Diffuse large B cell lymphoma medical therapy: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Diffuse large B cell lymphoma}} | {{Diffuse large B cell lymphoma}} | ||
{{CMG}}; {{AE}} {{AS}} | 3){{CMG}}; {{AE}} {{AHS}}, {{AS}} | ||
==Overview== | ==Overview== | ||
The optimal therapy for diffuse large B cell lymphoma depends on the stage at diagnosis. The predominant therapy for diffuse large B cell lymphoma is chemotherapy. Adjunctive radiotherapy may be required. | The optimal therapy for diffuse large B cell lymphoma depends on the stage at diagnosis,age, [[IPI (International Prognostic Index)]] and [[aaIPI (Age adjusted International Prognostic index)]]. The predominant therapy for diffuse large B cell lymphoma is [[chemotherapy]]. Adjunctive [[radiotherapy]] may be required. Inclusion in a clinical trial is recommended when available. | ||
==Medical Therapy== | ==Medical Therapy== | ||
===Chemotherapy=== | ===Chemotherapy=== | ||
Main treatment of Choice for DLBCL. [[Chemotherapy]] is administered intravenously and people receiving chemotherapy commonly have a ([[peripherally inserted central catheter]]) in their arm near the elbow or a surgically implanted medical port. It is most effective when it is administered multiple times over a period of months (e.g. every 3 weeks, over 6 to 8 cycles). Different regimens of Chemotherapy with different durations/Cycles are used depending on the stage of disease, age of patient and prognsotic index. In general | |||
*Patients with limited stage disease receive 3 cycles of therapy | |||
*Patients with extensive disease 6 or 8 cycles of chemotherapy. In the United States, 6 cycles is the preferred approach rather than 8 cycles. | |||
===Radiation therapy=== | ===Radiation therapy=== | ||
[[Radiation]] is often added in the treatment. It is used commonly after completing 3 cycles of treatment in limited stage disease. In extensive disease, after 6-8 cycles of chemotherapy, radiation can be used at the end of the treatment to areas of bulky involvement. Radiation therapy alone is not an effective treatment for this disease. | [[Radiation]] is often added in the treatment. It is used commonly after completing 3 cycles of treatment in limited stage disease. In extensive disease, after 6-8 cycles of chemotherapy, radiation can be used at the end of the treatment to areas of bulky involvement. Radiation therapy alone is not an effective treatment for this disease | ||
===Stem Cell Transplantation=== | |||
High dose Chemotherapy coupled with stem cell transplantation is sometimes used to treat patients whose disease is refractory or relapsed following initial chemotherapy. Most common is [[Autologous stem cell transplant]] in which patients receive their own stem cells. Other option is [[Allogenic stem cell transplant]] in which patient will receive stem cells from a [[donor]] | |||
===Regimens of Chemotherapy=== | |||
'''1) R-CHOP''' | |||
*Standard treatment is CHOP-R, also referred to as ''R-CHOP'', an improved form of [[CHOP]] with the addition of [[rituximab]] (Rituxan), which has increased the rates of complete responses for Diffuse large B cell lymphoma patients, particularly elderly patients.<ref name="pmid17105812">{{cite journal |doi=10.1182/blood-2006-08-038257 |pmid=17105812 |title=The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP |journal=Blood |volume=109 |issue=5 |pages=1857–61 |year=2007 |last1=Sehn |first1=L. H. |last2=Berry |first2=B. |last3=Chhanabhai |first3=M. |last4=Fitzgerald |first4=C. |last5=Gill |first5=K. |last6=Hoskins |first6=P. |last7=Klasa |first7=R. |last8=Savage |first8=K. J. |last9=Shenkier |first9=T. |last10=Sutherland |first10=J. |last11=Gascoyne |first11=R. D. |last12=Connors |first12=J. M. }}</ref><ref name="pmid27980306">{{cite journal| author=Miyazaki K| title=Treatment of Diffuse Large B-Cell Lymphoma. | journal=J Clin Exp Hematop | year= 2016 | volume= 56 | issue= 2 | pages= 79-88 | pmid=27980306 | doi=10.3960/jslrt.56.79 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27980306 }} </ref><ref name="cornelllymphoma">http://cornell-lymphoma.com/tag/dlbcl/{{full|date=April 2015}}</ref> | |||
