Other Chemotherapeutic Agents in Cutaneous T-Cell Lymphoma




Traditional chemotherapies, interleukins, phosphorylase inhibitors, and proteasome inhibitors are important therapies available to patients with cutaneous T-cell lymphoma (CTCL). Traditional chemotherapies, both in combination and as single agents, are commonly used in relapsed, refractory CTCLs that behave in an aggressive manner. Interleukins, phosphorylase inhibitors, and proteasome inhibitors are less commonly used but data support a role in patients with more refractory disease.


Key points







  • •

    Traditional chemotherapies are used throughout the world in the treatment of cutaneous T-cell lymphoma (CTCL).


  • •

    Both single and multiagent chemotherapies can benefit patients with CTCL.


  • •

    There currently are no data to support the use of traditional chemotherapies over other therapies for CTCL. Therefore, in patients with less advanced disease, alternative therapies should be considered.






Introduction


Currently, no traditional chemotherapy agents are Food and Drug Administration (FDA) approved for the treatment of mycosis fungoides (MF) or Sézary syndrome (SS). Multiple chemotherapeutic treatments for MF and SS, such as systemic nitrogen mustard and multiagent chemotherapy regimens (eg, cyclophosphamide, adriamycin, vincristine, and prednisone [CHOP]), were initially used because of established activity in other non-Hodgkin lymphomas (NHLs) or Hodgkin lymphomas. Over time, specific treatments were reported by astute physicians to be particularly effective in MF/SS, such as the Winkelmann chlorambucil regimen. More recently, however, it has been recognized that some of these regimens, which are often characterized by significant immunosuppression and toxicity, are not more effective than agents described elsewhere in this issue (eg, interferons [IFNs]). Nevertheless, these other “chemotherapeutic” agents remain an important therapy option for some patients with MF/SS. This article describes those chemotherapeutic agents not discussed elsewhere in this issue with a review of the data supporting their use. Table 1 summarizes single-agent therapies in MF/SS and Table 2 summarizes multiagent chemotherapies. Readers are further referred to a comprehensive review on the treatments used for SS and MF by Olsen and colleagues for additional in-depth discussion of many of the agents discussed later.



Table 1

Summary of single-agent and combination chemotherapy studies in the treatment of mycosis fungoides or Sézary syndrome





































































































































































































































