Domenico Ribatti
Roberto Tamma
Giuseppe Ingravallo
Giorgina Specchia- 1Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy
- 2Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Medical School, Bari, Italy
Targeting tumor angiogenesis is an advancement in the treatment of hematological malignancies. This article summarizes the most recent advancements in the use of anti-angiogenic agents in the treatment of human lymphomas. Preclinical and clinical studies have evidenced that treating lymphomas with anti-angiogenic monotherapy may not be successful. Alternative therapeutic strategies may be used to overcome resistance to anti-angiogenic therapy, including the association of different anti-angiogenic molecules or their combination with other treatment regimens.
Introduction
Anti-angiogenesis was proposed as a cancer therapy in 1971, when J. Folkman published a hypothesis that tumor growth is angiogenesis-dependent (1). Anti-angiogenic agents include anti- vascular endothelial growth factor (VEGF) molecules agents, including bevacizumab, VEGF-Trap, and VEGF-antisense; receptor tyrosine kinase inhibitors (TKIs);immunomodulatory drugs (iMiDs), including thalidomide, lenalidomide, and pamalidomide; other new compounds targeting signaling checkpoints downstream of pro-angiogenic growth factors, including mammalian target of rapamycin (mTOR) inhibitors, histone deacetylases (HDAC) inhibitors, and proteasome inhibitors, such as bortezomib and carfilzomib.
It is important to note that among these agents, iMiDs and proteasome inhibitors are primarily known for other mechanisms of action. In detail, iMiDs work by either enhancing or suppressing the immune system, with specific mechanisms varying by drug type. They can degrade target proteins within tumor cells and activate immune cells like T cell and NK cells, leading to tumor cell death and a stronger immune response. Other immunomodulators, such as checkpoint inhibitors, block proteins that suppress immune responses, while others, like colony-stimulating factors, stimulate the production of immune cells. Proteasome inhibitors block the 20S proteasome, a complex that degrades damaged or unneeded proteins, causing an accumulation of misfolded proteins within the cell, leading to cellular stress, ER stress, and the eventual activation of apoptotic pathways. In this context the anti-angiogenic activity of these molecules may be considered expression of a secondary mechanism of action.
This article summarizes the most recent advancements concerning anti-angiogenic agents in the treatment of human lymphomas.
Non-Hodgkin lymphomas
Monotherapy trials
Bevacizumab has shown modest clinical activity in lymphoma patients as a single agent in the setting of relapsed aggressive non-Hodgkin lymphoma (NHL) when administered at 10 mg/kg every 2 weeks in a Southwest Oncology group (SWOG) phase II trial (2, 3).
As concerns sorafenib, in phase II study, 30 patients with relapsed lymphoma received sorafenib 400 mg twice daily for a median of 4 months (4). Despite a disappointing 13% overall response rate (ORR), sorafenib was well tolerated and produced some degree of clinical activity. The low efficacy of sorafenib as a single agent was also reported in phase II study with 14 relapsed diffuse large B cell lymphoma (DLBCL) patients who failed or were not candidates for autologous stem cell transplant, as shown by only 1 patient had complete response (CR) and 13 patients died (5). Brander et al. (6) conducted a phase II open-label study to assess the efficacy and safety of vatalanib in relapsed or refractory DLBCL patients who received it at a target dose of 1250 mg once daily. Imatinib, a impairs lymphoma growth in both human xenograft and murine allograft models by inhibiting tumor-associated angiogenesis (7).
Single-agent thalidomide demonstrated a limited and modest overall response rate of 12.5% when given to patients with relapsed/refractory indolent NHL (8). One patient with gastric mucosa-associated lymphoid tissue (MALT) lymphoma achieved complete response 2 months after initiation of thalidomide, which was accompanied with significantly decreased serum levels of VEGF-A and fibroblast growth factor-2 (FGF-2) (9).
