Transformed lymphoma

From HemOnc.org - A Hematology Oncology Wiki
Jump to navigation Jump to search

Section editor
TarsheenSethi.jpg
Tarsheen Sethi, MD, MSCI
Yale University
New Haven, CT

Social-twitter-icon.png tarsheen2
16 regimens on this page
16 variants on this page


Transformed lymphoma, often referred to as Richter's transformation, most commonly arises from a preceding indolent lymphoma - usually follicular lymphoma or chronic lymphocytic leukemia. It is typically treated as per the histologic subtype, which is usually DLBCL. However, some regimens specific to transformed lymphoma have been developed and are included here.

All lines of therapy

Axicabtagene ciloleucel monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Efficacy
Locke et al. 2017 (ZUMA-1) 2015-2016 Phase 1/2, <20 pts in subgroup (RT) ORR: 82%

Preceding treatment

  • Lymphodepletion with FC

Immunotherapy

Supportive therapy

One course; patients with initial response and disease progression at least 3 months later could be retreated

References

  1. ZUMA-1: Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, Ghobadi A, Budde LE, Bot A, Rossi JM, Jiang Y, Xue AX, Elias M, Aycock J, Wiezorek J, Go WY. Phase 1 results of ZUMA-1: A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017 Jan 4;25(1):285-295. Epub 2017 Jan 4. link to original article link to PMC article PubMed NCT02348216
    1. Update: Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. Epub 2017 Dec 10. link to original article contains dosing details in manuscript link to PMC article PubMed
    2. Update: Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Wiezorek JS, Navale L, Xue A, Jiang Y, Bot A, Rossi JM, Kim JJ, Go WY, Neelapu SS. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan;20(1):31-42. Epub 2018 Dec 2. link to original article link to PMC article contains dosing details in manuscript PubMed

Bendamustine monotherapy

Regimen

Study Evidence
Friedberg et al. 2008 Phase 2, <20 pts in this subgroup

Chemotherapy

21-day cycle for up to 12 cycles

References

  1. Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article contains dosing details in manuscript PubMed

131Iodine-Tositumomab monotherapy

Regimen

Study Evidence
Vose et al. 2000 Phase 2

Note: This was also evaluated in low-grade NHL but subtype was not specified. Now obsolete as this drug has been discontinued.

Radioconjugate therapy, dosimetric step

  • On Day 0, infusions of:
  • Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
  • Day 6 or 7: Third scan of whole body dosimetry & redistribution

Radioconjugate therapy, therapeutic step

Calculated dose of I-131 is based on information from serial total-body gamma-camera counts

References

  1. Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Radford JA, Zelenetz AD, Tidmarsh GF, Stagg RJ, Kaminski MS. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2000 Mar;18(6):1316-23. link to original article contains dosing details in manuscript PubMed

Lenalidomide monotherapy

Regimen

Study Evidence
Witzig et al. 2011 (NHL-003) Phase 2

Targeted therapy

28-day cycles

References

  1. NHL-003: Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, Bouabdallah R, Haioun C, Tilly H, Guo P, Pietronigro D, Ervin-Haynes AL, Czuczman MS. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol. 2011 Jul;22(7):1622-7. Epub 2011 Jan 12. link to original article contains dosing details in manuscript PubMed NCT00413036

Lenalidomide & Rituximab (R2)

Regimen

Study Evidence
Wang et al. 2013 (MDACC 2005-0461) Phase 2, <20 pts in this subgroup

Targeted therapy

28-day cycles

References

  1. MDACC 2005-0461: Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, Hagemeister F, Fanale M, Oki Y, Pro B, Shah J, Thomas S, Younes A, Hosing C, Zhang L, Newberry KJ, Desai M, Cheng N, Badillo M, Bejarano M, Chen Y, Young KH, Champlin R, Kwak L, Fayad L. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013 Sep;27(9):1902-9. Epub 2013 Apr 2. link to original article contains dosing details in manuscript PubMed NCT00294632

Lenalidomide & Tafasitamab

Regimen

Study Years of enrollment Evidence
Salles et al. 2020 (L-MIND) 2016-2017 Phase 2 (RT)

Targeted therapy

  • Lenalidomide (Revlimid) as follows:
    • Cycles 1 to 12: 25 mg PO once per day on days 1 to 21
  • Tafasitamab (Monjuvi) as follows:
    • Cycle 1: 12 mg/kg IV over 2 hours once per day on days 1, 4, 8, 15, 22
    • Cycles 2 & 3: 12 mg/kg IV over 2 hours once per day on days 1, 8, 15, 22
    • Cycle 4 onwards: 12 mg/kg IV over 2 hours once per day on days 1 & 15

