Efficacy of a third BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL who failed standard 2-dose vaccination.

Patients with chronic lymphocytic leukemia (CLL) have an impaired antibody response to coronavirus disease 2019 (COVID-19) vaccination. Here, we evaluated the antibody response to a third BNT162b2 mRNA vaccine in patients with CLL/small lymphocytic lymphoma (SLL) who failed to achieve a humoral response after standard 2-dose vaccination regimen. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies were measured 3 weeks after administration of the third dose. In 172 patients with CLL, the antibody response rate was 23.8%. Response rate among actively treated patients (12.0%; n = 12/100) was lower compared with treatment-naïve patients (40.0%; n = 16/40; OR = 4.9, 95% CI 1.9-12.9; P < .001) and patients off-therapy (40.6%; n = 13/32; OR = 5.0, 95% CI 1.8-14.1; P < .001), (P < .001). In patients actively treated with Bruton's tyrosine kinase (BTK) inhibitors or venetoclax ± anti-CD20 antibody, response rates were extremely low (15.3%, n = 9/59, and 7.7%, n = 3/39, respectively). Only 1 of the 28 patients (3.6%) treated with anti-CD20 antibodies <12 months prior to vaccination responded. In a multivariate analysis, the independent variables that were associated with response included lack of active therapy (OR = 5.6, 95% CI 2.3-13.8; P < .001) and serum immunoglobulin A levels ≥80 mg/dL (OR = 5.8, 95% CI 2.1-15.9; P < .001). In patients with CLL/SLL who failed to achieve a humoral response after standard 2-dose BNT162b2 mRNA vaccination regimen, close to a quarter responded to the third dose of vaccine. The antibody response rates were lower during active treatment and in patients with a recent exposure (<12 months prior to vaccination) to anti-CD20 therapy. This trial was registered at www.clinicaltrials.gov as #NCT04862806.

A phase 2 study of ibrutinib maintenance following first-line high-dose methotrexate-based chemotherapy for elderly patients with primary central nervous system lymphoma.

BACKGROUND: Elderly patients account for nearly 70% of all primary central nervous system lymphoma (PCNSL) cases. They cannot tolerate aggressive treatment and have poor prognosis with a median overall survival (OS) of less than 2 years and progression-free survival (PFS) of 6-16 months. Ibrutinib penetrates the blood-brain barrier and has shown activity in PCNSL. METHODS: This prospective study investigated whether ibrutinib maintenance is feasible, and whether it can benefit elderly PCNSL patients in terms of expected 2-year PFS. It is an open label, phase 2 study in newly diagnosed PCNSL patients 60-85 years old who responded to first-line high-dose methotrexate (HDMTX)-based treatment with partial or complete response. Ibrutinib maintenance (560 mg/d) was continued until disease progression or intolerable toxicity. RESULTS: Twenty patients were enrolled, with a median age of 72 years (range, 61-80). Median time on ibrutinib maintenance was 12.5 (range, 2-46) months. Twelve patients stopped treatment: five due to central nervous system relapse and seven due to adverse events that were mainly grade 2. Five patients died (25%) all due to relapse. The 1- and 2-year PFS are 90% and 72.6%, respectively, and the 2-year OS is 89%. CONCLUSIONS: The study reached its primary end points and also showed that ibrutinib maintenance is tolerated reasonably well by the elderly. Therefore, this study supports the concept that ibrutinib maintenance should be further evaluated as an optional consolidation measure in the elderly.

A retrospective study of 222 patients with newly diagnosed primary central nervous system lymphoma-Outcomes indicative for improved survival overtime.

Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person-years. As there is a limited number of prospective randomized trials in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials. We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in five referral centers in Israel between 2001 and 2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high-dose chemotherapy with or without autologous stem cell transplantation (HDC-ASCT). Patients older than 60 comprised 67.5% of the study population. First-line treatment included high-dose methotrexate (HD-MTX) in 94% of patients with a median MTX dose of 3.5 g/m2 (range 1.14-6 g/m2 ) and a median cycle number of 5 (range 1-16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD-MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow-up of 24 months, the median progression-free survival (PFS) and overall survival (OS) were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS: 12.5 vs. 34.2 p = 0.006 and OS: 19.9 vs. 77.3 p = 0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and Eastern Cooperative Oncology Group performance status. The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD-MTX-based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the introduction of HDC-ASCT.