Agent(s) Response Rate (Responders/Total) Dosing Study
Fludarabine 2/5 25 mg/m 2 × 5 d, q3–4 wk Redman et al, 1992
6/31 18–25 mg/m 2 × 5 d, q4 wk Von Hoff et al, 1990
Fludarabine + ECP 7/27 MF; 6/17 SS 25 mg/m 2 × 5 d, q4 wk Quaglino et al, 2000
Fludarabine + IFN 18/35 25 mg/m 2 × 5 d q4 wk; 5 million units, TIW Foss et al, 1994
Fludarabine + cyclophosphamide 5/6 18 mg/m 2 × 3 d, q4wk; 250 mg/m 2 × 3 d, q4wk Scarisbrick et al, 2011
Cladribine 2/2 0.1 mg/kg × 7 d, q4wk Betticher et al, 1994
2/9 4 mg/m 2 × 7 d, q4wk O’Brien et al, 1994
9/22 0.1 mg/kg × 5–7 d, q4wk Kuzel et al, 1996
2/8 0.06 mg/kg × 5 d, q4wk Trautinger et al, 1999
Pentostatin 10/32 3.75–5 mg/m 2 × 3 d, q3wk Tsimberidou et al, 2004
4/8 5 mg/m 2 × 3 d, q3wk Cummings et al, 1991
7/18 Varied Greiner et al, 1997
5/22 MF; 7/21 SS 4 mg/m 2 q1–4wk Ho et al, 1999
4/6 MF; 10/14 SS 5 mg/m 2 × 3 d, q3wk ± 1.25 mg/m 2 on subsequent cycles Kurzrock et al, 1999
Pentostatin, cyclophosphamide, and bexarotene 5/5 MF; 2/3 SS 4 mg/m 2 q2wk; 600 mg/m 2 q2wk; 300 mg/m 2 qd × 8 mo Calderon Cabrera et al, 2013
Pentostatin + IFN 17/41 4 mg/m 2 × 3 d Foss et al, 1992
Gemcitabine 9/19 1200 mg/m 2 d 1, 8, 15, and 28 Zinzani et al, 2010
19/26 MF; 0/1 SS 1200 mg/m 2 d 1, 8, 15, and 28 Marchi et al, 2005
21/30 1000 mg/m 2 d 1, 8, and 15 Duvic et al, 2006
3/3 1000 mg/m 2 d 1, 8, and 15 then 250 mg/m 2 weekly Buhl et al, 2009
7/9 MF; 2/4 SS 1000 mg/m 2 d 1 and 8 of a 21-d cycle or d 1, 8, ± 15 of a 28-d cycle Jidar et al, 2009
Mechlorethamine 34/41 Varied Van Scott et al, 1975
Chlorambucil + prednisone 23/26 (all SS) 2–6 mg/d; 20 mg/d Winkelmann et al, 1984
6/6 2–6 mg/d; 5–20 mg/d Hamminga et al, 1979
Chlorambucil + fluocortolone 13/13 Clorambucil 10–12 mg/d × 3 d; fluocortolone 75 mg d 1, 50 mg d 2, 25 mg d 3 Coors & von den Driesch, 2000
Chlorambucil + prednisone + leukapheresis 11/11 4 mg/d; 20 mg/d; Leukapheresis 2–3 × per wk Winkelmann et al, 1984
Bendamustine 2/3 60–100 mg/m 2 Zaja et al, 2013
Cyclophsphamide 4/4 Varied: 200–700 mg/d Abele & Dobson, 1960
5/11 Varied: 50–300 mg/d Van Scott et al, 1962
TMZ 3/9 150 mg/m 2 /d × 5 d, q4wk, Then 200 mg/m 2 /d × 5 d q4wk Tani et al, 2005
7/26 200 mg/m 2 /d PO × 5 d q4wk Querfeld et al, 2011
Liposomal daunorubicin 3/3 20–40 mg/m 2 q3–4wk Wollina et al, 2003
Doxorubicin 7/13 60 mg/m 2 q3wk Levi et al, 1977
26/30 MF; 1/1 SS 20–40 mg/m 2 q2–4wk Wollina et al, 2003
3/10 20 mg/m 2 q4wk Di Lorenzo et al, 2005
12/13 MF; 1/3 SS; 20 mg/m 2 q4wk Pulini et al, 2007
6/10 MF; 3/5 SS 40 mg/m 2 q4wk Quereux et al, 2008
20/49 20 mg/m 2 q2wk Dummer et al, 2012
Doxorubicin + bexarotene 14/34 (Doxorubicin only); 7/15 (doxorubicin + bexarotene) Doxil 20 mg/m 2 q2wk; bexarotene 300 mg/m 2 /d Straus et al, 2014
Etoposide ± cyclophosphamide 2/5 (Etoposide only); 3/4 (etoposide + cyclophosphamide) 100 mg/m 2 IV × 5 d, q2–3wk ± cyclophosphamide Molin et al, 1979
IL-2 3/3 MF; 1/3 SS 20 million units/m 2 on d 1–5, 14–17, and 28–30 (induction) followed by 2 d/mo for 5 mo (consolidation) Baccard et al, 1997
5/7 20 million units/m 2 /d for 5, 4, and 3 d (wk 1, 3, and 5) followed by optional monthly maintenance × 5 d Gisselbrecht et al, 1994
4/22 20 million units/m 2 /d on d 1–4 × 6 wk in an 8-wk cycle Querfeld et al, 2007
IL-12 5/10 50, 100, or 300 ng/kg twice weekly, up to 24 wk Rook et al, 1999
10/23 100 ng/kg twice weekly × 2 wk then 300 mg/kg twice weekly through 24 wk Rook et al, 2001
Forodesine 9/13 40–320 mg/m 2 BID × 4 d in a 16-d cycle Lansigan & Foss, 2010
10/37 (MF/SS + other T-cell lymphomas) 40–320 mg/m 2 /d × 4 wk Duvic et al, 2006
11/101 200 mg daily (approximately 80 mg/m 2 ) Dummer et al, 2014
Bortezomib 7/10 1.3 mg/m 2 twice weekly × 2 wk in a 3-wk cycle Zinzani et al, 2007

Abbreviation: TIW, three times weekly.