Single agent IMiD lenalidomide has been studied in a phase II trial setting in relapsed/refractory indolent and aggressive NHL, with a 34% ORR rate in aggressive NHL and a 26% ORR rate in in indolent NHL (10–12). Three phase II studies (13–15) reported that single-agent lenalidomide was active and safe in both indolent and aggressive B-NHL. In DLBCL, lenalidomide exhibited preferential activities in non-germinal center B-cell-like (non-GCB) subtype than in GCB subtype (16). A phase II study demonstrated a better response of lenalidomide in patients with relapsed or refractory mantle cell lymphoma (MCL) when compared to control therapies such as rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine (17). Treatment with the immunomodulatory lenalidomide, depleted VEGF-C expressing tumor associated macrophages (TAMs) resulted in impaired lymphangiogenesis in MCL (18).
Two fully humanized IgG4-kappa immune checkpoint inhibitors blocking monoclonal antibodies targeting the PD-1 receptor on human T cells, nivolumab and pembrolizumab and three anti-PD-L1 antibodies (durvalumab, atezolizumab, and avelumab) have been approved for the treatment of B cell lymphomas (19, 20). Follicular lymphoma (FL) and DLBCL presented the highest objective response to therapy with nivolumab, while MCL lacked a response to treatment (21). In DLBCL treatment with nivolumab, a phase I study demonstrated an ORR of 36% (21), and a phase II study with the same treatment an objective RR of 3% (22).
Combination therapy trials
Bevacizumab has been combined with rituximab- CHOP (R-CHOP) in upfront treatment (23). The combination of bevacizumab and standard-dose R-CHOP (RA-CHOP) did not improve the survival time of untreated DLBCL and MCL patients (24, 25). Moreover, the addition of bevacizumab to R-CHOP in a phase II DLBCL trial increased cardiac events without significantly improving efficacy (26).
A significantly improved progression free survival (PFS) was observed in patients who received rituximab plus bevacizumab compared to those who received rituximab alone in relapsed FL (27). Overall survival (OS) was also prolonged numerically but did not reach statistical significance. Both regimens were well tolerated even though the addition of bevacizumab did increase side effects (27).
Thalidomide has indicated therapeutic potential in patients with relapsed MCL, either as a single agent (28) or combined with chemotherapy (29). Thalidomide enhances the efficacy of CHOP in treating patients with DLBCL. Compared to patients treated by CHOP alone, although there was no significant OS difference between the two groups, the median PFS in T-CHOP group was significantly prolonged (30).
The generalized effect of lenalidomide plus rituximab was highly active, achieving a 92% ORR and a 64% CR in untreated MCL patients (31) and a 57% ORR and a 36% CR in relapsed or refractory MCL patients (32).
A combination of rituximab, thalidomide, and metronomic oral chemotherapy with prednisone, etoposide, procarbazine, and cyclophosphamide have been used as anti-angiogenic therapy in relapsed/refractory MCL (33). Another metronomic lymphoma therapy is the Prednisone, etoposide, procarbazine, and cyclophosphamide (PEPC) (C3) regimen (34). This regimen is well tolerated and is associated with significant clinical activity in the recurrent NHL including MCL (35, 36).
Durvalumab administration in combination with rituximab and bendamustine was associated with an ORR of 88.9% in FL, and of 30% in DLBCL (37). Combination therapy with durvalumab and ibrutinib, a Bruton’s tyrosine kinase (BKT) inhibitor, was associated with an ORR in MCL (37). Atezolizumab in combination with R-CHOP in patients with previously untreated DLBCL improves complete remission rates compared with controls (38). Otherwise, a favorable clinical activity has been reported when a PD-1 inhibitor was administrated with an anti-CD20 monoclonal antibodies in RR B-cell lymphomas (39). Dual checkpoint blockades with anti-PD-1 and CTLA-4 monoclonal antibodies, with or without STAT3 inhibitors, did not show clinical activity in DLBCL and FL (40).
Hodgkin lymphomas
Monotherapy trials
Pembrolizumab, that blocks the PD-1/PD-L1 and PD-2/PDL2 pathway, showed positive survival outcomes in patients with RR cHL (41). Tislelizumab, a humanized anti PD-1 monoclonal antibody, demonstrated a favorable safety profile for patients with RR cHL (42).