Many People With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Benefit From Ibrutinib Treatment Up To 8 Years: A Plain Language Summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022. WHAT WERE THE RESULTS?: Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated and followed for up to 8 years, with results showing that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7 years after starting treatment than participants who took chlorambucil (9%). Almost half of the participants (42%) were able to stay on ibrutinib treatment for up to 8 years. WHAT DO THE RESULTS OF THE STUDY MEAN?: In people with CLL or SLL, more participants who were taking ibrutinib were alive without worsening of their disease after 7 years compared with participants who took chlorambucil. Clinical Trial Registration: NCT01722487 (ClinicalTrials.gov) Clinical Trial Registration: NCT01724346 (ClinicalTrials.gov).

Safety and efficacy of the BNT162b mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.

Consolidation Treatment for Primary Central Nervous System Lymphoma: Which Modality for Whom?

Primary central nervous system lymphoma is a rare aggressive disease that largely affects elderly patients and is associated with poor prognosis. The optimal treatment approach is not yet defined and it consists of induction and consolidation phases. The combination of high-dose (HD) methotrexate-based chemotherapy followed by whole-brain radiotherapy (WBRT) prolongs the median progression-free survival (PFS) and overall survival 2- to 3-fold as compared to WBRT alone but is associated with significant delayed neurotoxicity. Alternative strategies are being investigated in order to improve disease outcomes and spare patients the neurocognitive side effects. These include reduced-dose WBRT, non-myeloablative HD chemotherapy, or HD chemotherapy with autologous stem cell transplantation (HDC/ASCT). There are no randomized studies that compare all these consolidation regimens head to head but recently HDC/ASCT has been evaluated versus WBRT in prospective randomized studies. These studies proved that WBRT and HDC/ASCT yield similar 2-year PFS with preserved or improved cognitive function after HDC/ASCT. Yet, the proportion of patients treated with such intensive consolidation is low, both in real life and in specialized centers, leaving many unsettled issues. This review is appraising current dilemmas related to the choice of consolidating therapeutic modalities, their associated acute and delayed toxicity, and future prospects for alternative approaches in the elderly.

Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: Results of a multinational, multicenter study by ERIC and the Israeli CLL study group.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Low-dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD-FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience.

Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. The fludarabine, cyclophosphamide, and rituximab (FCR) regimen is considered the treatment of choice for young fit patients with CLL; however, this combination is toxic for older patients. At the time this study was first planned and initiated, there was no standard chemo-immunotherapy regimen regarded as standard therapy for the less fit elderly patient with CLL. Here, we conducted a single-arm, phase II trial to examine the efficacy and safety of lower-dose fludarabine and cyclophosphamide combined with a standard dose of rituximab (LD-FCR) in elderly patients with previously untreated CLL. Forty patients received LD-FCR and were included in the efficacy analysis. Two patients treated with FC alone were only included in the safety analysis. The median age was 72.7 years (range, 65.0 to 85.0). The overall response and complete response rates were 67.5% and 42.5%, respectively. Median progression-free survival (PFS) was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Hematological toxicities and infections were the most common complications encountered; grade 3 to 4 treatment-related neutropenia occurred in 20 (47.6%) patients. During the entire study follow-up, 26 patients (61.9%) had all grades of infection including six (14.3%) with neutropenic fever and eight (19%) with grade 3 to 4 non-neutropenic infections. In conclusion, LD-FCR is an effective and relatively safe regimen for previously untreated patients with CLL. It has the advantage of being both "time and cost limited" and, even in the era of novel agents, can still be considered when planning treatment for elderly patients without high-risk biomarkers. However, recent results in fit elderly patients using the combination of bendamustine and rituximab which have achieved longer PFS with good safety profile must be taken into consideration in this regard.

