Complete Remission of a Diffuse Large B-Cell Lymphoma in a Young Patient, with Severe Tuberous Sclerosis, Treated with Metronomic Chemotherapy and Ibrutinib: A Case Report.

Tuberous sclerosis (TS) is a rare autosomal dominant genetic multisystem disease caused by mutations in either the TSC1 or TSC2 gene and results in the growth of non-cancerous masses in several organs. Diffuse large B-cell lymphoma (DLBCL) is the predominant non-Hodgkin lymphoma in adolescents and young adults. Metronomic chemotherapy (mCHEMO) can be defined as the frequent, regular administration of drug doses able to maintain a low, but active, range of concentrations of chemotherapeutic drugs during prolonged periods of time. We present the case of a young woman with severe TS who developed DLBCL. She was treated consecutively with the mCHEMO schedule R-DEVEC (prednisone, vinorelbine, etoposide, cyclophosphamide, plus rituximab) and then ibrutinib, achieving an impressive long-lasting complete remission. In conclusion, alternative treatments could be necessary when comorbidities are present in patients, and mCHEMO can be a potential successful therapeutic approach in frail subjects.

Advances and perspectives of dendritic cell-based active immunotherapies in follicular lymphoma.

Follicular lymphoma (FL) is a remarkably immune-responsive malignancy, which is still considered incurable. As, standard immunochemotherapy is complex, toxic and not curative, improvement in FL care is now a crucial topic in hemato-oncology. Recently, we and others have shown that dendritic cell (DC)-based therapies allow a specific immune response associated with sustained lymphoma regression in a proportion of low-tumor burden FL patients. Importantly, the rate of objective clinical response (33-50%) and of sustained remission is remarkably higher compared to similar studies in solid tumors, corroborating the assumption of the immune responsiveness of FL. Our experimental intra-tumoral strategy combined injection with rituximab and interferon-α-derived dendritic cells (IFN-DC), a novel DC population particularly efficient in biasing T-helper response toward the Th1 type and in the cross-priming of CD8 + T cells. Noteworthy, intra-tumoral injection of DC is a new therapeutic option based on the assumption that following the induction of cancer-cell immunogenic death, unloaded DC would phagocytize in vivo the tumor associated antigens and give rise to a specific immune response. This approach allows the design of easy and inexpensive schedules. On the other hand, advanced and straightforward methods to produce clinical-grade antigenic formulations are currently under development. Both unloaded DC strategies and DC-vaccines are suited for combination with radiotherapy, immune checkpoint inhibitors, immunomodulators and metronomic chemotherapy. In fact, studies in animal models have already shown impressive results, while early-phase combination trials are ongoing. Here, we summarize the recent advances and the future perspectives of DC-based therapies in the treatment of FL patients.

Improving the international prognostic index score using peripheral blood counts: Results of a large multicenter study involving 520 patients with diffuse large B cell lymphoma.

The main purpose of this study was to assess whether it is possible to improve the prognostic impact of international prognostic index (IPI) score by combining it with peripheral blood counts. Thus, we evaluated the prognostic power of lymphocyte, neutrophil, and monocyte counts in 520 patients with diffuse large B cell lymphoma treated with R-CHOP, confirming that these parameters have a strong impact on overall survival (OS). Using revised IPI (R-IPI), 44% of patients were categorized as poor-risk and showed an OS at 5 years of 46%. As OS at 5 years of the 520 patients is 67%, it is clearly evident that R-IPI tends to overestimate the proportion of patients with poor prognosis. Accordingly, in an attempt to improve the discriminating power of R-IPI, we evaluated and compared three different scores by combining the neutrophil lymphocyte ratio (NLR) and absolute monocyte count (AMC) with the following values: (a) IPI score 3-5, (b) age > 60 years and performance status, (c) age ≥ 65 years and LDH > ULN. The three indexes studied, had a similar 5 years OS for the high-risk group (46%-52%), but the proportion of patients classified as poor-risk were 37%, 20%, and 32%, respectively, which are lower than 44% identified with R-IPI. Thus, while R-IPI overestimates the number of high-risk patients, after applying our models, it is possible to recognize patients who are truly at high-risk. Of the three scores, the most accurate appears to be that based on NLR, AMC, LDH > ULN and age ≥ 65 years, which identifies 32% of high-risk patients, correlating well with what is seen in clinical practice.

Preliminary results of a counselling programme for fertility preservation in female cancer patients: The experience of the GEMME DORMIENTI network.