R-CHOP is a combination of one monoclonal antibody, 3 chemotherapy drugs and one steroid:<ref>{{cite journal |first1=Charles M. |last1=Farber |first2=Randy C. |last2=Axelrod |title=The Clinical and Economic Value of Rituximab for the Treatment of Hematologic Malignancies |journal=Contemporary Oncology |volume=3 |issue=1|year=2011 |url=http://www.onclive.com/publications/contemporary-oncology/2011/spring-2011/the-clinical-and-economic-value-of-rituximab-for-the-treatment-of-hematologic-malignancies}}</ref> | |||
*[[Rituximab]] (Rituxan) | |||
*[[Cyclophosphamide]] (Cytoxan) | |||
*[[Doxorubicin]] (Hydroxydaunorubicin) | |||
*[[Vincristine]] (Oncovin) | |||
*[[Prednisone]] | |||
'''2) R-ACVBP''' | |||
Alternate Intensive immmunochemotherapy that is preferred in patients with an age-adjusted [[IPI]] score of 1. However, its clinically significant toxic [[Adverse effect (medicine)|adverse effects]] have limited its use. It is a combination of: | |||
*[[Rituximab]] | |||
*[[Doxorubicin]] | |||
*[[Cyclophosphamide]] | |||
*[[Vindesine]] | |||
*[[Bleomycin]] | |||
*[[Prednisone]] | |||
'''3) R-CHOEP''' | |||
*[[Rituximab]] | |||
*[[Cyclophosphamide]] | |||
*[[Doxorubicin]] | |||
*[[Vincristine]] | |||
*[[etoposide]] | |||
*Prednisolone | |||
<br /> | |||
===Limited-Stage Disease (stage I or II disease, non-bulky and localized) with Age Younger Than 60 Years and Low IPI ( 0 )=== | |||
*This represents about 30% of patients | |||
*Those patients often have low-risk clinical features and a favorable outcome | |||
*Four Cycles of [[R-CHOP regimen|R-CHOP]] are enough<ref name="pmid33657296">{{cite journal| author=Sehn LH, Salles G| title=Diffuse Large B-Cell Lymphoma. | journal=N Engl J Med | year= 2021 | volume= 384 | issue= 9 | pages= 842-858 | pmid=33657296 | doi=10.1056/NEJMra2027612 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=33657296 }}</ref> | |||
*[[Radiation therapy|Radiotherapy]] [[Consolidation (medicine)|Consolidation]] treatment has no proven benefit in patients with non-bulky disease. It may cause late [[relapses]] and second [[Cancer|cancers]] <br /> | |||
===Patients Who Are Not Candidate For Standard Therapy=== | |||
*This represents about 20 to 25% of patients who are not candidates for the standard treatment such as [[R-CHOP regimen|R-CHOP]] | |||
*The etiology is poor fitness due to advanced [[Ageing|age]], [[heart disease]], or coexisting medical conditions | |||
*A detailed [[geriatric]] [[Assessment and Plan|assessment]] or simple functional testing can be helpful to recognize patients for whom a modified approach is required | |||
*Patients with low [[functional status]] may benefit from dose-reduced regimens of [[R-CHOP regimen|R-CHOP]], such as [[R-mini-CHOP]] | |||
*To reduce the [[Adverse effect (medicine)|adverse effects]], a short prephase of [[glucocorticoids]], with or without [[vincristine]] can be useful for that purpose | |||
*If there is a [[contraindication]] to [[anthracycline]], replacement with [[gemcitabine]] or [[etoposide]] is an option <br /> | |||
===Central Nervous System Prophylaxis=== | |||
*[[Central nervous system]] (CNS) [[Recurrence quantification analysis|recurrence]] occurs in 3 to 5% of patients, with median survival of less than 6 months<ref name="pmid336572962">{{cite journal| author=Sehn LH, Salles G| title=Diffuse Large B-Cell Lymphoma. | journal=N Engl J Med | year= 2021 | volume= 384 | issue= 9 | pages= 842-858 | pmid=33657296 | doi=10.1056/NEJMra2027612 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=33657296 }}</ref> | |||
*Risk factors: | |||
*CNS-IPI risk model including the five IPI risk factors in addition to [[Kidney|renal]] or [[Adrenal gland|adrenal]] involvement, stratifies patients into risk categories, with 12% of patients having a high risk of CNS recurrence | |||