Table 2

Combination chemotherapy used in the treatment of mycosis fungoides/Sézary syndrome




























































































































































































Therapy Regimen No. of Patients Complete Response + Partia Response, n (%) Complete Response, n (%) Median Duration of Response (mo) Stage Reference
MOPP/COPP + TSEB 21 19 (70) 11 (52) 14 I–III Hallahan et al, 1988; Bunn et al, 1994
BLM + MTX 10 9 (90) 1 (10) 6 T3 Groth et al, 1979
CHOP/HOP 12 10 (83) 5 (42) 5 II–IV Grozea et al, 1979; Lamberg et al, 1979
CHOP/COP 30 9 (30) 3 (10) 6 Not reported Fierro et al, 1998
CHOP 1 0 0 — T3 Molin et al, 1980; Raafat & Oster, 1980
CVP 4 3 (75) 1 (25) Not reported IV Lutzner et al, 1975
CVP 3 2 (67) 0 (0) Not reported T3 Molin et al, 1980; Raafat & Oster, 1980
CVP 16 8 (50) 4 (25) 12 IIB (4), III (1), IV (11) Tirelli et al, 1986
CVP ± TSEB 12 6 (50) 4 (33) Not reported III Hamminga et al, 1982
CBP 8 5 (63) 2 (25) Not reported Not reported Molin et al, 1987
CBP + retinoid 12 7 (58) 3 (25) Not reported Not reported Molin et al, 1987
CBP + retinoid 20 18 (90) 16 (80) 8 — Zachariae & Thestrup-Pedersen, 1987
CBP + retinoid + TF 10 8 (80) 8 (80) Not reported — Zachariae et al, 1987
CAVOP 5 4 (80) 1 (20) Not reported T3 Molin et al, 1980; Raafat & Oster, 1980
COP + BLM 12 11 (92) 2 (17) 11.5 II–IV Grozea et al, 1979; Lamberg et al, 1979
VICOP-B 25 a (84) (36) a 8.7 IIB and IV Fierro et al, 1997
EPOCH 15 12 (80) 4 (27) 8 IIB–IVB Akpek et al, 1999
Cyclophosphamide + VP-16 4 3 (75) 1 (25) 6 Various, majority T3 Molin et al, 1979
MBPE 11 8 (73) 1 (9) 6 II–IV Doberauer & Ohl, 1989
CAVE 52 47 (90) 20 (38) Not reported II–IV Kaye et al, 1989
TSEB + doxorubicin + cyclophosphamide 50 49 (98) 44 (88) Range 2–75 I (20); II (20); III (7); IV (3) Braverman et al, 1987
BAM 10 8 (80) 7 (70) 41 IIB–IVB Zakem et al, 1986

Abbreviations: BAM, bleomycin, adriamycin, and MTX; BLM, bleomycin; BVP, bleomycin, vinblastine, and prednisone; CAVE, cyclophosphamide, adriamycin, vincristine, and etoposide; CAVOP, cyclophosphamide, adriamycin, vincristine, VP-16, and prednisone; CBP, cyclophosphamide, bleomycin, and prednisone; COMP, cyclophosphamide, vincristine, MTX, and prednisone; COP/CVP, cyclophosphamide, vincristine, and prednisone; COPP, cyclophosphamide, vincristine, procarbazine, and prednisone; MBPE, MTX, bleomycin, prednisone, and etoposide; MOPP, meclorethamine, vincristine, procarbazine, and prednisone; TF, transfer factor; TSEB, total skin electron beam therapy.

a Includes a cohort of patients with pleomorphic lymphoma.





Introduction


Currently, no traditional chemotherapy agents are Food and Drug Administration (FDA) approved for the treatment of mycosis fungoides (MF) or Sézary syndrome (SS). Multiple chemotherapeutic treatments for MF and SS, such as systemic nitrogen mustard and multiagent chemotherapy regimens (eg, cyclophosphamide, adriamycin, vincristine, and prednisone [CHOP]), were initially used because of established activity in other non-Hodgkin lymphomas (NHLs) or Hodgkin lymphomas. Over time, specific treatments were reported by astute physicians to be particularly effective in MF/SS, such as the Winkelmann chlorambucil regimen. More recently, however, it has been recognized that some of these regimens, which are often characterized by significant immunosuppression and toxicity, are not more effective than agents described elsewhere in this issue (eg, interferons [IFNs]). Nevertheless, these other “chemotherapeutic” agents remain an important therapy option for some patients with MF/SS. This article describes those chemotherapeutic agents not discussed elsewhere in this issue with a review of the data supporting their use. Table 1 summarizes single-agent therapies in MF/SS and Table 2 summarizes multiagent chemotherapies. Readers are further referred to a comprehensive review on the treatments used for SS and MF by Olsen and colleagues for additional in-depth discussion of many of the agents discussed later.



