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The phase 2 CLL2-BZAG trial tested a measurable residual disease (MRD)-guided combination treatment of zanubrutinib, venetoclax and obinutuzumab after an optional bendamustine debulking in patients with relapsed/refractory CLL. In total, 42 patients were enrolled and two patients with ≤2 induction cycles were excluded from the analysis population per protocol. Patients had a median of one prior therapy (range 1-5), 18 patients (45%) had already received a BTK inhibitor (BTKi), seven patients (17.5%) venetoclax, and of these, five (12.5%) had received both. Fifteen patients (37.5%) had a TP53 mutation/deletion and 31 (77.5%) had unmutated IGHV. With a median observation time of 21.5 months (range 8.0-35.3) the most common adverse events were COVID-19 (n=26 patients), diarrhea (n=15), infusion-related reactions (n=15), thrombocytopenia (n=14), nausea (n=12), fatigue (n=12) and neutropenia (n=12). Two patients had fatal adverse events (COVID-19, fungal pneumonia secondary to COVID-19). After six months of the triple combination all patients responded and 21 (52.5%, 95% confidence interval 36.1%-68.5%) showed uMRD in peripheral blood. In many patients remissions deepened over time with a best uMRD rate of 85%. The best uMRD rate was similar in patients with TP53 aberrations (80%) and patients previously exposed to venetoclax/BTKi (80%). The estimated progression-free and overall survival rates at 18 months were 96% and 96.8%. No patient has yet required a subsequent treatment. In summary, the MRD-guided triple combination of zanubrutinib, venetoclax and obinutuzumab induced deep remissions in a relapsed CLL population enriched for patients previously treated with a BTKi/venetoclax. ClinicalTrials.gov NCT04515238., (Copyright © 2025 American Society of Hematology.)

During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL) therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL with favorable disease features-particularly mutated immunoglobulin heavy chain variable region (IGHV) genes-derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. The advent of oral targeted therapies, particularly ibrutinib and idelalisib, has provided generally well-tolerated and highly effective additional options that have come into widespread use in the relapsed setting. Additional agents are advancing in clinical development, with the BCL-2 inhibitor venetoclax likely to be approved by the U.S. Food and Drug Administration (FDA) in 2016. With the development of these novel therapies for patients with relapsed CLL, many unanswered questions remain, including the optimal sequence (first vs. second line), duration, discontinuation, and combination of these agents. In addition, recent publications show the emergence of a pattern of treatment resistance in certain subgroups of patients with del(17p) and complex karyotype that needs further study and improvement. Because the field of CLL management has become much more complex, we focus here on understanding the recent data and discuss many of the questions and controversies important for how we approach patients with CLL.

The number of hematopoietic stem cell transplantations is continuously increasing. On the one hand reduced intensity conditioning and improved supportive therapies allow for transplantations in patients with significant comorbidities and up to their eighth decade of life. Due to this development the number of complex and critically ill patients in need of intensive care is constantly growing. Recent developments in general critical care such as sepsis bundles and non-invasive ventilation contribute to a better outcome of these patients. However, treatment algorithms that identify patients potentially benefitting from intensive care but also reduce overtreatment of moribund patients represent a central multidisciplinary challenge not only for the treating transplant physician and intensivist.

Background: Currently the majority of cancer patients are considered ineligible for intensive care treatment and oncologists are struggling to get their patients admitted to intensive care units. Critical care and oncology are frequently two separate worlds that communicate rarely and thus do not share novel developments in their fields. However, cancer medicine is rapidly improving and cancer is eventually becoming a chronic disease. Oncology is therefore characterized by a growing number of older and medically unfit patients that receive numerous novel drug classes with unexpected side effects., Discussion: All of these changes will generate more medically challenging patients in acute distress that need to be considered for intensive care. An intense exchange between intensivists, oncologists, psychologists and palliative care specialists is warranted to communicate the developments in each field in order to improve triage and patient treatment. Here, we argue that "critical care of cancer patients" needs to be recognized as a medical subspecialty and that there is an urgent need to develop it systematically., Conclusion: As prognosis of cancer improves, novel therapeutic concepts are being introduced and more and more older cancer patients receive full treatment the number of acutely ill patients is growing significantly. This development a major challenge to current concepts of intensive care and it needs to be redefined who of these patients should be treated, for how long and how intensively.

Progress in our understanding of chronic lymphocytic leukemia and its treatment has resulted in a more tailored approach to patient management, with different therapeutic regimens for different patient populations. The current standard of care has evolved from single-agent therapy with chlorambucil or cyclophosphamide, through the introduction of purine analogs to the more recent introduction of chemoimmunotherapy. Selection of appropriate initial therapy should be based primarily on patient characteristics such as age, performance status and the expected clinical course of the leukemia based on established risk factors. Achieving a complete and durable response is the major goal for fit patients; chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab would be advantageous. Alternatively, in unfit patients, controlling symptoms is the essential treatment goal and a regimen with a more favorable toxicity profile should be applied. This manuscript reviews the data that has lead to current treatment choices, advises on tailored therapies and discusses emerging trends. Data for this review was identified by a search of electronic information including Medline and PubMed databases, conference proceedings and trial registers. Critical analysis of extracted data was undertaken with attention to trial phase, treatment schedules and end points, including response rates, follow-up times, progression-free survival and overall survival.

