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Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy.

Disease overviewChronic lymphocytic leukemia (CLL) is the most frequent type of leukemia. It typically occurs in older patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and apoptosis in clonal B-cells.DiagnosisThe diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers.Prognosis and stagingTwo clinical staging systems, Rai

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… Similarly, cladribine monotherapy produces a higher CR rate than chlorambucil plus prednisone, without improving survival [ 90 ]. Bendamustine [ 91 ] was compared to chlorambucil and produced improved response rates, but showed greater toxicity and no survival benefit [ 92 ]. … The Illuminate study produced a significant PFS benefit for the combination of ibrutinib and obinutuzumab versus chlorambucil‐obinutuzumab. …

2019 ASCO Annual Meeting Highlights for the Advanced Practitioner: Hematologic Malignancies.

Amy Pierre, MSN, ANP-BC, of the Memorial Sloan Kettering Cancer Center, and Nancy M. Nix, PharmD, BCPS, BCOP of St. Joseph's/Candler Health System offer an advanced practitioner perspective on trials assessing the efficacy and safety of novel agents in smoldering and relapsed/refractory multiple myeloma, chronic lymphocytic leukemia, and acute myeloid leukemia.

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… Our study showed it is superior to fixed-duration chlorambucil and obinutuzumab. … Fatal events during treatment occurred in 5 patients in the venetoclax/obinutuzumab group compared with 4 in the chlorambucil/obinutuzumab group and after treatment in 11 vs 4 patients, respectively. …

Emerging treatment options for patients with p53-pathway-deficient CLL.

Over the past 40 years, p53 has been the most widely studied protein in cancer biology. Originally thought to be an oncogene due to its stabilization in many cancers, it is now considered to be one of the most critical tumor suppressors in a cell's ability to combat neoplastic transformation. Due to its critical roles in apoptosis, cell-cycle arrest, and senescence, TP53 deletions and mutations are commonly observed and are often a portent of treatment failures and poor clinical outcomes. This is particularly true in chronic lymphocytic leukemia (CLL), as patients with p53 alterations have his

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… Chlorambucil is still widely used in Europe and in elderly patients for palliative disease control. 52 In a meta-analysis of seven clinical trials of the German CLL study group, of 3552 patients, 77% received chlorambucil plus anti-CD20 antibody therapy. 53 Notably, 152 patients were more than 80-years … , as median PFS was not reached in the ibrutinib group and was 19 months in the chlorambucil–obinutuzumab group. …

The place of cyclical therapy for the treatment of membranous nephropathy in the era of rituximab.

Primary membranous nephropathy (MN) is the most frequent cause of nephrotic syndrome in adults, due to a variety of autoantibodies, most frequently against phospholipase A2 receptor (PLA2R). In severe cases or when spontaneous remission is not achieved, immunosuppression is required. Cyclical therapy, based on glucocorticoids and cyclophosphamide on alternate months for 6 months, has proven effective to induce remission and reduce the risk of end-stage renal disease. Since the early 2000s, rituximab (RTX) has emerged as a key player in the management of MN, showing overall comparable effective

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… Importantly, when the alkylating agent employed was chlorambucil, an increased risk of cancer was observed [ 7 ]. … Treatment with chlorambucil and azathioprine in primary glomerulonephritis. Results of a “controlled” study. J Urol Nephrol (Paris) 1975;81:655–72. 8. Ponticelli C, Zucchelli P, Imbasciati Eet al. Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. …

Novel bicistronic retroviral vector expressing gamma-glutamylcysteine synthetase and the multidrug resistance protein 1 (MRP1) protects cells from MRP1-effluxed drugs and alkylating agents.