Combination therapy trials
Sorafenib and perifosine (an oral Akt inhibitor) combination therapy demonstrated antitumor activities in HL patients (43). The efficacy and safety of nivolumab have been investigated in RR classic HL (cHL), demonstrating an ORR of 87% and a progression-free survival of 86% in 24 weeks (44).
The combination of the immune checkpoint inhibitor nivolumab with doxorubicin, vinblastine, and dacarbazine (AVD) was evaluated in patients with stage III and IV cHL, showing an objective RR of 84% with complete remission in 67% of patients (45). Nivolumab-AVD versus brentuximab-AVD was studied in advanced stage cHL, demonstrating an increase in PFS with nivolumab-AVD group compared to the brentuximab-AVD group (46). Pembrolizumab and brentuximab have been compared vedotin in patients with RR cHL, demonstrating that the two-year PFS and safety outcomes favored the use of pembrolizumab (47). It is important to note that the primary mechanism of action of both nivolumab and pembrolizumab is not anti-angiogenesis, but their effectiveness is due to a separate, through potentially synergistic, immune-mediated process.
Comparative efficacy, toxicity and mechanisms of resistance
Anti-angiogenic therapy with bevacizumab has modest activity in DLBCL. The combination of bevacizumab and R-CHOP has been investigated in both DLBCL and MCL. iMiDs, either as single agent or in combination with fludarabine or rituximab, have clinical activity against a wide variety of NHL including DLBCL, CLL and MCL. Metronomic low-dose chemotherapy has clinical applicability in in relapsed and refractory settings. Biological agents, targeting RTKs, are in various stages of clinical development and investigation in human lymphoma patients.
As concerns resistance mechanisms, when VEGF-targeted therapies are discontinued, the tumor vasculature is rapidly re-established (48). Resistance to anti-angiogenic therapies can be intrinsic, when it is observed at the beginning of the treatment due to inefficacy of treatment or acquired, i.e., that it affects the relapsing disease after an initial response to therapy (49). Resistance mechanisms are mediated by hypoxia. VEGF blockade aggravates hypoxia that, in turn, upregulates the production of angiogenic factors or increases tumor invasiveness (49); redundancy of the angiogenic signals, and activation of alternative signaling pathways (50); Upregulation of other pro-angiogenic factors, including FGF-2 and platelet derived growth factor (PDGF) (50).
Side effects of anti-angiogenic agents of lymphoma treatment include hypertension, bleeding, impaired wound healing, and proteinuria (51–53). While not directly a “side effect” of the anti-angiogenic mechanism, these drugs can also increase the risk of neutropenia when combined with traditional chemotherapy, highlighting potential overlapping toxicities. Anti-angiogenic agents share common side effects, including hypertension, proteinuria, impaired wound healing, and bleeding, though the frequency and severity vary between specific drugs. Other common adverse events can include thrombosis fatigue, diarrhea, and hand-foot syndrome. For example, bevacizumab has a higher incidence of bleeding complications, while small-molecule VEGF receptors (VEGFRs) inhibitors are associated with hand-foot syndrome and elevated liver enzymes.
Concluding remarks
Treating human lymphomas with anti-angiogenic monotherapy is not successful. The limitations of may be the effect of drug resistance, metastasis promotion, and reduced delivery of chemotherapeutic agents, because of the decrease in tumor vasculature.
Different anti-angiogenic biomarkers have been introduced, including changes in systemic blood pressure, VEGF polymorphisms, plasma levels of VEGF, tumor microvascular density and imaging parameters. The dose and schedule of anti-angiogenic and cytotoxic therapies when used in combination might not be optimal, and biomarkers could be useful in optimizing the dose and schedule of these agents.