Table 1

Summary of single-agent and combination chemotherapy studies in the treatment of mycosis fungoides or Sézary syndrome





































































































































































































































Agent(s) Response Rate (Responders/Total) Dosing Study
Fludarabine 2/5 25 mg/m 2 × 5 d, q3–4 wk Redman et al, 1992
6/31 18–25 mg/m 2 × 5 d, q4 wk Von Hoff et al, 1990
Fludarabine + ECP 7/27 MF; 6/17 SS 25 mg/m 2 × 5 d, q4 wk Quaglino et al, 2000
Fludarabine + IFN 18/35 25 mg/m 2 × 5 d q4 wk; 5 million units, TIW Foss et al, 1994
Fludarabine + cyclophosphamide 5/6 18 mg/m 2 × 3 d, q4wk; 250 mg/m 2 × 3 d, q4wk Scarisbrick et al, 2011
Cladribine 2/2 0.1 mg/kg × 7 d, q4wk Betticher et al, 1994
2/9 4 mg/m 2 × 7 d, q4wk O’Brien et al, 1994
9/22 0.1 mg/kg × 5–7 d, q4wk Kuzel et al, 1996
2/8 0.06 mg/kg × 5 d, q4wk Trautinger et al, 1999
Pentostatin 10/32 3.75–5 mg/m 2 × 3 d, q3wk Tsimberidou et al, 2004
4/8 5 mg/m 2 × 3 d, q3wk Cummings et al, 1991
7/18 Varied Greiner et al, 1997
5/22 MF; 7/21 SS 4 mg/m 2 q1–4wk Ho et al, 1999
4/6 MF; 10/14 SS 5 mg/m 2 × 3 d, q3wk ± 1.25 mg/m 2 on subsequent cycles Kurzrock et al, 1999
Pentostatin, cyclophosphamide, and bexarotene 5/5 MF; 2/3 SS 4 mg/m 2 q2wk; 600 mg/m 2 q2wk; 300 mg/m 2 qd × 8 mo Calderon Cabrera et al, 2013
Pentostatin + IFN 17/41 4 mg/m 2 × 3 d Foss et al, 1992
Gemcitabine 9/19 1200 mg/m 2 d 1, 8, 15, and 28 Zinzani et al, 2010
19/26 MF; 0/1 SS 1200 mg/m 2 d 1, 8, 15, and 28 Marchi et al, 2005
21/30 1000 mg/m 2 d 1, 8, and 15 Duvic et al, 2006
3/3 1000 mg/m 2 d 1, 8, and 15 then 250 mg/m 2 weekly Buhl et al, 2009
7/9 MF; 2/4 SS 1000 mg/m 2 d 1 and 8 of a 21-d cycle or d 1, 8, ± 15 of a 28-d cycle Jidar et al, 2009
Mechlorethamine 34/41 Varied Van Scott et al, 1975
Chlorambucil + prednisone 23/26 (all SS) 2–6 mg/d; 20 mg/d Winkelmann et al, 1984
6/6 2–6 mg/d; 5–20 mg/d Hamminga et al, 1979
Chlorambucil + fluocortolone 13/13 Clorambucil 10–12 mg/d × 3 d; fluocortolone 75 mg d 1, 50 mg d 2, 25 mg d 3 Coors & von den Driesch, 2000
Chlorambucil + prednisone + leukapheresis 11/11 4 mg/d; 20 mg/d; Leukapheresis 2–3 × per wk Winkelmann et al, 1984
Bendamustine 2/3 60–100 mg/m 2 Zaja et al, 2013
Cyclophsphamide 4/4 Varied: 200–700 mg/d Abele & Dobson, 1960
5/11 Varied: 50–300 mg/d Van Scott et al, 1962
TMZ 3/9 150 mg/m 2 /d × 5 d, q4wk, Then 200 mg/m 2 /d × 5 d q4wk Tani et al, 2005
7/26 200 mg/m 2 /d PO × 5 d q4wk Querfeld et al, 2011
Liposomal daunorubicin 3/3 20–40 mg/m 2 q3–4wk Wollina et al, 2003
Doxorubicin 7/13 60 mg/m 2 q3wk Levi et al, 1977
26/30 MF; 1/1 SS 20–40 mg/m 2 q2–4wk Wollina et al, 2003
3/10 20 mg/m 2 q4wk Di Lorenzo et al, 2005
12/13 MF; 1/3 SS; 20 mg/m 2 q4wk Pulini et al, 2007
6/10 MF; 3/5 SS 40 mg/m 2 q4wk Quereux et al, 2008
20/49 20 mg/m 2 q2wk Dummer et al, 2012
Doxorubicin + bexarotene 14/34 (Doxorubicin only); 7/15 (doxorubicin + bexarotene) Doxil 20 mg/m 2 q2wk; bexarotene 300 mg/m 2 /d Straus et al, 2014
Etoposide ± cyclophosphamide 2/5 (Etoposide only); 3/4 (etoposide + cyclophosphamide) 100 mg/m 2 IV × 5 d, q2–3wk ± cyclophosphamide Molin et al, 1979
IL-2 3/3 MF; 1/3 SS 20 million units/m 2 on d 1–5, 14–17, and 28–30 (induction) followed by 2 d/mo for 5 mo (consolidation) Baccard et al, 1997
5/7 20 million units/m 2 /d for 5, 4, and 3 d (wk 1, 3, and 5) followed by optional monthly maintenance × 5 d Gisselbrecht et al, 1994
4/22 20 million units/m 2 /d on d 1–4 × 6 wk in an 8-wk cycle Querfeld et al, 2007
IL-12 5/10 50, 100, or 300 ng/kg twice weekly, up to 24 wk Rook et al, 1999
10/23 100 ng/kg twice weekly × 2 wk then 300 mg/kg twice weekly through 24 wk Rook et al, 2001
Forodesine 9/13 40–320 mg/m 2 BID × 4 d in a 16-d cycle Lansigan & Foss, 2010
10/37 (MF/SS + other T-cell lymphomas) 40–320 mg/m 2 /d × 4 wk Duvic et al, 2006
11/101 200 mg daily (approximately 80 mg/m 2 ) Dummer et al, 2014
Bortezomib 7/10 1.3 mg/m 2 twice weekly × 2 wk in a 3-wk cycle Zinzani et al, 2007

