Most patients with Diffuse Large B-cell Lymphoma (DLBCL) are old (>65 years of age) and this population is expected to increase in the following years. A simplified geriatric assessment based on a ...careful evaluation of the fitness status and comorbidities is essential to choose the correct intensity of treatment. Fit older patients can benefit from a standard immunochemotherapy, while unfit/frail patients frequently need reduced doses or substitution of particular agents with less toxic ones. This review focuses on new therapies (e.g., polatuzumab vedotin, tafasitamab, bispecific antibodies) that have indicated promising results in relapsed/refractory patients, particularly in cases not eligible to transplant. Some of these new drugs have been tested as single agents or in combinations as first-line treatment, aiming to improve the outcome of the traditional chemotherapy. If preliminary efficacy and safety data are confirmed in future clinical trials, a chemo-free immunotherapic approach could become an alternative option to offer a curative treatment even in frail patients.
Background
International guidelines suggest hepatitis C virus (HCV) eradication by direct‐acting antivirals (DAAs) after first‐line immunochemotherapy (I‐CT) in patients with HCV‐positive diffuse ...large B‐cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I‐CT have been reported.
Subjects, Materials, and Methods
We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV‐positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort ConC: n = 9) or subsequently (sequential cohort SeqC: n = 38) to first‐line I‐CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone R‐CHOP‐like).
Results
Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I‐CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir‐based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1–2 adverse events. Twenty‐three patients experienced hepatic toxicity (grade 3–4 in seven) following I‐CT in SeqC, compared to only one patient in ConC. At a median follow‐up of 2.8 years, two patients died (2‐year overall survival, 97.4%) and three progressed (2‐year progression‐free survival, 93.1%).
Conclusion
Excellent outcome of this cohort of HCV‐positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I‐CT. Moreover, concurrent DAAs and R‐CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity.
Implications for Practice
Hepatitis C virus (HCV)‐associated diffuse large B‐cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune‐chemotherapy (I‐CT) and long‐term hepatic complications. The advent of highly effective and toxicity‐free direct‐acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first‐line immunochemotherapy (usually R‐CHOP). This retrospective international study reports the real‐life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I‐CT) in 47 patients. The favorable reported results on long‐term outcome seem to support the eradication of HCV with DAAs in all patients with HCV‐positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I‐CT.
Epidemiological studies have established that hepatitis C virus (HCV) is associated with diffuse large B‐cell lymphoma (DLBCL). This article reports on patients with HCV‐positive DLBCL treated with direct‐acting antivirals either concurrently or subsequently to a curative‐intent first‐line immunochemotherapy.
Octogenarian patients with diffuse large B-cell lymphoma are managed mainly with palliation, but recent improvement in their overall condition makes potentially curative treatment a possibility. ...Studies have shown that half of selected octogenarians may be cured using reduced-dose anthracycline chemoimmunotherapy. However, patients aged >85 (late octogenarians LO) were underrepresented, and selection criteria were poorly defined. We analyzed the clinical characteristics and outcomes of LO enrolled in the FIL Elderly Project in terms of the treatment received (palliative vs. curative) and of their simplified geriatric assessment (sGA), then compared them with early octogenarians (EO) aged 80- 84 and with those aged 65-79 classified as UNFIT or FRAIL according to sGA enrolled in the same study. Of the 1,163 patients, 370 were >80 and 129 LO. Clinical characteristics were similar between LO and EO, but LO more frequently received palliation (50% vs. 23%; P=0.001) and had worse 2-year overall survival (OS) (48% vs. 63%; P=0.001) and 2-year progression-free survival (PFS) (43% vs. 56%; P=0.01). Patients receiving anthracycline did better than patients receiving palliation (P<0.001), without any difference between full or reduced doses. Rituximab within palliation improved outcome (2-yr OS with or without rituximab 42% vs. 22%; P=0.008). Elderly Prognostic Index (EPI) performed better than sGA in identifying different risk categories, and high-risk EPI retained an independent unfavorable effect on OS and PFS, together with treatment without anthracycline. In conclusion, late octogenarians can benefit from a curative approach with reduced-dose anthracycline and from rituximab within palliation. EPI may help in patient selection more than sGA can.