The fact that tumors may grow without angiogenesis, through the alternative mode of vasculature neo-formation, including vascular co-option, intussusceptive microvascular growth, and vasculogenic mimicry (54) makes them less likely to respond to anti-angiogenic drugs. Crivellato et al. (55) demonstrated that in B-cell NHLs at the ultrastructural level, tumor cells are closely intermingled with endothelial cells and that this relationship can be recognized in the early stages of vessel formation, as an expression of vasculogenic mimicry. Moreover, Crivellato et al. (55) showed that both low- and high-grade B-NHLs develop transluminal bridges in larger vessels, causing the parent vessel to split into two or more sections, suggesting that an intussusceptive modality of vascular growth also takes place in B-NHLs.
Other therapeutic strategies may be used to overcome resistance to anti-angiogenic therapy, including the association of multiple anti-angiogenic compounds or a combination of anti-angiogenic drugs with other treatment regimens, such as immunotherapies to enhance antitumor immune responses has proven to be an effective approach. Combining anti-VEGF agents with immunotherapies an established and effective cancer treatment strategy that has improved outcomes for patients with several types of cancer, including non-small cell lung cancer, renal cell carcinoma, and hepatocellular carcinoma. This combination therapy works by not only directly targeting cancer cells but also by decreasing the immunosuppressive effects of VEGF, thereby allowing the immune system to better attack the tumor. Combining anti-VEGF agents with immunotherapies offers several advantages, including normalizing tumor blood vessels to improve immune cell infiltration, enhancing antigen presentation by maturing dendritic cells, and reducing the presence of immunosuppressive cells. This synergy leads to improved clinical outcomes, such as OS and PFS (56, 57).
Author contributions
DR: Writing – original draft, Writing – review & editing. RT: Data curation, Writing – review & editing, Validation. GI: Data curation, Writing – review & editing, Validation. GS: Funding acquisition, Data curation, Validation, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research and/or publication of this article. This work was supported by Associazione “Il Sorriso di Antonio,” Corato, Italy, and Associazione Italiana Contro le Leucemie, Linfomi e Mielomi (AIL), Bari, Italy.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. (1971) 285:1182–6. doi: 10.1056/NEJM197111182852108
2. Stopeck AT, Bellamy W, Unger J, Rimsza L, Iannone M, Fisher RI, et al. Phase II trial of single agent bevacizumab in patients with relapsed aggressive non-Hodgkin’s lymphoma (NHL): southwest oncology group study S0108. J Clin Oncol. (2005) 23:6592. doi: 10.1200/jco.2005.23.16_suppl.6592
3. Stopeck AT, Unger JM, Rimsza LM, Bellamy WT, Iannone M, Persky DO, et al. A phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin lymphoma: Southwest oncology group study S0108. Leuk Lymphoma. (2009) 50:728–35. doi: 10.1080/10428190902856808
4. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Pierdominici M, Barbati C, et al. Phase II study of sorafenib in patients with relapsed or refractory lymphoma. Br J Haematol. (2012) 158:108–19. doi: 10.1111/j.1365-2141.2012.09139.x
5. Greenwald DR, Li H, Luger SM, Go RS, King D, Patel T, et al. A phase II study of sorafenib (BAY 43-9006) in recurrent diffuse large B cell lymphoma: an eastern cooperative oncology group study (E1404). J Hematol Oncol. (2013) 6:46. doi: 10.1186/1756-8722-6-46