*Double [[Gene expression|expression]] of [[MYCBP2|MYC]] and [[BCL2-like 1|BCL2]]<ref name="pmid30617197">{{cite journal| author=Klanova M, Sehn LH, Bence-Bruckler I, Cavallo F, Jin J, Martelli M | display-authors=etal| title=Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL. | journal=Blood | year= 2019 | volume= 133 | issue= 9 | pages= 919-926 | pmid=30617197 | doi=10.1182/blood-2018-07-862862 | pmc=6396175 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30617197 }}</ref><ref name="pmid27382100">{{cite journal| author=Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH | display-authors=etal| title=CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP. | journal=J Clin Oncol | year= 2016 | volume= 34 | issue= 26 | pages= 3150-6 | pmid=27382100 | doi=10.1200/JCO.2015.65.6520 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27382100 }}</ref><ref name="pmid26834242">{{cite journal| author=Savage KJ, Slack GW, Mottok A, Sehn LH, Villa D, Kansara R | display-authors=etal| title=Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL. | journal=Blood | year= 2016 | volume= 127 | issue= 18 | pages= 2182-8 | pmid=26834242 | doi=10.1182/blood-2015-10-676700 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26834242 }}</ref> | |||
*ABC subtype | |||
*[[Testicular]] involvement at the time of presentation | |||
*The role of [[CNS]] prophylaxis is still [[controversial]] | |||
*The use of [[Prophylaxis|prophylactic]] [[intrathecal]] [[chemotherapy]] is no longer recommended for [[Diffuse large B cell lymphoma|DLBCL]]<ref name="pmid31488560">{{cite journal| author=Eyre TA, Djebbari F, Kirkwood AA, Collins GP| title=Efficacy of central nervous system prophylaxis with stand-alone intrathecal chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a systematic review. | journal=Haematologica | year= 2020 | volume= 105 | issue= 7 | pages= 1914-1924 | pmid=31488560 | doi=10.3324/haematol.2019.229948 | pmc=7327624 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31488560 }}</ref> <br /> | |||
===Management of Refractory or Relapsed Cases=== | |||
*Primary [[refractory]] disease (i.e., an incomplete response or a [[relapse]] within 6 months after [[therapy]]) occurs in about 10-15% of patients treated with [[R-CHOP regimen|R-CHOP]] | |||
*Approximately 20-25% will develop a [[relapse]] after the initial [[Response rate|response]], often within the first 2 years<ref name="pmid24550425">{{cite journal| author=Maurer MJ, Ghesquières H, Jais JP, Witzig TE, Haioun C, Thompson CA | display-authors=etal| title=Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. | journal=J Clin Oncol | year= 2014 | volume= 32 | issue= 10 | pages= 1066-73 | pmid=24550425 | doi=10.1200/JCO.2013.51.5866 | pmc=3965261 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24550425 }}</ref> | |||
*Failure of frontline treatment indicates poor outcome with a [[median]] overall [[Survival analysis|survival]] of about 6 months<ref name="pmid28774879">{{cite journal| author=Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J | display-authors=etal| title=Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. | journal=Blood | year= 2017 | volume= 130 | issue= 16 | pages= 1800-1808 | pmid=28774879 | doi=10.1182/blood-2017-03-769620 | pmc=5649550 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28774879 }}</ref> | |||
*Patients with late [[Relapse|relapses]] (more than 2 years after treatment) have better outcomes <br /> | |||
====Transplantation-Eligible Patients==== | |||
*Using high-dose [[chemotherapy]] in addition to [[autologous]] [[stem cell transplantation]] ([[ASCT]]) has been found to achieve the best chance of cure in cases of [[relapsed]] or [[refractory]] disease; however, advanced age and coexisting medical conditions prevent half of such patients from being candidates for [[transplantation]] | |||
*In randomized trials, the most frequently used [[platinum]]-based [[Salvage therapy|salvage]] regimens are ([[rituximab]] with [[dexamethasone]], high-dose [[cytarabine]], and [[cisplatin]] [R-DHAP], [[rituximab]] with [[ifosfamide]], [[carboplatin]], and [[etoposide]] [R-ICE], and [[rituximab]] with [[gemcitabine]], [[dexamethasone]], and [[cisplatin]] [R-GDP]). These regimens have been found to be equally effective<ref name="pmid25267740">{{cite journal| author=Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT | display-authors=etal| title=Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. | journal=J Clin Oncol | year= 2014 | volume= 32 | issue= 31 | pages= 3490-6 | pmid=25267740 | doi=10.1200/JCO.2013.53.9593 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25267740 }}</ref> | |||