Characteristics, management and outcome of DLBCL patients, presenting with simultaneous systemic and CNS disease at diagnosis: A retrospective multicenter study.

The incidence of systemic diffuse large B cell lymphoma (DLBCL) concurrently involving the central nervous system (CNS) at diagnosis, is very low and data regarding the clinical course of these patients are scarce. We investigated characteristics, efficacy of treatment regimens including consolidative autologous stem cell transplantation and outcome of patients presenting with concomitant systemic and CNS DLBCL. The records of 44 patients, diagnosed between 2004 and 2017, who fulfilled the inclusion criteria, were retrospectively reviewed. CNS involvement was diagnosed as solely parenchymal in 41%, solely leptomeningeal in 43%, and paranchymal with leptomeningeal in 11% of the patients. Induction regimens were anthracycline-based combined with high-dose methotrexate (HD-MTX) in 80% (n = 35) of patients, anthracycline-based combined with intrathecal MTX in 3, cytarabine-based (without antracyclines) in 2, HD-MTX in 1 and palliative in three. Five of 41 patients treated with chemotherapy died of treatment-related toxicity, all due to infections. Nineteen patients had consolidative autologous transplantation. Overall response rate following induction was 80% (complete responses 66% and partial responses 15%). All relapses (n = 11) occurred within less than 2 years. Within a median follow-up of 26.8 months, 3-years projected overall survival (OS) and progression free survival rates for the entire cohort were 56% ± 8.3 and 42% ± 8.9, respectively. In multivariate analysis, RCHOP-HD MTX-based induction [HR = 0.228, (0.054-0.964)], administration of 3.5 g/m2 MTX [HR = 0.735 (0.620-0.871)], and attaining CR following induction [HR = 0.185, (0.051-0.667)] predicted longer OS. RCHOP-HD MTX can provide prolonged remissions in DLBCL patients presenting with concomitant systemic and CNS involvement whereas role of autograft remains uncertain.

Primary CNS Lymphoma in the Elderly: The Challenge.

Primary central nervous system (CNS) lymphoma is an aggressive brain tumor sensitive to chemotherapy and radiotherapy. Its incidence has increased in the elderly, and they account for the majority of patients. The median survival of patients older than 70 years did not change over the last 40 years and remained in the range of 6-7 months. The definition of elderly is nonuniform, and chronological age is not the best marker of treatment tolerability or a predictor of treatment-related toxicity. Some patients who are fit can tolerate induction, consolidation, and even high-dose chemotherapy with autologous stem cell transplantation, whereas others who have multiple comorbidities with reduced renal and bone marrow function can tolerate only intermediate doses of methotrexate. The latter may benefit from maintenance treatment. The "elderly" are also susceptible to the accelerated and detrimental cognitive side effects of whole-brain irradiation which is an alternative consolidation to high-dose chemotherapy. The optimal treatment remains an unresolved matter. A comprehensive comorbidity and geriatric assessment is imperative for appraisal of treatment-induced risks for CNS and systemic toxicity. An individualized approach is required aiming to prolong survival while minimizing toxicity. Future studies should assess the potential of new agents for improving outcome and maintaining quality of life.

Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies.

Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Down-regulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.

The Utility of 18F-fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography in Cutaneous B-Cell Lymphoma.