Background
Elderly classical Hodgkin lymphoma (cHL) (ecHL) is a rare disease with dismal prognosis and no standard treatment. Fitness‐based approaches may help design appropriate treatments. ...Sarcopenia has been associated with an increased risk of treatment‐related toxicities and worse survival in various solid tumours, but its impact in ecHL is unknown. The aim of this retrospective multicentre study was to investigate the prognostic role of sarcopenia in ecHL.
Methods
We included newly diagnosed >64 years old cHL patients who performed a baseline comprehensive geriatric assessment and high‐dose computed tomography (CT) or 18fluorine‐fluorodeoxyglucose positron emission tomography/CT before any treatment. Sarcopenia was measured as skeletal muscle index (SMI, cm2/m2) by the analysis of high‐dose CT or low‐dose positron emission tomography/CT images at the L3 level. The specific cut‐offs for the SMI were determined by receiver operator curve analysis and compared with those proposed in literature and studied in diffuse large B‐cell lymphoma. Survival functions progression‐free survival PFS and overall survival (OS) were calculated for the whole population and for different subgroups defined as per different sarcopenia cut‐off levels.
Results
We included 154 patients (median age 71 years old, 76 female). The median L3‐SMI was 42 cm2/m2. The specific cut‐off derived in our male population was 45 cm2/m2; using this cut‐off, 27 male patients (35%) were defined as sarcopenic. After a median follow‐up of 5.9 years, the overall 5‐year PFS and OS rates were 53% and 65%, respectively, and were significantly shorter in sarcopenic male patients compared with non‐sarcopenic (PFS 31% vs. 61%, P = 0.008; OS 51% vs. 74%, P = 0.042). Applying diffuse large B‐cell lymphoma‐derived sarcopenic thresholds, there were no significant differences between sarcopenic and non‐sarcopenic patients for both PFS and OS, with a sole exception of a significant reduced PFS in sarcopenic male patients using Namakura cut‐off. The comprehensive geriatric assessment‐determined frail functional status was an independent adverse prognostic factor for both female and male patients.
Conclusions
Baseline evaluation of sarcopenia through radiological examinations performed for ecHL staging may help define a proportion of male patients with unfavourable outcome with current treatment strategies. Also the functional status evaluation could allow to identify a frail subgroup of patients with worse outcome.
Recent studies have demonstrated feasibility and substantial benefit of direct-acting antivirals (DAAs) administration during or after first-line immune-chemotherapy (I-CT) in patients with hepatitis ...C virus (HCV)-positive diffuse large B-cell lymphomas (DLBCL). However, data on DAAs used during or after salvage treatments are still lacking. In this study we assessed clinical and virological outcome in 11 patients with relapsed (n = 7) or refractory (n = 4) HCV-positive DLBCL. DAAs were given either concurrently (n = 3) or subsequent (n = 8) to salvage I-CT. Most patients (10 of 11) received sofosbuvir-based regimens. All patients completed their planned courses of DAAs and achieved sustained virological response. DAAs were well tolerated, with no grade ≥2 adverse events. At a median follow-up of 3.6 years four patients died (4-year OS: 76%). In conclusion, we provide evidence that DAAs in HCV-positive relapsed/refractory DLBCL are extremely safe and effective, suggesting that they should be used if HCV eradication was not instituted before.
Background
T cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several ...limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells.
Case presentation
We report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkin-like phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T
+
cells showed a persistent CD8
+
senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8
+
T cells compartment.
Conclusions
PBZ is not able to reinvigorate exhausted CAR
+
T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR
+
T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8
+
T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity.
Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for ...relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. Since the evidence in the literature on its use in normal clinical practice is scarce, a retrospective multicenter study was conducted to evaluate effectiveness and tolerability in a real-life context. Seventy-two patients with a median age at diagnosis of 57.2 years-mostly with an advanced stage (88.9%) and relapsed to the most recent therapy (79.1%)-were enrolled. The median number of prior therapies was three (20.8% refractory to the last therapy before idelalisib). With a median number of 4 months of treatment, the overall response rate was 41.7% (20.8% complete responses). Median disease-free survival and overall survival were achieved at 8.4 months and at 4 years, respectively. Forty-four percent of patients experienced at least one drug-related toxicity: 6.9% hematological ones and 43% non-hematological. The study confirmed that idelalisib has anticancer effectiveness and an acceptable safety profile in relapsed/refractory FL with unfavorable prognostic characteristics, even in the context of normal clinical practice.
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