*About half of patients have a response to initial salvage treatment and then undergo [[ASCT]] | |||
*The overall [[cure rate]] is 25 to 35%<ref name="pmid20660832">{{cite journal| author=Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M | display-authors=etal| title=Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. | journal=J Clin Oncol | year= 2010 | volume= 28 | issue= 27 | pages= 4184-90 | pmid=20660832 | doi=10.1200/JCO.2010.28.1618 | pmc=3664033 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20660832 }}</ref> | |||
====Transplantation-Ineligible Patient==== | |||
*This includes patients with advanced age or coexisting medical conditions, those who are refractory to salvage therapy, and those with a [[relapse]] following ASCT | |||
*Palliative therapy can be achieved by sequential single-agent [[chemotherapy]] or a multiagent regimen with an acceptable [[Side effects|side effect]] profile | |||
====CAR T-Cell Therapy==== | |||
*This is a [[gene]]-[[Modified Intent to Treat|modified]] [[Cell (biology)|cellular]] treatment, that is considered a breakthrough in the treatment of [[refractory]] or [[relapsed]] [[Diffuse large B cell lymphoma|DLBCL]] (who had at least two lines of systemic therapy) | |||
*Initially, it included [[autologous]] [[T cell|T cells]] targeting [[CD19]] | |||
*It is not appropriate for all patients due to its associated [[toxic effects]] | |||
*The toxic effects include grade 3 to 4 [[cytokine release syndrome]] (in 2 to 22% of patients) and [[Neurological|neurologic]] [[Adverse effect (medicine)|side effects]] (10 to 28% of patients)<ref name="pmid32888407">{{cite journal| author=Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J | display-authors=etal| title=Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. | journal=Lancet | year= 2020 | volume= 396 | issue= 10254 | pages= 839-852 | pmid=32888407 | doi=10.1016/S0140-6736(20)31366-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32888407 }}</ref><ref name="pmid29226797">{{cite journal| author=Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA | display-authors=etal| title=Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. | journal=N Engl J Med | year= 2017 | volume= 377 | issue= 26 | pages= 2531-2544 | pmid=29226797 | doi=10.1056/NEJMoa1707447 | pmc=5882485 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29226797 }}</ref><ref name="pmid30501490">{{cite journal| author=Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP | display-authors=etal| title=Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. | journal=N Engl J Med | year= 2019 | volume= 380 | issue= 1 | pages= 45-56 | pmid=30501490 | doi=10.1056/NEJMoa1804980 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30501490 }}</ref> | |||
====Novel Therapies==== | |||
*There is an increased demand for novel therapies for management of relapsed or refractory DLBCL | |||
*Antibody–drug [[conjugates]] are used for selective delivery of [[cytotoxic]] agents to [[tumor cells]] using targeted antibodies | |||
*The combination of [[Polatuzumab vedotin|'''polatuzumab vedotin''']] with [[bendamustine]]–[[rituximab]] got regulatory approval based on a randomized phase 2 trial involving [[transplantation]]-[[ineligible]] patients. That combination has been found to improve the rates of [[metabolic response]] and overall [[Survival rate|survival]], as compared with [[bendamustine]]–[[rituximab]] alone<ref name="pmid31693429">{{cite journal| author=Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M | display-authors=etal| title=Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. | journal=J Clin Oncol | year= 2020 | volume= 38 | issue= 2 | pages= 155-165 | pmid=31693429 | doi=10.1200/JCO.19.00172 | pmc=7032881 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31693429 }}</ref> | |||