BACKGROUND: Whole-body integrated positron emission tomography / contrast-enhanced computed tomography (PET/CT) scan is increasingly used in cutaneous lymphomas. However, the value of PET/CT in the detection of cutaneous lesions in primary cutaneous B-cell lymphoma (PCBCL) has barely been investigated. OBJECTIVES: To investigate the diagnostic accuracy of PET/CT in tracking cutaneous involvement in PCBCL. METHODS: A retrospective study was conducted on 35 consecutive patients diagnosed with cutaneous B-cell lymphoma according to the World Health Organization classification who were evaluated with PET/CT as the initial staging procedure before treatment. RESULTS: Thirty-five patients met the study criteria. In two patients extracutaneous disease was detected by PET/CT and CT and confirmed by biopsy. Of the 33 patients with PCBCL, 26 (79%) had small cell PCBCL (18 marginal-zone, 8 follicle-center lymphoma) and 7 (21%) had large cell PCBCL (3 follicle-center, 3 leg-type, 1 indeterminate). PET/CT detected skin lesions in 3 of 26 patients (12%) with small-cell PCBCL as compared to 6 of 7 patients with large-cell PCBLC (86%), a 7.4-fold detection risk (95% confidence interval, 2.4-22, P = 0.004). The PET-positive subgroup was characterized by larger lesion size (P < 0.001) and a higher Ki-67 proliferation index (P < 0.001). CONCLUSIONS: The sensitivity of PET/CT for detecting cutaneous involvement of lymphomas is low for small-cell PCBCL but high for large-cell types, and thus may facilitate therapeutic strategies.

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS: We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS: The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS: Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2.

Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged ≥65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P<0.0001). The 24-month progression-free survival was 89% with ibrutinib (97% and 89% in patients with del[11q] and unmutated immunoglobulin heavy chain variable region gene, respectively). Progression-free survival rates at 24 months were also similar regardless of age (<75 years [88%], ≥75 years [89%]). Overall response rate was 92% (125/136). Rate of complete response increased substantially from 7% at 12 months to 18% with extended follow up. Greater quality of life improvements occurred with ibrutinib versus chlorambucil in Functional Assessment of Chronic Illness Therapy-Fatigue (P=0.0013). The most frequent grade ≥3 adverse events were neutropenia (12%), anemia (7%), and hypertension (5%). Rate of discontinuations due to adverse events was 12%. Results demonstrated that first-line ibrutinib for elderly patients with chronic lymphocytic leukemia provides sustained response and progression-free survival benefits over chemotherapy, with depth of response improving over time without new toxicity concerns. This trial was registered at clinicaltrials.gov identifier 01722487 and 01724346.

Persistently low lymphocyte counts after FCR therapy for chronic lymphocytic leukemia are associated with longer overall survival.

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis (<4.0 × 103 cells/µL) or better after FCR. Absolute lymphocyte counts were recorded at 3-, 6-, 9-, and 12-month posttreatment and correlated with overall survival (OS) and event-free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC < 1.0 × 103 cells/µL) at 3 m after FCR (69% of patients n = 68), was associated with a longer OS (5y OS 91% vs 64%, P = .001), as were ALC ≤ 2 × 103 cells/µL at 6 m (5y OS 85% vs 48%, P = .004) and ALC ≤ 1.8 × 103 cells/µL at 9 m (5y OS 93% vs 54%, P = .009). A normal-range ALC (≤4 × 103 cells/µL) at 12 m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27 months for ALC > 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P < .0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted Treg depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored.

Outcomes of second-line treatment after fludarabine cyclophosphamide and rituximab in patients with chronic lymphocytic leukemia outside clinical trials.

OBJECTIVE: To evaluate disease characteristics and long-term outcomes in patients requiring second-line treatment following fludarabine, cyclophosphamide, and rituximab (FCR), for relapsed/refractory disease (R/R), or following discontinuation due to toxicities. METHOD: A retrospective analysis of 126 chronic lymphocytic leukemia patients treated with frontline FCR: 63 received second-line treatment (41 relapsed, nine refractory [SD/PD], 13 prior toxicity). Time to next treatment (TTNT) was calculated from beginning FCR to initiation of second-line therapy. Overall and event-free survival was calculated from initiation of salvage treatment (OS2/EFS2). RESULTS: Median follow-up for the entire cohort was 67 and 37 months from second-line therapy. TTNT < 24 months was associated with shorter OS2 and EFS2 similar to those observed with primary refractory disease (OS2 19 and 23 months; EFS2 12 and 9 months for TTNT < 24 months and SD/PD, respectively). TTNT ≥ 24 months (71% chemotherapy-based second-line), had longer OS2 and EFS2 (48 and 20 months). Among the 13 patients receiving second-line therapy after discontinuing FCR due to toxicity EFS2 was 41 months (59 months from initiation of FCR). CONCLUSION: With limitations of sample size and treatment heterogeneity, patients progressing <24 months following FCR have poor outcomes, similar to refractory patients, while longer remissions are indicative of a chemoimmunotherapy sensitive disease. Patients who discontinue FCR for toxicities may achieve excellent outcomes with subsequent treatment.

Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies.

Chemoimmunotherapy (CIT) and targeted therapy with single-agent ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with ibrutinib. Grade ≥ 3 neutropenia was 12% for ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings.

Modification of initial therapy in early and advanced Hodgkin lymphoma, based on interim PET/CT is beneficial: a prospective multicentre trial of 355 patients.

This multicentre study evaluated 5-year progression-free (PFS) and overall survival (OS) in early and advanced Hodgkin lymphoma (HL), where therapy was individualized based on initial prognostic factors and positron emission tomography-computed tomography performed after two cycles (PET-2). Between September 2006 and August 2013, 359 patients aged 18-60 years, were recruited in nine Israeli centres. Early-HL patients initially received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ×2. Depending on initial unfavourable prognostic features, PET-2-positive patients received additional ABVD followed by involved-site radiotherapy (ISRT). Patients with negative PET-2 and favourable disease received ISRT or ABVD ×2; those with unfavourable disease received ABVD ×2 with ISRT or, alternatively, ABVD ×4. Advanced-HL patients initially received ABVD ×2 or escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; EB) ×2 based on their international prognostic score (≤2 or ≥3). PET-2-negative patients further received ABVD ×4; PET-2-positive patients received EB ×4 and ISRT to residual masses. With a median follow-up of 55 (13-119) months, 5-year PFS was 91% and 69% for PET-2-negative and positive early-HL, respectively; 5-year OS was 100% and 95%, respectively. For advanced-HL, the PFS was 81% and 68%, respectively (P = 0·08); 5-year OS was 98% and 91%, respectively. PET-2 positivity is associated with inferior prognosis in early-HL, even with additional ABVD and ISRT. Advanced-HL patients benefit from therapy escalation following positive PET-2. EB can be safely de-escalated to ABVD in PET-2-negative patients.

18F-FDG-PET/CT Pulmonary Infiltrates in Non-Hodgkin Lymphoma Patients Treated with Combined Immunochemotherapy: Incidence and Clinical Characteristics.

BACKGROUND: Pulmonary infiltrates (PIs) detected in patients with non-Hodgkin lymphoma (NHL) may present a diagnostic challenge due to their wide differential diagnosis, including infection, pulmonary lymphoma and immunochemotherapy-associated pulmonary toxicity. OBJECTIVES: To characterize therapy-associated PIs by positron emission tomography/computed tomography (PET/CT) imaging. METHODS: We conducted a historical analysis of fluorodeoxyglucose-PET/CT (18F-FDG-PET/CT) PIs in NHL patients treated with combined immunochemotherapy including rituximab. Incidence of PIs, radiological features, patients' characteristics, underlying NHL type, rituximab/chemotherapy dosing schedules, and symptoms were recorded. Therapy-associated PIs were defined as new or worsening PIs appearing after treatment onset, without evidence of active pulmonary lymphoma or infection. RESULTS: Among 80 patients who met the pre-specified criteria, therapy-associated PIs were identified in 17 (21%), 6 of whom had accompanying symptoms. Increased FDG uptake was observed in nine, and PI resolution in six. The incidence of PIs was higher in females and in patients with aggressive lymphoma, at advanced stages, and in those who had received treatment consisting of a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 14 days (R-CHOP-14). CONCLUSIONS: This characterization of therapy-associated PIs may support the clinician managing NHL patients. Further prospective studies are needed to establish the role of each therapeutic component and the natural history of this phenomenon.