6. Brander D, Rizzieri D, Gockerman J, Diehl L, Shea TC, Decastro C, et al. Phase II open label study of the oral vascular endothelial growth factor-receptor inhibitor PTK787/ZK222584 (vatalanib) in adult patients with refractory or relapsed diffuse large B-cell lymphoma. Leuk Lymphoma. (2013) 54:2627–30. doi: 10.3109/10428194.2013.784969
7. Ruan J, Luo M, Wang C, Fan L, Yang SN, Cardenas M, et al. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes. Blood. (2013) 121:5192–202. doi: 10.1182/blood-2013-03-490763
8. Smith SM, Grinblatt D, Johnson JL, Niedzwiecki D, Rizzieri D, Bartlett NL, et al. Thalidomide has limited single-agent activity in relapsed or refractory indolent non-Hodgkin lymphomas: a phase II trial of the cancer and Leukemia group B. Br J Haematol. (2008) 140:313–9. doi: 10.1111/j.1365-2141.2007.06937.x
9. Pro B, Younes A, Albitar M, Dang NH, Samaniego F, Romaguera J, et al. Thalidomide for patients with recurrent lymphoma. Cancer. (2004) 100:1186–9. doi: 10.1002/cncr.20070
10. Wiernik PH, Lossos IS, Tuscano J, Justice G, Vose JM, Pietronigro D, et al. Preliminary results from a phase II study of lenalidomide oral monotherapy in relapsed/refractory aggressive non- Hodgkin lymphoma. J Clin Oncol. (2007) 25:8052. doi: 10.1200/jco.2007.25.18_suppl.8052
11. Witzig TE, Vose J, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis J, et al. Preliminary results from a phase II study of lenalidomide oral monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. J Clin Oncol. (2007) 25:8066. doi: 10.1200/jco.2007.25.18_suppl.8066
12. Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol. (2008) 26:4952–7. doi: 10.1200/JCO.2007.15.3429
13. Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol. (2009) 27:5404–9. doi: 10.1200/JCO.2008.21.1169
14. Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, et al. An international phase II trial of single agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol. (2011) 22:1622–7. doi: 10.1093/annonc/mdq626
15. Wiernik PH. Treatment of hematologic neoplasms with new immunomodulatory drugs (IMiDs). Curr Treat Options Oncol. (2009) 10(1-2):1–15. doi: 10.1007/s11864-008-0077-
16. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. (2011) 117:5058–66. doi: 10.1002/cncr.26135
17. Trneny M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, et al. Lenalidomide versus investigator’s choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. (2016) 17:319–31. doi: 10.1016/S1470-2045(15)00559-8
18. Song K, Herzog BH, Sheng M, Fu J, McDaniel JM, Chen H, et al. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma. Can Res. (2013) 73:7254–64. doi: 10.1158/0008-5472.CAN-13-0750
19. Sokołowski M, Sokołowska A, Mazur G, and Butrym A. Programmed cell death protein receptor and ligands in haematological Malignancies–Current status. Crit Rev Oncol Hematol. (2019) 135:47–58. doi: 10.1016/j.critrevonc.2019.01.003
20. Xu-Monette Z, Zhou J, and Young KH. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. (2018) 131:68–83. doi: 10.1182/blood-2017-07-740993
21. Lesokhin AM, Ansell SM, Armand P, Scott EC, Alwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic Malignancy: Preliminary results of a phase ib study. J Clin Oncol. (2016) 34:2698–704. doi: 10.1200/JCO.2015.65.9789
22. Ansell SM, Minnema MC, Johnson P, Timmermann JM, Armand P, Shipp MA, et al. Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: A single-arm, phase II study. J Clin Oncol. (2019) 37:481–9. doi: 10.1200/JCO.18.00766
23. Ganjoo KN, An CS, Robertson MJ, Gordon LI, Sen JA, Weisenbach J, et al. Rituximab, Bevacizumab and CHOP (RACHOP) in untreated diffuse large B-cell lymphoma: safety, biomarker and pharmacokinetic analysis. Leuk Lymphoma. (2006) 47:998–1005. doi: 10.1080/10428190600563821