*Another novel drug called '''selinexor''', a [[Selective and non-selective|selective]] [[inhibitor]] of the [[nuclear export protein]] [[XPO1]], resulting in accumulation of [[tumor suppressor]] [[proteins]] in the [[nucleus]], also got [[Regulatory requirement|regulatory]] approval for patients with refractory or relapsed [[Diffuse large B cell lymphoma|DLBCL]] who have received at least two lines of [[treatment]], based on phase 2 trial that revealed a modest single-agent activity<ref name="pmid32589977">{{cite journal| author=Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP | display-authors=etal| title=Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. | journal=Lancet Haematol | year= 2020 | volume= 7 | issue= 7 | pages= e511-e522 | pmid=32589977 | doi=10.1016/S2352-3026(20)30120-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32589977 }}</ref> | |||
*Also, '''tafasitamab''', a humanized [[Anti-CD19 immunotoxin|anti-CD19]] [[monoclonal antibody]], combined with [[lenalidomide]] were shown to be effective, so they received regulatory approval for [[transplantation]]-ineligible patients with [[Diffuse large B cell lymphoma|DLBCL]]<ref name="pmid32511983">{{cite journal| author=Salles G, Duell J, González Barca E, Tournilhac O, Jurczak W, Liberati AM | display-authors=etal| title=Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. | journal=Lancet Oncol | year= 2020 | volume= 21 | issue= 7 | pages= 978-988 | pmid=32511983 | doi=10.1016/S1470-2045(20)30225-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32511983 }}</ref> | |||
*A [[macrophage]] [[immune checkpoint inhibitor]] called [[magrolimab|'''magrolimab''']] block [[CD47]], the “don’t eat me” molecule, has shown [[synergism]] with [[rituximab]], augmenting [[macrophage]] cellular [[phagocytosis]]<ref name="pmid30380386">{{cite journal| author=Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL, Ghosh N | display-authors=etal| title=CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma. | journal=N Engl J Med | year= 2018 | volume= 379 | issue= 18 | pages= 1711-1721 | pmid=30380386 | doi=10.1056/NEJMoa1807315 | pmc=8058634 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30380386 }}</ref> | |||
*[[Bispecific antibodies]] are those [[antibodies]] that target the [[Antigen|antigens]] on [[T cell|T cells]] and [[tumor]] cells resulting in [[Cell-mediated immunity|cell-mediated]] [[cytotoxicity]]. they have shown efficacy in refractory and relapsed cases of [[Diffuse large B cell lymphoma|DLBCL]]. For example, [[blinatumomab|'''blinatumomab''']], that targets [[CD3 (immunology)|CD3]] and [[CD19]]; however, the development of this [[Agent study|agent]] is stopped due to its continuous [[infusion]] schedule and [[neurotoxicity]]<ref name="pmid26755709">{{cite journal| author=Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N | display-authors=etal| title=Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. | journal=Blood | year= 2016 | volume= 127 | issue= 11 | pages= 1410-6 | pmid=26755709 | doi=10.1182/blood-2015-06-651380 | pmc=4797019 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26755709 }}</ref> | |||
*'''[[Mosunetuzumab]]''' has been found to be effective in patients with refractory or relapsed [[Diffuse large B cell lymphoma|DLBCL]] in an ongoing phase 1–1b study including patients with failed CAR T-cell therapy<ref name="pmid16462024">{{cite journal| author=Maeda T, Wakasawa T, Shima Y, Tsuboi I, Aizawa S, Tamai I| title=Role of polyamines derived from arginine in differentiation and proliferation of human blood cells. | journal=Biol Pharm Bull | year= 2006 | volume= 29 | issue= 2 | pages= 234-9 | pmid=16462024 | doi=10.1248/bpb.29.234 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16462024 }}</ref> | |||
*Several other agents are still under investigation <br /> <br /> | |||
. | |||
==References== | ==References== | ||
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Latest revision as of 00:28, 30 April 2021
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3)Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2], Sowminya Arikapudi, M.B,B.S. [3]
Overview
The optimal therapy for diffuse large B cell lymphoma depends on the stage at diagnosis,age, IPI (International Prognostic Index) and aaIPI (Age adjusted International Prognostic index). The predominant therapy for diffuse large B cell lymphoma is chemotherapy. Adjunctive radiotherapy may be required. Inclusion in a clinical trial is recommended when available.