We have constructed two retroviral vectors, one expressing multidrug resistance protein 1 (MRP1) alone (SF91MRP) and the other expressing MRP1 and gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme of glutathione biosynthesis (SF91GCS-MRP). We have utilized the hybrid FMEV (Friend mink cell focus-forming/murine embryonic stem cell virus) backbone, previously shown to be efficient in early hematopoietic cells, even when coexpressing two distinct genes. In SF91GCS-MRP, the cDNAs were combined via an internal ribosomal entry site (IRES) sequence from poliovirus, resulting in

Hematologic Malignancies: 2022 ASCO Annual Meeting Highlights for the Advanced Practitioner.

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… The 5-year follow-up study randomly assigned patients to receive acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, or obinutuzumab plus chlorambucil. Patients whose disease progressed on obinutuzumab/chlorambucil treatment could cross over to acalabrutinib monotherapy. … However, the overall survival rate was significantly longer with acalabrutinib/obinutuzumab than with obinutuzumab/chlorambucil. The estimated 60-month overall survival rates were 90% with acalabrutinib/obinutuzumab, 84% with acalabrutinib monotherapy, and 82% with obinutuzumab/chlorambucil. …

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lymphoma.

The recent development and clinical implementation of novel immunotherapies for the treatment of Hodgkin and non-Hodgkin lymphoma have improved patient outcomes across subgroups. The rapid introduction of immunotherapeutic agents into the clinic, however, has presented significant questions regarding optimal treatment scheduling around existing chemotherapy/radiation options, as well as a need for improved understanding of how to properly manage patients and recognize toxicities. To address these challenges, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in lymphoma

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… In CLL11 ( NCT01010061 ), patients received obinutuzumab+chlorambucil, rituximab+chlorambucil, or chlorambucil alone. 128 Compared with chlorambucil alone, obtinutuzumab+chlorambucil treatment was associated with a significantly longer median PFS of 31.1 months versus 11.1 months (HR 0.21; 95% CI 0.16 … At a median follow-up of 59.4 months, patients treated with obinutuzumab+chlorambucil also exhibited a clear advantage in median PFS over patients treated with rituximab+chlorambucil, at 28.9 months versus 15.7 months (HR 0.49; 95% CI 0.41 to 0.58; p<0.0001). 129 On the basis of data from CLL11, the …

How to manage Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) is very distinct from other indolent lymphoma subtypes: by definition it is accompanied by a monoclonal IgM gammopathy; it presents always with bone marrow infiltration and often with clinical symptoms such as neuropathy or hyperviscosity. These disease characteristics and the frequently advanced age of the WM patient pose a major challenge to the treating clinician even today. Recently, there has been not only substantial progress in our understanding of the biology of WM, but we have also significantly improved our tools to prognostify and to treat patien

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… Three MDS/AMLs were observed during the follow-up, all cases in the chlorambucil arm. … The ORR was higher in the fludarabine arm with 47.8% compared with 38.6% for chlorambucil ( P =0.07). The median duration of response was 38.5 versus 21.3 months for fludarabine and chlorambucil, respectively ( P =0.0024). …

Non-conventional dosing of oral anticancer agents in oncology and malignant haematology: a systematic review protocol.

BackgroundRecent advances in cancer therapeutics have resulted in significantly improved overall survival and progression-free survival for patients. Targeted oral systemic anticancer therapies (SACT) offer a range of treatment approaches that differ from traditional cytotoxic chemotherapy: non-cytotoxic oral SACT target malignant disease continuously, have less broad and more favourable safety profiles, which can improve patients' quality of life (QoL). Toxicities associated with daily oral SACT administration can, however, result in non-adherence and a reduced QoL. Non-conventional dosing of

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… Chlorambucil/ 6. Cyclophosphamide/ 7. Estramustine/ 8. Etoposide/ 9. Hydroxyurea/ or hydroxycarbamide.mp. 10. Melphalan/ 11. mercaptopurine.mp. or 6-Mercaptopurine/ 12. Lomustine/ 13. Mitotane/ 14. Procarbazine/ 15. Tegafur/ 16. temozolomide.mp. 17. Thioguanine/ 18. … Chlorambucil/ 6. Cyclophosphamide/ 7. Estramustine/ 8. Etoposide/ 9. Hydroxyurea/ or hydroxycarbamide.mp. 10. Melphalan/ 11. mercaptopurine.mp. or 6-Mercaptopurine/ 12. Lomustine/ 13. Mitotane/ 14. Procarbazine/ 15. Tegafur/ 16. temozolomide.mp. 17. Thioguanine/ 18. …

Therapy-related acute myeloid leukemia following treatment of lymphoid malignancies.

