Section editor
	Tarsheen Sethi, MD, MSCI Yale University New Haven, CT tarsheen2

18 regimens on this page 18 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

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Efficacy
Nellapu et al. 2017 (ZUMA-1)	2015-2016	Phase II, <20 pts in subgroup (RT)	ORR: 82%

Preceding treatment

Lymphodepletion with FC

Immunotherapy

Axicabtagene ciloleucel (Yescarta) target dose of 2 × 10⁶ CAR T cells/kg IV once on day 0

Supportive medications

Acetaminophen (Tylenol) 650 mg PO once on day 0, approximately 60 minutes prior to Axicabtagene ciloleucel (Yescarta)
Diphenhydramine (Benadryl) 12.5 mg IV or PO once on day 0, approximately 60 minutes prior to Axicabtagene ciloleucel (Yescarta)

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

References

ZUMA-1: 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 verified protocol link to PMC article PubMed

Bendamustine monotherapy

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Regimen

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

Chemotherapy

Bendamustine 120 mg/m² IV once per day on days 1 & 2

21-day cycle for up to 12 cycles

References

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 verified protocol PubMed

¹³¹Iodine-Tositumomab monotherapy

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Regimen

Study	Evidence
Vose et al. 2000	Phase II

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:
- Tositumomab 450 mg IV over 1 hour
- Tositumomab 35 mg labeled with 5 mCi of Iodine-131 IV over 20 minutes
- First scan of whole body dosimetry & redistribution
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

Any day from day 7-14, infusions of:
- Tositumomab 450 mg IV over 1 hour
- Tositumomab 35 mg labeled with an individually calculated dose of Iodine-131 that will provide 75 cGy of radiation to the total body IV over 20 minutes
  - 65 cGy total body dose used for patients with platelet counts of 100-150,000/mm3

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

References

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 verified protocol PubMed

Lenalidomide monotherapy

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Regimen

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

Targeted therapy

Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles

References

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 verified protocol PubMed

Lenalidomide & Rituximab

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Regimen

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

Targeted therapy

Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

References

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 verified protocol PubMed NCT00294632

Lenalidomide & Tafasitamab

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Regimen

Study	Evidence
Salles et al. 2020 (L-MIND)	Phase II

Note: dosing details in the abstract are unclear and not consistent with earlier abstracts.

Targeted therapy

Lenalidomide (Revlimid) 25 mg PO once per day
Tafasitamab (Monjuvi) 12 mg/kg IV once on day 1

28-day cycle for 12 cycles

Subsequent treatment

Tafasitamab maintenance

References

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 PubMed NCT02399085

Lisocabtagene maraleucel monotherapy

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Regimen

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

Immunotherapy

Lisocabtagene maraleucel (Breyanzi)

References

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

OFAR

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

Regimen

Study	Evidence	Efficacy
Tsimberidou et al. 2008	Phase II	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 medications

Pegfilgrastim (Neulasta) 6 mg SC once on day 6
Herpes zoster and PCP (Pneumocystis jiroveci pneumonia) prophylaxis used

28-day cycle for up to 6 cycles

References

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 protocol PubMed

Pembrolizumab monotherapy

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Regimen

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

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

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

References

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 verified protocol link to PMC article PubMed

R-DHAP

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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 III (C)	R-GDP	Not reported

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
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

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 verified protocol PubMed
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 verified protocol PubMed

R-EPOCH

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

Regimen

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

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

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

Etoposide (Vepesid) 65 mg/m²/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 195 mg/m²)
Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 14
Vincristine (Oncovin) 0.5 mg/m²/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 1.5 mg/m²)
Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 5
Doxorubicin (Adriamycin) 15 mg/m²/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 45 mg/m²)

21-day cycle for 4 to 6 cycles

References

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 verified protocol PubMed

R-GDP

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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 III (E-switch-ic)	R-DHAP	Not reported

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
Cisplatin (Platinol) 75 mg/m² IV once on day 1

21-day cycle for up to 3 cycles

Subsequent treatment

Responders: autologous HSCT

References

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 verified protocol PubMed
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 verified protocol PubMed

Tisagenlecleucel monotherapy

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Regimen

FDA-recommended dose

Study	Evidence	Efficacy
Schuster et al. 2017 (JULIET)	Phase II	ORR: 59% (95% CI, 44-72)

The range given is the FDA-recommended dose.

Preceding treatment

Lymphodepleting therapy with FC or Bendamustine

Immunotherapy

Tisagenlecleucel (Kymriah) 0.6 to 6.0 x 10⁸ CTL019 transduced viable T-cells IV once on day 0

One course

References

Abstract: Schuster SJ, Bishop MR, Tam C, et al. Global Pivotal Phase 2 Trial of the CD19-Targeted Therapy CTL019 in Adult Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)—an Interim Analysis. Hematological Oncology. 2017;35(S2):27. link to abstract

Consolidation after salvage therapy

BFR, then allo HSCT

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BFR: Bendamustine, Fludarabine, Rituximab

Regimen

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

Chemotherapy

Bendamustine 130 mg/m² IV once per day on days -5 to -3
Fludarabine (Fludara) 30 mg/m² IV over 30 minutes once per day on days -5 to -3

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once per day on days -13, -6, +1, +8

Immunotherapy

Allogeneic stem cells transfused on day 0

GVHD prophylaxis

See article for GVHD prophylaxis information

One course

Immunotherapy

Allogeneic stem cells

Stem cells transfused on day 0

References

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 verified protocol link to PMC article PubMed

Transformed lymphoma

All lines of therapy

Axicabtagene ciloleucel monotherapy

Regimen

Preceding treatment

Immunotherapy

Supportive medications

References

Bendamustine monotherapy

Regimen

Chemotherapy

References

131Iodine-Tositumomab monotherapy

Regimen

Radioconjugate therapy, dosimetric step

Radioconjugate therapy, therapeutic step

References

Lenalidomide monotherapy

Regimen

Targeted therapy

References

Lenalidomide & Rituximab

Regimen

Targeted therapy

References

Lenalidomide & Tafasitamab

Regimen

Targeted therapy

Subsequent treatment

References

Lisocabtagene maraleucel monotherapy

Regimen

Immunotherapy

References

OFAR

Regimen

Chemotherapy

Targeted therapy

Supportive medications

References

Pembrolizumab monotherapy

Regimen

Immunotherapy

References

R-DHAP

Regimen

Targeted therapy

Chemotherapy

References

R-EPOCH

Regimen

Targeted therapy

Chemotherapy

References

R-GDP

Regimen

Targeted therapy

Chemotherapy

Subsequent treatment

References

Tisagenlecleucel monotherapy

Regimen

Preceding treatment

Immunotherapy

References

Consolidation after salvage therapy

BFR, then allo HSCT

Regimen

Chemotherapy

Targeted therapy

Immunotherapy

GVHD prophylaxis

Immunotherapy

References

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¹³¹Iodine-Tositumomab monotherapy