Medical Therapy
Chemotherapy
Main treatment of Choice for DLBCL. Chemotherapy is administered intravenously and people receiving chemotherapy commonly have a (peripherally inserted central catheter) in their arm near the elbow or a surgically implanted medical port. It is most effective when it is administered multiple times over a period of months (e.g. every 3 weeks, over 6 to 8 cycles). Different regimens of Chemotherapy with different durations/Cycles are used depending on the stage of disease, age of patient and prognsotic index. In general
- Patients with limited stage disease receive 3 cycles of therapy
- Patients with extensive disease 6 or 8 cycles of chemotherapy. In the United States, 6 cycles is the preferred approach rather than 8 cycles.
Radiation therapy
Radiation is often added in the treatment. It is used commonly after completing 3 cycles of treatment in limited stage disease. In extensive disease, after 6-8 cycles of chemotherapy, radiation can be used at the end of the treatment to areas of bulky involvement. Radiation therapy alone is not an effective treatment for this disease
Stem Cell Transplantation
High dose Chemotherapy coupled with stem cell transplantation is sometimes used to treat patients whose disease is refractory or relapsed following initial chemotherapy. Most common is Autologous stem cell transplant in which patients receive their own stem cells. Other option is Allogenic stem cell transplant in which patient will receive stem cells from a donor
Regimens of Chemotherapy
1) R-CHOP
- Standard treatment is CHOP-R, also referred to as R-CHOP, an improved form of CHOP with the addition of rituximab (Rituxan), which has increased the rates of complete responses for Diffuse large B cell lymphoma patients, particularly elderly patients.[1][2][3]
R-CHOP is a combination of one monoclonal antibody, 3 chemotherapy drugs and one steroid:[4]
- Rituximab (Rituxan)
- Cyclophosphamide (Cytoxan)
- Doxorubicin (Hydroxydaunorubicin)
- Vincristine (Oncovin)
- Prednisone
2) R-ACVBP
Alternate Intensive immmunochemotherapy that is preferred in patients with an age-adjusted IPI score of 1. However, its clinically significant toxic adverse effects have limited its use. It is a combination of:
3) R-CHOEP
- Rituximab
- Cyclophosphamide
- Doxorubicin
- Vincristine
- etoposide
- Prednisolone
Limited-Stage Disease (stage I or II disease, non-bulky and localized) with Age Younger Than 60 Years and Low IPI ( 0 )
- This represents about 30% of patients
- Those patients often have low-risk clinical features and a favorable outcome
- Four Cycles of R-CHOP are enough[5]
- Radiotherapy Consolidation treatment has no proven benefit in patients with non-bulky disease. It may cause late relapses and second cancers
Patients Who Are Not Candidate For Standard Therapy
- This represents about 20 to 25% of patients who are not candidates for the standard treatment such as R-CHOP
- The etiology is poor fitness due to advanced age, heart disease, or coexisting medical conditions
- A detailed geriatric assessment or simple functional testing can be helpful to recognize patients for whom a modified approach is required
- Patients with low functional status may benefit from dose-reduced regimens of R-CHOP, such as R-mini-CHOP
- To reduce the adverse effects, a short prephase of glucocorticoids, with or without vincristine can be useful for that purpose
- If there is a contraindication to anthracycline, replacement with gemcitabine or etoposide is an option
Central Nervous System Prophylaxis
- Central nervous system (CNS) recurrence occurs in 3 to 5% of patients, with median survival of less than 6 months[6]
- Risk factors:
- CNS-IPI risk model including the five IPI risk factors in addition to renal or adrenal involvement, stratifies patients into risk categories, with 12% of patients having a high risk of CNS recurrence
- Double expression of MYC and BCL2[7][8][9]
- ABC subtype
- Testicular involvement at the time of presentation
- The role of CNS prophylaxis is still controversial
- The use of prophylactic intrathecal chemotherapy is no longer recommended for DLBCL[10]
Management of Refractory or Relapsed Cases
- Primary refractory disease (i.e., an incomplete response or a relapse within 6 months after therapy) occurs in about 10-15% of patients treated with R-CHOP
- Approximately 20-25% will develop a relapse after the initial response, often within the first 2 years[11]