28-day cycles

References

  1. L-MIND: Salles G, Duell J, González Barca E, Tournilhac O, Jurczak W, Liberati AM, Nagy Z, Obr A, Gaidano G, André M, Kalakonda N, Dreyling M, Weirather J, Dirnberger-Hertweck M, Ambarkhane S, Fingerle-Rowson G, Maddocks K. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020 Jul;21(7):978-988. Epub 2020 Jun 5. link to original article contains dosing details in manuscript PubMed NCT02399085

Lisocabtagene maraleucel monotherapy

Regimen

Study Years of enrollment Evidence
Abramson et al. 2020 (TRANSCEND NHL-001) 2016-2019 Phase 1 (RT)

References

  1. TRANSCEND NHL-001: Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C, Sehgal A, Solomon SR, Ghosh N, Albertson TM, Garcia J, Kostic A, Mallaney M, Ogasawara K, Newhall K, Kim Y, Li D, Siddiqi T. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020 Sep 19;396(10254):839-852. Epub 2020 Sep 1. link to original article PubMed NCT02631044

Loncastuximab tesirine monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence
Caimi et al. 2021 (LOTIS-2) 2018-2019 Phase 2 (RT)

Antibody-drug conjugate therapy

  • Loncastuximab tesirine (Zynlonta) as follows:
    • Cycles 1 & 2: 0.15 mg/kg IV over 30 minutes once on day 1
    • Cycle 3 onwards: 0.075 mg/kg IV over 30 minutes once on day 1

Supportive therapy

21-day cycles for up to 18 cycles (1 year)

References

  1. LOTIS-2: Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, Kahl BS, Radford J, Solh M, Stathis A, Zinzani PL, Havenith K, Feingold J, He S, Qin Y, Ungar D, Zhang X, Carlo-Stella C. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):790-800. Epub 2021 May 11. link to original article contains dosing details in abstract PubMed NCT03589469

OFAR

OFAR: Oxaliplatin, Fludarabine, Ara-C (Cytarabine), Rituximab

Regimen

Study Years of enrollment Evidence Efficacy
Tsimberidou et al. 2008 2004-2006 Phase 2 Likely has true ORR > 20%

Note: the manuscript does not specify what sequence the rituximab is given in.

Chemotherapy

  • Oxaliplatin (Eloxatin) 25 mg/m2 IV over 2 hours once per day on days 1 to 4, given first (see note)
  • Fludarabine (Fludara) 30 mg/m2 IV once per day on days 2 & 3, given second, within 30 minutes of completion of oxaliplatin (see note)
  • Cytarabine (Ara-C) 1000 mg/m2 IV over 2 hours once per day on days 2 & 3, given third, 4 hours after start of fludarabine (see note)

Targeted therapy

  • Rituximab (Rituxan) as follows (see note):
    • Cycle 1: 375 mg/m2 IV over 4 to 6 hours once on day 3
    • Cycles 2 to 6: 375 mg/m2 IV over 4 to 6 hours once on day 1

Supportive therapy

28-day cycle for up to 6 cycles

References

  1. Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008 Jan 10;26(2):196-203. link to original article contains dosing details in abstract PubMed

Pembrolizumab monotherapy

Regimen

Study Evidence Efficacy
Ding et al. 2017 (MC1485) Phase 2, <20 pts in this subgroup Unlikely to have true ORR > 20%

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. MC1485: Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, Shanafelt TD, Sinha S, Le-Rademacher J, Feldman AL, Habermann TM, Witzig TE, Wiseman GA, Lin Y, Asmus E, Nowakowski GS, Conte MJ, Bowen DA, Aitken CN, Van Dyke DL, Greipp PT, Liu X, Wu X, Zhang H, Secreto CR, Tian S, Braggio E, Wellik LE, Micallef I, Viswanatha DS, Yan H, Chanan-Khan AA, Kay NE, Dong H, Ansell SM. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017 Jun 29;129(26):3419-3427. Epub 2017 Apr 19. link to original article contains dosing details in manuscript link to PMC article PubMed

R-DHAP

R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Crump et al. 2014 (NCIC-CTG LY.12) 2003-2011 Phase 3 (C) R-GDP Not reported

Targeted therapy

Glucocorticoid therapy

Chemotherapy

  • Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
  • Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1