24. Ruan J, Gregory SA, Christos P, Martin P, Furman RR, Coleman M, et al. Long-term follow-up of R-CHOP with bevacizumab as initial therapy for mantle cell lymphoma: clinical and correlative results. Clin Lymphoma Myeloma Leuk. (2014) 14:107–13. doi: 10.1016/j.clml.2013.10.002
25. Stopeck AT, Unger JM, Rimsza LM, LeBlanc M, Farnsworth B, Iannone M, et al. A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515. Blood. (2012) 120:1210–7. doi: 10.1182/blood-2012-04-423079
26. Seymour JF, Pfreundschuh M, Trneny M, Sehn LH, Catalano J, Csinady E, et al. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: Final MAIN study outcomes. Haematologica. (2014) 99:1343–9. doi: 10.3324/haematol.2013.100818
27. Hainsworth JD, Greco FA, Raefsky EL, Thompson DS, Lunin S, Reeves J Jr, et al. Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma. Clin Lymphoma Myeloma Leuk. (2014) 14:277–83. doi: 10.1016/j.clml.2014.02.010
28. Damaj G, Lefrere F, Delarue R, Varet B, Furman R, and Hermine O. Thalidomide therapy induces response in relapsed mantle cell lymphoma. Leukemia. (2003) 17:1914–5. doi: 10.1038/sj.leu.2403058
29. Ruan J, Martin P, Coleman M, Furman RR, Cheung K, Faye A, et al. Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma. Cancer. (2010) 116:2655–64. doi: 10.1002/cncr.25055
30. Ji D, Li Q, Cao J, Guo Y, Lv F, Liu X, et al. Thalidomide enhanced the efficacy of CHOP chemotherapy in the treatment of diffuse large B cell lymphoma: A phase II study. Oncotarget. (2016) 7:33331–9. doi: 10.18632/oncotarget.8973
31. Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. (2015) 373:1835–44. doi: 10.1056/NEJMoa1505237
32. Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. (2012) 13:716–23. doi: 10.1016/S1470-2045(12)70200-0
33. Ruan J, Coleman M, Furman RR, Glynn P, Joyce M, Ketas J, et al. Cell lymphoma: clinical efficacy and correlative studies of a phase II trial of RT-PEPC (rituximab, thalidomide and metronomic oral chemotherapy with prednisone, etoposide, procarbazine and cyclophosphamide) in relapsed/refractory disease. Blood. (2006) 108:2751. doi: 10.1182/blood.V108.11.2751.2751
34. Coleman M, Leonard JP, and Lee C. The PEP-C (C3) oral combination chemotherapy regimen for refractory/relapsed lymphoma: daily prednisone, etoposide, procarbazine, and cyclophosphamide. Blood. (1999) 94:94A. doi: 10.1002/cncr.23422
35. Coleman M, Martin P, Ruan J, Furman R, Niesvizky R, Elstrom R, et al. Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP-C) oral combination chemotherapy regimen for recurring/refractory lymphoma: low-dose metronomic, multidrug therapy. Cancer. (2008) 112:2228–32. doi: 10.1002/cncr.23422
36. Coleman M, Martin P, Ruan J, Furman R, Niesvizky R, Elstrom R, et al. Low-dose metronomic, multidrug therapy with the PEP-C oral combination chemotherapy regimen for mantle cell lymphoma. Leuk Lymphoma. (2008) 49:447–50. doi: 10.1080/10428190701837330
37. Armengol M, Santos JC, Fernandez-Serrano M, Profitos-Peleja N, Ribeiro ML, and Roue G. Immune-checkpoint inhibitors in B-cell lymphoma. Cancers. (2021) 13:214. doi: 10.3390/cancers13020214
38. Younes A, Burke JM, Cheson BD, Diefenbach CS, Ferrari S, Hahn UH, et al. Safety and efficacy of atezolizumab with rituximab and CHOP in previously untreated diffuse large B-cell lymphoma. Blood Adv. (2023) 7:1488–95. doi: 10.1182/bloodadvances.2022008344
39. Tuscano JM, Maverakis E, Groshen S, Tsao-Wei D, Luxardi G, Merleev AA, et al. A phase I study of the combination of rituximab and ipilimumab in patients with relapsed/refractory B-cell lymphoma. Clin Cancer Res. (2019) 25:7004–13. doi: 10.1158/1078-0432.CCR-19-0438
40. Ansell S, Gutierrez ME, Shipp MA, Gladstone D, Moskowitz A, Borello I, et al. A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic Malignancies (CheckMate 039). Blood. (2016) 128:183. doi: 10.1182/blood.V128.22.183.183