- Failure of frontline treatment indicates poor outcome with a median overall survival of about 6 months[12]
- Patients with late relapses (more than 2 years after treatment) have better outcomes
Transplantation-Eligible Patients
- Using high-dose chemotherapy in addition to autologous stem cell transplantation (ASCT) has been found to achieve the best chance of cure in cases of relapsed or refractory disease; however, advanced age and coexisting medical conditions prevent half of such patients from being candidates for transplantation
- In randomized trials, the most frequently used platinum-based salvage regimens are (rituximab with dexamethasone, high-dose cytarabine, and cisplatin [R-DHAP], rituximab with ifosfamide, carboplatin, and etoposide [R-ICE], and rituximab with gemcitabine, dexamethasone, and cisplatin [R-GDP]). These regimens have been found to be equally effective[13]
- About half of patients have a response to initial salvage treatment and then undergo ASCT
- The overall cure rate is 25 to 35%[14]
Transplantation-Ineligible Patient
- This includes patients with advanced age or coexisting medical conditions, those who are refractory to salvage therapy, and those with a relapse following ASCT
- Palliative therapy can be achieved by sequential single-agent chemotherapy or a multiagent regimen with an acceptable side effect profile
CAR T-Cell Therapy
- This is a gene-modified cellular treatment, that is considered a breakthrough in the treatment of refractory or relapsed DLBCL (who had at least two lines of systemic therapy)
- Initially, it included autologous T cells targeting CD19
- It is not appropriate for all patients due to its associated toxic effects
- The toxic effects include grade 3 to 4 cytokine release syndrome (in 2 to 22% of patients) and neurologic side effects (10 to 28% of patients)[15][16][17]
Novel Therapies
- There is an increased demand for novel therapies for management of relapsed or refractory DLBCL
- Antibody–drug conjugates are used for selective delivery of cytotoxic agents to tumor cells using targeted antibodies
- The combination of polatuzumab vedotin with bendamustine–rituximab got regulatory approval based on a randomized phase 2 trial involving transplantation-ineligible patients. That combination has been found to improve the rates of metabolic response and overall survival, as compared with bendamustine–rituximab alone[18]
- Another novel drug called selinexor, a selective inhibitor of the nuclear export protein XPO1, resulting in accumulation of tumor suppressor proteins in the nucleus, also got regulatory approval for patients with refractory or relapsed DLBCL who have received at least two lines of treatment, based on phase 2 trial that revealed a modest single-agent activity[19]
- Also, tafasitamab, a humanized anti-CD19 monoclonal antibody, combined with lenalidomide were shown to be effective, so they received regulatory approval for transplantation-ineligible patients with DLBCL[20]
- A macrophage immune checkpoint inhibitor called magrolimab block CD47, the “don’t eat me” molecule, has shown synergism with rituximab, augmenting macrophage cellular phagocytosis[21]
- Bispecific antibodies are those antibodies that target the antigens on T cells and tumor cells resulting in cell-mediated cytotoxicity. they have shown efficacy in refractory and relapsed cases of DLBCL. For example, blinatumomab, that targets CD3 and CD19; however, the development of this agent is stopped due to its continuous infusion schedule and neurotoxicity[22]
- Mosunetuzumab has been found to be effective in patients with refractory or relapsed DLBCL in an ongoing phase 1–1b study including patients with failed CAR T-cell therapy[23]
- Several other agents are still under investigation
.
References
- ↑ Sehn, L. H.; Berry, B.; Chhanabhai, M.; Fitzgerald, C.; Gill, K.; Hoskins, P.; Klasa, R.; Savage, K. J.; Shenkier, T.; Sutherland, J.; Gascoyne, R. D.; Connors, J. M. (2007). "The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP". Blood. 109 (5): 1857–61. doi:10.1182/blood-2006-08-038257. PMID 17105812.
- ↑ Miyazaki K (2016). "Treatment of Diffuse Large B-Cell Lymphoma". J Clin Exp Hematop. 56 (2): 79–88. doi:10.3960/jslrt.56.79. PMID 27980306.
- ↑ http://cornell-lymphoma.com/tag/dlbcl/[full citation needed]
- ↑ Farber, Charles M.; Axelrod, Randy C. (2011). "The Clinical and Economic Value of Rituximab for the Treatment of Hematologic Malignancies". Contemporary Oncology. 3 (1).