OBJECTIVE: To describe a population of patients referred for fertility preservation (FP), how to efficiently provide FP care, and how FP care changed over time. METHODS: This longitudinal observational study enrolled 281 female cancer patients referred between 2013 and 2016 to the non-profit organisation Gemme Dormienti ONLUS (GD) for FP care. All patients underwent the same battery of instrumental and laboratory diagnostic tests. GnRHa therapy was started at least seven days before CTh treatment. RESULTS: From 2013 to 2016, we observed a progressive increase in the number of patients referred for FP care. Out of 251 eligible patients, 135 patients were treated with GnRHa only, and 72 patients underwent GnRHa therapy and cryopreservation. The median time from GD referral to oocyte and ovarian tissue cryopreservation was 11 and 5 days respectively. Tissue cryopreservation requests increased during our study period (from four cases in 2013 to 17 cases in 2016). During follow-up, 17ß-estradiol and FSH levels were significantly increased (p < .0001), and AMH levels were significantly decreased (p < .0001). CONCLUSION: The rapid increase in the number of patients who requested FP care and in the complexity of FP procedures overtime reflects the need to improve quality of life for cancer patients.

Lenalidomide in Pretreated Patients with Diffuse Large B-Cell Lymphoma: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma subtype, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis with currently available treatments. Lenalidomide is available in Italy for patients with rrDLBCL based on a local disposition of the Italian Drug Agency. SUBJECTS, MATERIALS, AND METHODS: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use for rrDLBCL in real practice. RESULTS: One hundred fifty-three patients received lenalidomide for 21/28 days with a median of four cycles. At the end of therapy, there were 36 complete responses (23.5%) and 9 partial responses with an overall response rate (ORR) of 29.4%. In the elderly (>65 years) subset, the ORR was 33.6%. With a median follow-up of 36 months, median overall survival was reached at 12 months and median disease-free survival was not reached at 62 months. At the latest available follow-up, 29 patients are still in response out of therapy. Median progression-free survivals differ significantly according to age (2.5 months vs. 9.5 in the younger vs. elderly group, respectively) and to disease status at the latest previous therapy (15 months for relapsed patients vs. 3.5 for refractory subjects). Toxicities were manageable, even if 30 of them led to an early drug discontinuation. CONCLUSION: Lenalidomide therapy for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients. IMPLICATIONS FOR PRACTICE: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis, reflected by the remarkably short life expectancy of 12 months with currently available treatments. The rrDLBCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients.

Lenalidomide improves the therapeutic effect of an interferon-α-dendritic cell-based lymphoma vaccine.

The perspective of combining cancer vaccines with immunomodulatory drugs is currently regarded as a highly promising approach for boosting tumor-specific T cell immunity and eradicating residual malignant cells. The efficacy of dendritic cell (DC) vaccination in combination with lenalidomide, an anticancer drug effective in several hematologic malignancies, was investigated in a follicular lymphoma (FL) model. First, we evaluated the in vitro activity of lenalidomide in modulating the immune responses of lymphocytes co-cultured with a new DC subset differentiated with IFN-α (IFN-DC) and loaded with apoptotic lymphoma cells. We next evaluated the efficacy of lenalidomide and IFN-DC-based vaccination, either alone or in combination, in hu-PBL-NOD/SCID mice bearing established human lymphoma. We found that lenalidomide reduced Treg frequency and IL-10 production in vitro, improved the formation of immune synapses of CD8 + lymphocytes with lymphoma cells and enhanced anti-lymphoma cytotoxicity. Treatment of lymphoma-bearing mice with either IFN-DC vaccination or lenalidomide led to a significant decrease in tumor growth and lymphoma cell spread. Lenalidomide treatment was shown to substantially inhibit tumor-induced neo-angiogenesis rather than to exert a direct cytotoxic effect on lymphoma cells. Notably, the combined treatment with the vaccine plus lenalidomide was more effective than either single treatment, resulting in the significant regression of established tumors and delayed tumor regrowth upon treatment discontinuation. In conclusion, our data demonstrate that IFN-DC-based vaccination plus lenalidomide exert an additive therapeutic effect in xenochimeric mice bearing established lymphoma. These results may pave the way to evaluate this combination in the clinical ground.

Lenalidomide in Pretreated Mantle Cell Lymphoma Patients: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice (the Lenamant Study).