Therapy-related acute myeloid leukemia (t-AML) is a heterogeneous entity most frequently related to breast cancer or lymphoproliferative diseases (LD). Population-based studies have reported an increased risk of t-AML after treatment of lymphomas. The aim of this study was to describe the characteristics and outcome of 80 consecutive cases of t-AML following treatment of LD. t-AML accounted for 2.3% of all AML cases, occurred 60 months after LD diagnosis, and were characterized by a high frequency of FAB M6 AML and poor-risk cytogenetic abnormalities. Time to t-AML diagnosis was influenced by

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… Among the 74 patients who received chemotherapy, 11 (15%) received a fludarabine-based regimen (all of them in association with an alkylating agent), 34 (46%) a CHOP-like regimen, 19 (26%) chlorambucil, and 34 (46%) rituximab. … Time to LD/t-AML was not significantly different when considering fludarabine-based regimens, chlorambucil, or ASCT (58.4, 62.4, and 93.5 months, respectively). …

From Time-Limited Therapy to Treatment-Free Observation: The Evolving Role of MRD in CLL Management.

The integration of measurable residual disease (MRD) into the management of chronic lymphocytic leukemia (CLL) has emerged as a major advance in risk stratification and trial design, particularly in the context of time-limited, targeted regimens. High-sensitivity MRD assessment, enabled by multicolor flow cytometry, allele-specific oligonucleotide PCR, and next-generation sequencing (NGS), provides a robust, quantifiable measure for depth of remission and long-term outcomes. Landmark trials-including CLL14, MURANO, CAPTIVATE, and GLOW-have consistently demonstrated that achieving undetectable

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… The RESONATE‐2 study [ 47 ] evaluated first‐line ibrutinib in older patients and confirmed exceptional long‐term PFS (median 8.9 years) compared with chlorambucil (1.3 years). … The ELEVATE‐TN study, which evaluated frontline acalabrutinib with or without obinutuzumab versus chlorambucil–obinutuzumab, showed that the addition of obinutuzumab to acalabrutinib significantly increased uMRD rates (40.9% vs. 8.8% with acalabrutinib monotherapy and 8.3% with chlorambucil–obinutuzumab …

Update in the management of chronic lymphocytic leukemia.

Advances in the treatment of chronic lymphocytic leukemia (CLL) have improved initial overall response (OR) rates, complete response (CR) rates and progression free survival (PFS). Despite these advances, CLL remains incurable with standard therapies. Thus, there remains a need for more effective therapies in both the upfront and relapsed setting, particularly for patients with high-risk cytogenetic abnormalities such as del(11q22) and del(17p13). The 2008 American Society of Hematology (ASH) Annual Meeting featured several presentations which highlighted the ongoing clinical advances in CLL.

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… Lastly, the United Kingdom CLL4 study randomized 777 patients to oral chlorambucil, fludarabine, or FC [ 5 ]. Again, patients receiving FC achieved superior OR (94% vs. 80%), CR (38% vs. 15%), and 5-year PFS (36% vs. 10%). … OR, CR and median PFS favored bendamustine (67%, 32%, 21.5 months) over chlorambucil (30%, 2%, 8.3 months), although bendamustine caused greater hematologic toxicity (40% vs. 19%), especially grade 3–4 neutropenia (23% vs. 9%) [ 17 ]. …

Primary Gastric Lymphoma, Epidemiology, Clinical Diagnosis, and Treatment.

Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma and represents a wide spectrum of disease, ranging from indolent low-grade marginal zone lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma to aggressive diffuse large B-cell lymphoma. The PGL is a relatively rare cancer and easily misdiagnosed due to its unspecific symptoms of the digestive tract. The medical literature and ongoing clinical trials were reviewed on the clinical presentation, diagnosis, prognosis, prevention, and treatment of PGL. Primary gastric lymphoma is an event in the course of ca

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… Alkylating agents: Chlorambucil is probably the most studied agent in MALT lymphoma, either in monotherapy or in combination. … In 2017, the 3-arm study results showed superior efficacy of the combined therapy (R and chlorambucil) in treatment of MALT lymphoma. …

Alkylating anticancer agents and their relations to microRNAs.

Alkylating agents represent an important class of anticancer drugs. The occurrence and emergence of tumor resistance to the treatment with alkylating agents denotes a severe problem in the clinics. A detailed understanding of the mechanisms of activity of alkylating drugs is essential in order to overcome drug resistance. In particular, the role of non-coding microRNAs concerning alkylating drug activity and resistance in various cancers is highlighted in this review. Both synthetic and natural alkylating agents, which are approved for cancer therapy, are discussed concerning their interplay w

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… Figure 1 Structures of the N -mustard alkylating agents melphalan, chlorambucil, cyclophosphamide and estramustine Chlorambucil has been the standard treatment for chronic lymphocytic leukemia (CLL) for decades and the drug is still recommended as a mainstay for the currently widely applied antibody-based … A miR-210 targeting/inhibiting chlorambucil conjugate was synthesized, which suppressed a cancer relevant hypoxic mechanism and was active against hypoxic triple-negative breast cancer in mice [ 24 ] . A list of miRNAs associated with chlorambucil activity is provided in Table 1 . …

Tolerability of obinutuzumab therapy in patients with rituximab-relapsed/refractory B-cell malignancies - a retrospective single center cohort study.

Background & aimIn randomised clinical trials, the type II anti-CD20 antibody obinutuzumab has been shown to be more effective than rituximab for therapy of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). However, this enhanced efficacy was linked with elevated rates of high-grade adverse events. The aim of this study was to assess the tolerability and toxicity profile of obinutuzumab treatment in routine patients with CLL and FL, of whom the majority had experienced toxicity or resistance to rituximab.MethodsThis retrospective cohort study investigated fifteen obinutuzumab-tr

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… If therapy-limiting co-morbidities are present, less toxic therapies such as rituximab-bendamustine, ofatumumab, obinutuzumab-chlorambucil or ibrutinib should be chosen [ 11 – 14 ]. … However, also infusion-related reactions and neutropenia were more common in the obinutuzumab-chlorambucil group than with rituximab-chlorambucil-treated patients. …

Comparison of Access to Novel Drugs for Lymphoma and Chronic Lymphocytic Leukemia Between India and the United States.

This review will compare and contrast the costs and access to novel drugs for treating chronic lymphocytic leukemia (CLL) and lymphoma in the United States and India during the last 5 years. Clinical outcomes for patients with hematologic malignancies have improved significantly since the approval of immunotherapeutic and targeted therapies. These new treatments have had an impact on overall outcomes and have helped determine the design for translational research and future trials. Although most of these novel drugs called "innovators" are initially approved and marketed in the United States,

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… Patients were randomly assigned to obinutuzumab plus chlorambucil chemotherapy or rituximab plus chlorambucil followed by obinutuzumab or rituximab maintenance in responders. The estimated 3-year PFS rate was 80.0% versus 73.3% (hazard ratio [HR], 0.66; P = .001) favoring the obinutuzumab arm. … The 2-year PFS was higher in the venetoclax-obinutuzumab arm (88.2% v 64.1%, with 28 months of follow-up) as compared with chlorambucil plus obinutuzumab. …

Bortezomib in mantle cell lymphoma: comparative therapeutic outcomes.