21-day cycle for up to 3 cycles

References

  1. NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. 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. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains dosing details in manuscript PubMed NCT00078949
    1. Subgroup Analysis: Kuruvilla J, MacDonald DA, Kouroukis CT, Cheung M, Olney HJ, Turner AR, Anglin P, Seftel M, Ismail WS, Luminari S, Couban S, Baetz T, Meyer RM, Hay AE, Shepherd L, Djurfeldt MS, Alamoudi S, Chen BE, Crump M. Salvage chemotherapy and autologous stem cell transplantation for transformed indolent lymphoma: a subset analysis of NCIC-CTG LY12. Blood. 2015 Aug 6;126(6):733-8. Epub 2015 Jun 24. link to original article contains dosing details in manuscript PubMed

R-EPOCH

R-EPOCH: Rituximab, Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin)

Regimen

Study Evidence
Jermann et al. 2004 Phase 2, <20 pts in this subgroup

Note: this is not the dose-adjusted R-EPOCH regimen

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for 4 to 6 cycles

References

  1. Jermann M, Jost LM, Taverna Ch, Jacky E, Honegger HP, Betticher DC, Egli F, Kroner T, Stahel RA. Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Ann Oncol. 2004 Mar;15(3):511-6. link to original article contains dosing details in manuscript PubMed

R-GDP

R-GDP: Rituximab, Gemcitabine, Dexamethasone, Platinol (Cisplatin)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Crump et al. 2014 (NCIC-CTG LY.12) 2003-2011 Phase 3 (E-switch-ic) R-DHAP Not reported

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for up to 3 cycles

Subsequent treatment

  • Responders: autologous HSCT

References

  1. NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. 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. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains dosing details in manuscript PubMed NCT00078949
    1. Subgroup Analysis: Kuruvilla J, MacDonald DA, Kouroukis CT, Cheung M, Olney HJ, Turner AR, Anglin P, Seftel M, Ismail WS, Luminari S, Couban S, Baetz T, Meyer RM, Hay AE, Shepherd L, Djurfeldt MS, Alamoudi S, Chen BE, Crump M. Salvage chemotherapy and autologous stem cell transplantation for transformed indolent lymphoma: a subset analysis of NCIC-CTG LY12. Blood. 2015 Aug 6;126(6):733-8. Epub 2015 Jun 24. link to original article contains dosing details in manuscript PubMed

Selinexor monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence
Kalakonda et al. 2020 (SADAL) 2015-2019 Phase 2b (RT)

Targeted therapy

7-day cycles

References

  1. SADAL: Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, Casasnovas O, Hamad N, Zijlstra JM, Bakhshi S, Bouabdallah R, Choquet S, Gurion R, Hill B, Jaeger U, Sancho JM, Schuster M, Thieblemont C, De la Cruz F, Egyed M, Mishra S, Offner F, Vassilakopoulos TP, Warzocha K, McCarthy D, Ma X, Corona K, Saint-Martin JR, Chang H, Landesman Y, Joshi A, Wang H, Shah J, Shacham S, Kauffman M, Van Den Neste E, Canales MA. 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. 2020 Jul;7(7):e511-e522. link to original article contains dosing details in abstract PubMed NCT02227251

Tisagenlecleucel monotherapy

Regimen

FDA-recommended dose
Study Evidence Efficacy
Schuster et al. 2018 (JULIET) Phase 2 ORR: 59% (95% CI, 44-72)

The range given is the FDA-recommended dose.

Preceding treatment

Immunotherapy

One course

References

  1. JULIET: Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak Ö, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. Epub 2018 Dec 1. link to original article PubMed NCT02445248
    1. Update: Schuster SJ, Tam CS, Borchmann P, Worel N, McGuirk JP, Holte H, Waller EK, Jaglowski S, Bishop MR, Damon LE, Foley SR, Westin JR, Fleury I, Ho PJ, Mielke S, Teshima T, Janakiram M, Hsu JM, Izutsu K, Kersten MJ, Ghosh M, Wagner-Johnston N, Kato K, Corradini P, Martinez-Prieto M, Han X, Tiwari R, Salles G, Maziarz RT. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1403-1415. Epub 2021 Sep 10. link to original article PubMed

Consolidation after salvage therapy

BFR, then allo HSCT

BFR: Bendamustine, Fludarabine, Rituximab

Regimen

Study Evidence
Khouri et al. 2014 (MDACC 2008-0246) Phase 2, <20 pts in this subgroup

Chemotherapy

Targeted therapy

Immunotherapy

GVHD prophylaxis

  • See article for GVHD prophylaxis information

References

  1. MDACC 2008-0246: Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, Anderlini P, Ciurea S, Jabbour E, Oran B, Popat UR, Rondon G, Bassett RL Jr, Gulbis A. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014 Oct 2;124(14):2306-12. Epub 2014 Aug 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00880815