- ↑ Sehn LH, Salles G (2021). "Diffuse Large B-Cell Lymphoma". N Engl J Med. 384 (9): 842–858. doi:10.1056/NEJMra2027612. PMID 33657296 Check
|pmid=value (help). - ↑ Sehn LH, Salles G (2021). "Diffuse Large B-Cell Lymphoma". N Engl J Med. 384 (9): 842–858. doi:10.1056/NEJMra2027612. PMID 33657296 Check
|pmid=value (help). - ↑ Klanova M, Sehn LH, Bence-Bruckler I, Cavallo F, Jin J, Martelli M; et al. (2019). "Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL". Blood. 133 (9): 919–926. doi:10.1182/blood-2018-07-862862. PMC 6396175. PMID 30617197.
- ↑ Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH; et al. (2016). "CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP". J Clin Oncol. 34 (26): 3150–6. doi:10.1200/JCO.2015.65.6520. PMID 27382100.
- ↑ Savage KJ, Slack GW, Mottok A, Sehn LH, Villa D, Kansara R; et al. (2016). "Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL". Blood. 127 (18): 2182–8. doi:10.1182/blood-2015-10-676700. PMID 26834242.
- ↑ Eyre TA, Djebbari F, Kirkwood AA, Collins GP (2020). "Efficacy of central nervous system prophylaxis with stand-alone intrathecal chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a systematic review". Haematologica. 105 (7): 1914–1924. doi:10.3324/haematol.2019.229948. PMC 7327624 Check
|pmc=value (help). PMID 31488560. - ↑ Maurer MJ, Ghesquières H, Jais JP, Witzig TE, Haioun C, Thompson CA; et al. (2014). "Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy". J Clin Oncol. 32 (10): 1066–73. doi:10.1200/JCO.2013.51.5866. PMC 3965261. PMID 24550425.
- ↑ Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J; et al. (2017). "Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study". Blood. 130 (16): 1800–1808. doi:10.1182/blood-2017-03-769620. PMC 5649550. PMID 28774879.
- ↑ Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT; et al. (2014). "Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12". J Clin Oncol. 32 (31): 3490–6. doi:10.1200/JCO.2013.53.9593. PMID 25267740.
- ↑ Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M; et al. (2010). "Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era". J Clin Oncol. 28 (27): 4184–90. doi:10.1200/JCO.2010.28.1618. PMC 3664033. PMID 20660832.
- ↑ Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J; et al. (2020). "Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study". Lancet. 396 (10254): 839–852. doi:10.1016/S0140-6736(20)31366-0. PMID 32888407 Check
|pmid=value (help). - ↑ Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA; et al. (2017). "Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma". N Engl J Med. 377 (26): 2531–2544. doi:10.1056/NEJMoa1707447. PMC 5882485. PMID 29226797.
- ↑ Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP; et al. (2019). "Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma". N Engl J Med. 380 (1): 45–56. doi:10.1056/NEJMoa1804980. PMID 30501490.
- ↑ Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M; et al. (2020). "Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma". J Clin Oncol. 38 (2): 155–165. doi:10.1200/JCO.19.00172. PMC 7032881 Check
|pmc=value (help). PMID 31693429. - ↑ Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP; et al. (2020). "Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial". Lancet Haematol. 7 (7): e511–e522. doi:10.1016/S2352-3026(20)30120-4. PMID 32589977 Check
|pmid=value (help). - ↑ Salles G, Duell J, González Barca E, Tournilhac O, Jurczak W, Liberati AM; et al. (2020). "Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study". Lancet Oncol. 21 (7): 978–988. doi:10.1016/S1470-2045(20)30225-4. PMID 32511983 Check
|pmid=value (help). - ↑ Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL, Ghosh N; et al. (2018). "CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma". N Engl J Med. 379 (18): 1711–1721. doi:10.1056/NEJMoa1807315. PMC 8058634 Check
|pmc=value (help). PMID 30380386. - ↑ Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N; et al. (2016). "Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma". Blood. 127 (11): 1410–6. doi:10.1182/blood-2015-06-651380. PMC 4797019. PMID 26755709.
- ↑ Maeda T, Wakasawa T, Shima Y, Tsuboi I, Aizawa S, Tamai I (2006). "Role of polyamines derived from arginine in differentiation and proliferation of human blood cells". Biol Pharm Bull. 29 (2): 234–9. doi:10.1248/bpb.29.234. PMID 16462024.