41. Chen R, Zinzani PL, Lee HJ, Armand P, Johnson NA, Brice P, et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE- 087. Blood. (2019) 134:1144–53. doi: 10.1182/blood.2019000324
42. Song Y, Gao Q, Zhang H, Fan L, Zhou J, Zou D, et al. Tislelizumab for relapsed/refractory Classical Hodgkin Lymphoma: 3-year follow-up and correlative biomarker analysis. Clin Cancer Res. (2022) 28:1147–56. doi: 10.1158/1078-0432.CCR-21-2023
43. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Mortarini R, Viviani S, et al. Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases. Clin Cancer Res. (2014) 20:5641–51. doi: 10.1158/1078-0432.CCR-14-0770
44. Ansell SM, Lesokhin AM, Borrello I, Alwani A, Scott EC, Gutierrezz M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. (2015) 372:311–9. doi: 10.1056/NEJMoa1411087
45. Ramchandren R, Domingo-Domenech E, Rueda A, Trneny M, Feldman TA, Lee HJ, et al. Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 study. J Clin Oncol. (2019) 37:1997–2007. doi: 10.1200/JCO.19.00315
46. Herrera A, Castellino SM, Li H, Rutherford SC, Evens AM, Davison K, et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin (BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin Oncol. (2023) 41:LBA4. doi: 10.1200/JCO.2023.41.17_suppl.LBA4
47. Kuruvilla J, Ramchandren R, Santoro A, Paszkiewicz-Kozik E, Gasiorowski R, Johnson NA, et al. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicenter, randomised, open-label, phase 3 study. Lancet Oncol. (2021) 22:512–24. doi: 10.1016/S1470-2045(21)00005-X
48. Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. (2006) 116:2610–21. doi: 10.1172/JCI24612
49. Bergers G and Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. (2008) 8:592–603. doi: 10.1038/nrc2442
50. Ribatti D. Novel angiogenesis inhibitors: Addressing the issue of redundancy in the angiogenic signaling pathway. Cancer Treat Rev. (2011) 37:344–52. doi: 10.1016/j.ctrv.2011.02.002
51. Martel CL, Presant CA, Ebrahimi B, Horns RC, Upadhyaya GH, Vakil MJ, et al. Bevacizumab-related toxicities: Association of hypertension and proteinuria. Commun Oncol. (2006) 3:90–3. doi: 10.1016/S1548-5315(11)70654-4
52. Wood LS. Managing the side effects of sorafenib and sunitinib. Commun Oncol. (2006) 3:558–62. doi: 10.1016/S1548-5315(11)70751-3
53. Force T, Krause DS, and Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. (2007) 7:332–44. doi: 10.1038/nrc2106
54. Ribatti D and Pezzella F. Overview on the different patterns of tumor vascularization. Cells. (2021) 10:639. doi: 10.3390/cells10030639
55. Crivellato E, Nico B, Vacca A, and Ribatti D. B-Cell Non-Hodgkin’s lymphomas express heterogeneous patterns of neovascularization. Haematologica. (2003) 88:671–8.
56. Yan Z, Ma J, Yao S, Yao Z, Wang H, Chu J, et al. Anti-angiogenic agent combined with anti-PD-1 immunotherapy showed activity in patients with classical hodgkin lymphoma who have failed immunotherapy: A retrospective case report study. Front Immunol. (2021) 12:727464. doi: 10.3389/fimmu.2021.727464
Keywords: angiogenesis, anti-angiogenesis, Hodgkin lymphomas, non-Hodgkin lymphomas, tumor progression
Citation: Ribatti D, Tamma R, Ingravallo G and Specchia G (2025) Anti-angiogenesis in human lymphomas. New insights. Front. Oncol. 15:1636332. doi: 10.3389/fonc.2025.1636332
Received: 27 May 2025; Accepted: 24 September 2025;
Published: 08 October 2025.
Edited by:
Rehan Khan, Rutgers University, Newark, United StatesReviewed by:
Eko Adhi Pangarsa, Dr. Kariadi Hospital, IndonesiaCopyright © 2025 Ribatti, Tamma, Ingravallo and Specchia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Domenico Ribatti, ZG9tZW5pY28ucmliYXR0aUB1bmliYS5pdA==