Mantle cell lymphoma (MCL) is an incurable, typically aggressive subtype of non-Hodgkin lymphoma, accounting for 4%-7% of newly diagnosed non-Hodgkin lymphoma cases. Chemoresistance commonly ensues in MCL, and patients with this heterogeneous disease invariably relapse, underscoring the unmet need for better therapies. Over the past few years, several novel agents with promising activity and unique mechanisms of action have been deemed effective in MCL. Bortezomib is a reversible proteasome inhibitor, approved as a single agent for patients with relapsed/refractory MCL who have received at lea

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… A number of bortezomib-containing regimens such as VR-CAP, modified R-HyperCVAD ± bortezomib with MR and RiPAD + C (rituximab, bortezomib, doxorubicin, dexamethasone, and chlorambucil), discussed in detail in the subsequent sections, have shown promising activity in recent years. … The Groupe Ouest Est d’Etude des Leucémies aiguës et Autres Maladies du Sang (GOELAMS) had developed RVAD + C (rituximab, vincristine, doxorubicin, dexamethasone, and chlorambucil), a frontline regimen for elderly patients that was found to be as effective as R-CHOP, but less toxic. …

Rituximab-Associated Flare of Cryoglobulinemic Vasculitis.

BackgroundPatients with cryoglobulinemic vasculitis (CV) can develop disease flare after rituximab administration. The objective of our study was to describe the prevalence, clinical characteristics, predisposing factors, and outcomes of patients with rituximab-associated flare of CV.MethodsWe conducted a retrospective study in a tertiary referral center until March 25, 2020.ResultsAmong 64 patients with CV who received rituximab therapy in our center, 14 (22%) developed disease flare. Median age was 67.5 years. Seven patients (50%) had type II CV and the other half had either type I (n = 6) o

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… The most used chemotherapeutic agent was cyclophosphamide ( n = 6), and the rest included vincristine, cladribine, methotrexate, chlorambucil, and bendamustine. … Rituximab was continued in 10 of these patients with the addition of cyclophosphamide, bortezomib, chlorambucil, or fludarabine for those with WM and bendamustine and/or lenalidomide for those with non-Hodgkin’s lymphoma. …

Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review.

IntroductionPatients with hematological malignancies (HMs), like chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), have a high risk of secondary immunodeficiency (SID), SID-related infections, and mortality. Here, we report the results of a systematic literature review on the potential association of various cancer regimens with infection rates, neutropenia, lymphocytopenia, or hypogammaglobulinemia, indicative of SID.MethodsA systematic literature search was performed in 03/2022 using PubMed to search for clinical trials that mentioned in the title and

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… Real-world data on efficacy and safety of obinutuzumab plus chlorambucil, rituximab plus chlorambucil, and rituximab plus bendamustine in the frontline treatment of chronic lymphocytic leukemia: The GO-CLLEAR study by the Czech CLL study group . … Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): A randomised, multicentre, open-label phase 3 trial . …

The evolving use of measurable residual disease in chronic lymphocytic leukemia clinical trials.

Measurable residual disease (MRD) status in chronic lymphocytic leukemia (CLL), assessed on and after treatment, correlates with increased progression-free and overall survival benefit. More recently, MRD assessment has been included in large clinical trials as a primary outcome and is increasingly used in routine practice as a prognostic tool, a therapeutic goal, and potentially a trigger for early intervention. Modern therapy for CLL delivers prolonged remissions, causing readout of traditional trial outcomes such as progression-free and overall survival to be inherently delayed. This repres

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… Four hundred thirty-two patients were randomized in a 1:1 ratio to receive 12 cycles of either venetoclax or chlorambucil both in combination with obinutuzumab for the first 6 cycles. … Residual disease kinetics among patients with high-risk factors treated with first-line fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O): The glow study. Blood 140:228–30. 51. …