BACKGROUND: Mantle cell lymphoma (MCL) has the worst prognosis of B-cell subtypes owing to its aggressive clinical disease course and incurability with standard chemo-immunotherapy. Options for relapsed MCL are limited, although several single agents have been studied. Lenalidomide is available in Italy for patients with MCL based on a local disposition of the Italian Drug Agency. SUBJECTS, MATERIALS, AND METHODS: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use in real practice. RESULTS: Seventy patients received lenalidomide for 21/28 days with a median of eight cycles. At the end of therapy, there were 22 complete responses (31.4%), 11 partial responses, 6 stable diseases, and 31 progressions, with an overall response rate of 47.1%. Eighteen patients (22.9%) received lenalidomide in combination with either dexamethasone (n = 13) or rituximab (n = 5). Median overall survival (OS) was reached at 33 months and median disease-free survival (DFS) at 20 months: 14/22 patients are in continuous complete response with a median of 26 months. Patients who received lenalidomide alone were compared with patients who received lenalidomide in combination: OS and DFS did not differ. Progression-free survivals are significantly different: at 56 months, 36% in the combination group versus 13% in patients who received lenalidomide alone. Toxicities were manageable, even if 17 of them led to an early drug discontinuation. CONCLUSION: Lenalidomide therapy for relapsed MCL patients is effective and tolerable even in a real-life context. IMPLICATION FOR PRACTICE: Several factors influence treatment choice in relapsed/refractory mantle cell lymphoma (rrMCL), and the therapeutic scenario is continuously evolving. In fact, rrMCL became the first lymphoma for which four novel agents have been approved: temsirolimus, lenalidomide, ibrutinib, and bortezomib. The rrMCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for rrMCL patients is effective and tolerable even in a real-life context.

TCD4pos lymphocytosis in rheumatoid and psoriatic arthritis patients following TNFα blocking agents.

BACKGROUND: Lymphocyte expansion and true lymphocytosis are commonly observed in the everyday clinical practice. The meaning of such phenomenon is often poorly understood so that discrimination between benign and malignant lymphocytosis remains difficult to establish. This is mainly true when lymphocytosis rises in patients affected by immune-mediated chronic inflammatory diseases under immunosuppressive treatment, conditions potentially associated with lymphomagenesis. In this brief report the development of mild T CD4pos lymphocytosis in a group of patients with chronic arthritis under anti-TNF-α treatment is described. METHODS: Two hundred eight rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients have been evaluated longitudinally for at least 1-year before and 2-years after anti-TNF-α therapy introduction for the possible appearance of a lymphocyte expansion. In patients who developed lymphocyte expansion, T, B and NK cells were analysed. RESULTS: Twenty-five out of 208 (12%) subjects developed a mild T CD4pos lymphocytosis, during anti-TNF-α therapy, which reverted after its interruption. Higher lymphocyte count, more frequent use of steroids and shorter disease duration, before biological therapy start, have emerged as risk factors for lymphocytosis development. CONCLUSIONS: This is the first longitudinal cohort study evaluating the onset of lymphocytosis in RA and PsA patients under anti-TNF-α treatment and its possible clinical relevance. A mild T CD4pos lymphocytosis has been observed in 12% of RA and PsA patients probably related to anti-TNF-α treatment as previously reported by anecdotal cases. Patients with higher baseline lymphocyte count, use of steroids and shorter disease duration before the introduction of biologic therapy, seem to be prone to develop this laboratory reversible abnormality.

Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: results of a large multicenter study involving 990 patients.

Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non-Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR >6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients.

Evaluation of the prognostic role of tumour-associated macrophages in newly diagnosed classical Hodgkin lymphoma and correlation with early FDG-PET assessment.

In Hodgkin Lymphoma (HL), about 20% of patients still have relapsed/refractory disease and late toxic effects rate continue to rise with time. 'Early FDG-PET' and tissue macrophage infiltration (TAM) emerged as powerful prognostic predictors. The primary endpoint was to investigate the prognostic role of both early FDG-PET and TAM; the secondary endpoint was to test if early FDG-PET positivity could correlate with high TAM score. A cohort of 200 HL patients was analysed. Induction treatment plan consisted of two to six courses of ABVD and, if indicated, involved field radiation therapy. All patients repeated CT scan and FDG-PET after two cycles and after the completion of therapy. TAM in diagnostic specimens was determined by immunohistochemistry with a monoclonal antibody (anti-CD68 KP1). Overall, early FDG-PET was negative in 163 patients (81.5%) and positive in 37 patients (18.5%), showing a significant correlation with the achievement of CR (p < 0.0001). After a median follow-up of 40 months, progression free survival (PFS) was significantly better for PET negative patients (p < 0.0001). CD68 expression was low, intermediate or high in 26 (13%), 100 (50%) and 74 (37%) cases, without difference in the distribution between responders and non-responders. PFS analysis showed no significant difference in any score group. TAM score did not show any correlation with early FDG-PET result. This study confirms that early FDG-PET has a high prognostic power, while TAM score does not seem to influence the outcome; in contrast to our original hypothesis, it does not correlate with FDG-PET assessment. Copyright © 2015 John Wiley & Sons, Ltd.