Allogeneic hematopoietic stem cell transplantation is an established treatment modality for malignant and nonmalignant hematologic diseases. Acute and chronic graft-versus-host diseases (GVHDs) are a major cause of morbidity and mortality after allogeneic stem cell transplantation. T cells have been identified as key players in the graft-versus-host reaction and, therefore, most established drugs used against GVHD target T cells. Despite our knowledge on the pathogenesis of the GVH reaction, success of established therapies for prevention and treatment of GHVD is unsatisfactory. Recently, animal and human studies demonstrated that B cells are involved in the immunopathophysiology of acute and chronic GVHD. Early phase clinical trials of B-cell depletion with rituximab have shown beneficial effects on both acute and chronic GVHD. This review summarizes the current experimental and clinical evidence for the involvement of B cells in the pathogenesis of acute and chronic GVHD and discusses the clinical implications for the management of patients undergoing allogeneic stem cell transplantation.

The eradication of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) predicts for improved outcome. However, the wide variety of MRD techniques makes it difficult to interpret and compare different clinical trials. Our aim was to develop a standardized flow cytometric CLL-MRD assay and compare it to real-time quantitative allele-specific oligonucleotide (RQ-ASO) Immunoglobulin heavy chain gene (IgH) polymerase chain reaction (PCR). Analysis of 728 paired blood and marrow samples demonstrated high concordance (87%) for patients off-therapy. Blood analysis was equally or more sensitive than marrow in 92% of samples but marrow analysis was necessary to detect MRD within 3 months of alemtuzumab therapy. Assessment of 50 CLL-specific antibody combinations identified three (CD5/CD19 with CD20/CD38, CD81/CD22 and CD79b/CD43) with low inter-laboratory variation and false-detection rates. Experienced operators demonstrated an accuracy of 95.7% (specificity 98.8%, sensitivity 91.1%) in 141 samples with 0.01-0.1% CLL. There was close correlation and 95% concordance with RQ-ASO IgH-PCR for detection of CLL above 0.01%. The proposed flow cytometry approach is applicable to all sample types and therapeutic regimes, and sufficiently rapid and sensitive to guide therapy to an MRD-negativity in real time. These techniques may be used as a tool for assessing response and comparing the efficacy of different therapeutic approaches.

A high incidence of autologous graft-versus-host-disease (auto-GVHD) was observed after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation (auto-SCT) for chronic lymphocytic leukemia (CLL). Skin rash developed in almost all surviving patients (87%). In 7 patients (58%), a diagnosis of auto-GVHD was made (compared with 0% after TBI/Cy; P = .01). All patients with auto-GVHD required immunosuppression, and 3 of 7 were hospitalized because of GVHD. The median duration of GVHD was 517 days (range, 60-867 days). Auto-GVHD was associated with an abnormally high CD4/CD8 ratio because of severe depletion of CD8(+) T cells, pointing to a potential pathomechanism. High non-relapse-related mortality led to the discontinuation of the trial. Current results do not support the use of high-dose alemtuzumab combined with total body irradiation (TBI) and autologous stem cell transplantation (auto-SCT). However, the addition of alemtuzumab led to improved disease control at the molecular level. Longer follow-up will show whether the GVHD-like syndrome may contribute to prolonged minimal residual disease (MRD) negativity.

Background and Objectives: Although bendamustine has been used for more than 30 years in the treatment of lymphoma, little is known about the optimal dosing schedule in relapsed or refractory B-cell chronic lymphocytic leukemia (CLL). Various dose and treatment schedules have been used empirically, and several phase II studies have shown impressive efficacy. To determine the maximal tolerated dose, dose-limiting toxicity and the optimal therapeutic dose of bendamustine for further phase III clinical trials the GCLLSG designed a phase I/II study for pre-treated CLL patients., Design and Methods: Sixteen patients (median age 67 years) with relapsed or refractory CLL were enrolled. All patients had been pre-treated with a median of three different regimens. Bendamustine was given at a starting dose of 100 mg/m2 on day 1 and 2, repeated every 3-4 weeks., Results: Major toxicities were leukocytopenia (CTC grade 3+4) in 8/16 and infections (CTC grade 3+4) in 7/16 patients. Six patients had dose-limiting toxicity which led to dose de-escalation from 100 to 70 mg/m2 in three patients. The maximum tolerated dose was 70 mg/m2. According to NCI-WG criteria, 9/16 patients (56%) responded to therapy, seven to doses

While chemotherapy based on alkylating agents has been the standard treatment of chronic lymphocytic leukemia (CLL) for decades, purine analogues and their combinations have emerged as effective new therapies for previously untreated and pretreated patients. As single agents, fludarabine and cladribine are the most promising, showing higher remission rates compared to chlorambucil. For younger and physically fit patients, the combination of fludarabine and cyclophosphamide has shown benefit. Fludarabine plus epirubicin appears equally potent. The addition of monoclonal antibodies, such as rituximab and alemtuzumab, to purine analogues alone or in combination seems to be even more effective for chemotherapy-naive and pretreated CLL patients. Another promising agent in the armamentarium of therapies for CLL is bendamustine, which has properties of both an alkylating agent and a purine analogue. Clinical trials are ongoing with novel drugs that interfere with cell cycle regulation and signaling molecules in CLL, including flavopiridol, UCN-01, bryostatin 1, depsipeptide, and oblimersen. It remains to be seen whether these chemotherapeutic approaches offer real benefit for patients by prolonging survival with an improved quality of life.