Abbreviation: TIW, three times weekly.


Table 2

Combination chemotherapy used in the treatment of mycosis fungoides/Sézary syndrome




























































































































































































Therapy Regimen No. of Patients Complete Response + Partia Response, n (%) Complete Response, n (%) Median Duration of Response (mo) Stage Reference
MOPP/COPP + TSEB 21 19 (70) 11 (52) 14 I–III Hallahan et al, 1988; Bunn et al, 1994
BLM + MTX 10 9 (90) 1 (10) 6 T3 Groth et al, 1979
CHOP/HOP 12 10 (83) 5 (42) 5 II–IV Grozea et al, 1979; Lamberg et al, 1979
CHOP/COP 30 9 (30) 3 (10) 6 Not reported Fierro et al, 1998
CHOP 1 0 0 — T3 Molin et al, 1980; Raafat & Oster, 1980
CVP 4 3 (75) 1 (25) Not reported IV Lutzner et al, 1975
CVP 3 2 (67) 0 (0) Not reported T3 Molin et al, 1980; Raafat & Oster, 1980
CVP 16 8 (50) 4 (25) 12 IIB (4), III (1), IV (11) Tirelli et al, 1986
CVP ± TSEB 12 6 (50) 4 (33) Not reported III Hamminga et al, 1982
CBP 8 5 (63) 2 (25) Not reported Not reported Molin et al, 1987
CBP + retinoid 12 7 (58) 3 (25) Not reported Not reported Molin et al, 1987
CBP + retinoid 20 18 (90) 16 (80) 8 — Zachariae & Thestrup-Pedersen, 1987
CBP + retinoid + TF 10 8 (80) 8 (80) Not reported — Zachariae et al, 1987
CAVOP 5 4 (80) 1 (20) Not reported T3 Molin et al, 1980; Raafat & Oster, 1980
COP + BLM 12 11 (92) 2 (17) 11.5 II–IV Grozea et al, 1979; Lamberg et al, 1979
VICOP-B 25 a (84) (36) a 8.7 IIB and IV Fierro et al, 1997
EPOCH 15 12 (80) 4 (27) 8 IIB–IVB Akpek et al, 1999
Cyclophosphamide + VP-16 4 3 (75) 1 (25) 6 Various, majority T3 Molin et al, 1979
MBPE 11 8 (73) 1 (9) 6 II–IV Doberauer & Ohl, 1989
CAVE 52 47 (90) 20 (38) Not reported II–IV Kaye et al, 1989
TSEB + doxorubicin + cyclophosphamide 50 49 (98) 44 (88) Range 2–75 I (20); II (20); III (7); IV (3) Braverman et al, 1987
BAM 10 8 (80) 7 (70) 41 IIB–IVB Zakem et al, 1986

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Feb 12, 2018 | Posted by in Dermatology | Comments Off on Other Chemotherapeutic Agents in Cutaneous T-Cell Lymphoma

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