Monocyte count at diagnosis is a prognostic parameter in diffuse large B-cell lymphoma: results from a large multicenter study involving 1191 patients in the pre- and post-rituximab era.

In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naïve patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993-2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm(3) and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count >630 mm(3) (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (>630/mm(3)) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era.

Metronomic chemotherapy in hematology: Lessons from preclinical and clinical studies to build a solid rationale for future schedules.

Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments.

A new digital droplet PCR method for looking at epigenetics in diffuse large B-cell lymphomas: The role of BMI1, EZH2, and USP22 genes.

INTRODUCTION: Epigenetics has been shown to be relevant in oncology: BMI1 overexpression has been reported in leukemias, EZH2 mutations have been found in follicular lymphoma, and USP22 seems to stabilize BMI1 protein. In this study, we measured the expression of BMI1, EZH2, and USP22 in lymph nodes from 56 diffuse large B-cell lymphoma (DLBCL) patients. METHODS: A new multiplex digital droplet PCR (ddPCR) has been set up to measure the expression of 4 genes (BMI1, EZH2, USP22, and GAPDH) in the same reaction on RNA extracted from paraffin-embedded tissues. RESULTS: The specificity of ddPCR was confirmed by a 100% alignment on the BLAST platform and its repeatability demonstrated by duplicates. A strict correlation between expression of BMI1 and EZH2 and BMI1 and USP22 has been found, and high expression of these genes was correlated with extra-nodal lymphomas. Progression-free survival (PFS) and overall survival (OS) were conditioned by IPI, bone marrow infiltration, and the complete response achievement. High levels of BMI1 and USP22 did not condition the response to therapy, but impaired the PFS, especially for patients defined at "high risk" based on the cell of origin (no germinal center [GCB]), high BCL2 expression, and IPI 3-5. In this subgroup, the probability of relapse/progression was twice higher than that of patients carrying low BMI1 and USP22 levels. CONCLUSION: High expression of BMI1 and of USP22 might be a poor prognostic factor in DLBCL, and might represent the target for novel inhibitors.

Efficacy and safety of bendamustine for the treatment of patients with recurring Hodgkin lymphoma.

The management of patients with Hodgkin lymphoma (HL) recurring after stem cell transplantation (SCT) and multiply relapsed disease remains challenging. We report on 41 such patients who received bendamustine hydrochloride, a bifunctional mechlorethamine derivative mechanistically unrelated to traditional alkylators, after a median of four prior chemotherapy lines, including SCT in 85% of cases. Bendamustine was given at doses of 90-120 mg/m(2) every 21 or 28 d. At first assessment (2-4 cycles), the overall response rate (ORR) was 78% with 12 (29%) complete (CR) and 20 (49%) partial responses (PR). Upon treatment prolongation to 6-8 courses, 40% of PRs progressed, yielding a final ORR of 58% with 31% of CRs. Eight patients (two CRs, six PRs) were subsequently allotransplanted. Median progression-free and overall survival exceeded 11 and 21 months respectively; complete responders displayed a median disease-free survival above 9 months with a relapse rate of only 30%. Outcomes were independent of disease chemosensitivity, previous transplant and bendamustine dose-intensity. No life-threatening or unexpected adverse events occurred. Within the limits of a retrospective analysis and schedule heterogeneity, these results appear very encouraging and prompt prospective trials to confirm bendamustine as a valuable option in the palliative setting and in cytoreductive strategies before allotransplantation.

Serum Paraprotein Is Associated with Adverse Prognostic Factors and Outcome, across Different Subtypes of Mature B-Cell Malignancies-A Systematic Review.

