential because of the different therapeutic implications of the various underlying conditions. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed and current guidelines from Germany and abroad. RESULTS: The diagnosis of a monoclonal IgM gammopathy is established by serum electrophoresis in combination with immune fixation. Further evaluation enables the identification of the underlying condition: the differential diagnosis includes IgM-MGUS (monoclonal gammopathy of unclear significance), Waldenström's disease, and IgM myeloma. The therapeutic implications of the under - lying condition vary from watchful waiting in IgM-MGUS to combined rituximab and antineoplastic chemotherapy (off-label first-line use of rituximab) in symptomatic Waldenström's macroglobulinemia. Ibrutinib has been approved for the treatment of patients with recurrences, or of those for whom first-line treatment with rituximab and chemotherapy is not suitable. The current treatment options do not result in cure. In symptomatic Waldenström's disease, the goal of treatment is to keep the disease under control for as long as possible without impairing the patient's quality of life. CONCLUSION: Evidence-based treatment decisions in Waldenström's macroglobulinemia now rely mainly on small-scale, single-armed trials. Patients with this disease should be treated in the setting of a clinical trial if possible. Trials aimed at improving the quality of treatment for other IgM-associated diseases, such as IgM neuropathies and cold agglutinin disease, would also be desirable.

VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice.

Homeobox genes are key regulators in normal and malignant hematopoiesis. The human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus laevis Xvent-2 gene, was shown to be highly expressed in normal myeloid cells and in patients with acute myeloid leukemia. We now demonstrate that constitutive expression of VENTX suppresses expression of genes responsible for terminal erythroid differentiation in normal CD34+ stem and progenitor cells. Transplantation of bone marrow progenitor cells retrovirally engineered to express VENTX caused massive expansion of primitive erythroid cells and partly acute erythroleukemia in transplanted mice. The leukemogenic potential of VENTX was confirmed in the AML1-ETO transplantation model, as in contrast to AML1-ETO alone co-expression of AML1-ETO and VENTX induced acute myeloid leukemia, partly expressing erythroid markers, in all transplanted mice. VENTX was highly expressed in patients with primary human erythroleukemias and knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked cell growth. In summary, these data indicate that VENTX is able to perturb erythroid differentiation and to contribute to myeloid leukemogenesis when co-expressed with appropriate AML oncogenes and point to its potential significance as a novel therapeutic target in AML.

[New developments in Waldenström's macroglobulinemia]. / Neue Entwicklungen beim Morbus Waldenström.

Waldenström's Macroglobulinemia (WM) is a rare subtype of B-cell lymphoma with mostly indolent course. Until now the backbone of therapy is still Rituximab / Chemotherapy. In recent years whole genome sequencing has revealed a number of genetic mutations, among them mutations of the MYD88 gene which occurs in over 90 % of patients and helps to validate diagnosis of WM in difficult cases. With the introduction of ibrutinib, an oral bruton-tyrosine-kinase inhibitor, an effective chemotherapy-free treatment option is available.