The presence of a serum paraprotein (PP) is usually associated with plasma-cell dyscrasias, Waldenstrom Macroglobulinemia/lymphoplasmacytic lymphoma, and cryoglobulinemia. However, PP is also often reported in other high- and low-grade B-cell malignancies. As these reports are sparse and heterogeneous, an overall view on this topic is lacking, Therefore, we carried out a complete literature review to detail the characteristics, and highlight differences and similarities among lymphoma entities associated with PP. In these settings, IgM and IgG are the prevalent PP subtypes, and their serum concentration is often low or even undetectable without immunofixation. The relevance of paraproteinemia and its prevalence, as well as the impact of IgG vs. IgM PP, seems to differ within B-NHL subtypes and CLL. Nonetheless, paraproteinemia is almost always associated with advanced disease, as well as with immunophenotypic, genetic, and clinical features, impacting prognosis. In fact, PP is reported as an independent prognostic marker of poor outcome. All the above call for implementing clinical practice, with the assessment of paraproteinemia, in patients' work-up. Indeed, more studies are needed to shed light on the biological mechanism causing more aggressive disease. Furthermore, the significance of paraproteinemia, in the era of targeted therapies, should be assessed in prospective trials.

Correction: Bocci et al. Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma. J. Clin. Med. 2022, 11, 7162.

In the original publication [...].

Effects of ABVD chemotherapy on ovarian function: epidemiology, hormonal dosages and ultrasound morphologic analyses in 270 patients with Hodgkin's disease.

Introduction: Classical Hodgkin Lymphoma (HL) is a lymphoproliferative disease typically diagnosed in the young. The excellent results obtained with current treatment lead to long survival with age-related complications affecting patients' survival and quality of life. One issue affecting HL patients is infertility. This problem can be easily overcome in males with seminal liquid cryopreservation, however, in females it is more complex either in terms of the quality of the cryopreserved material or the patients' age at diagnosis. Moreover, not all chemo- or radio-therapies have the same negative impact on fertility.The main objectives of this study was to collect epidemiological information on HL patients involved in fertility preservation counseling and to analyze the impact of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the standard treatment for HL, on ovarian function, hormonal levels and ovarian and uterine tissue morphologies. Patterns of fertility preservation were also reported. Methods: Data were obtained from 270 female patients at HL onset who were interested in fertility counseling prior to therapy initiation. Each patient was assessed at HL diagnosis for levels of Anti-Mullerian Hormone (AMH), Follicle Stimulating Hormone (FSH), and 17ß-oestradiol (17ß-oe), with additional assessments at 6 and 12 months after chemotherapy. Patients were evaluated with ultrasound scans to study the number of ovarian follicles and the degree of uterine thickness at the same timepoints. Results: The average patient AMH level showed a statistically significant reduction at 6 months after chemotherapy (p=0.05) and by the 12 month time point returned to near pre-chemotherapy values. FSH and 17ß-oe levels did not significantly vary throughout the study period. ABVD chemotherapy was associated with a significant reduction of both ovarian follicles and endometrial thickness at the 6 month time point followed by a recovery at the 12 time point in both ovaries. Different results were observed when patients changed treatment to a more intensive one. Discussion: Based on the results from the hormonal measurements and the follicle echography, it appears that the toxic effect of ABVD on fertility is transient, whereas, in contrast, more intensive therapies may potentially be more harmful and long-lasting.

Metronomic chemotherapy regimens and targeted therapies in non-Hodgkin lymphoma: The best of two worlds.

Novel drugs are rapidly moving forward the treatment-paradigm of non-Hodgkin-lymphomas (NHLs). Notwithstanding, especially in aggressive subtypes, chemotherapy remains the pillar of treatment. Indeed, the combination of highly effective Maximum-Tolerated-Dose Chemotherapy (MTD-CHEMO) + "novel drugs", has so far, fallen short from expectations, often because it caused excessive toxicity. Metronomic chemotherapy (mCHEMO), which is the frequent, long-term administration of low dose cytotoxic drugs, may allow more effective and tolerable combinations. mCHEMO pharmacodynamics, has been described as pleiotropic. In fact, it may have different cellular and molecular targets, when drugs or their schedules are modified. Although mCHEMO has been little explored in NHLs, pre-clinical studies - in lymphoma models - which addressed the activity of mCHEMO in combination with novel drugs, have shown very promising results. These included inhibitors of histone deacetylase, mTOR and PI3K/mTOR, as well as the immune checkpoint inhibitor anti-PD-L1. Moreover, a few impressive reports have recently shown all-oral mCHEMO schedules, with or without rituximab, can effectively shrink both B and T-cell aggressive NHLs. Indeed, these regimens allowed elderly-frail patients to achieve sustained remission, while toxicity proved manageable. In our opinion, all-oral mCHEMO, is an active, easy-to start, well-tolerated, and inexpensive therapeutic approach, which deserves further investigation. Most importantly, mCHEMO, holds promise to empower the activity of novel targeted therapies, without causing excessive toxicity.