Clinically significant responses achieved with romidepsin across disease compartments in patients with cutaneous T-cell lymphoma

Figures & data

Table I. Objective primary disease response evaluation criteria.*

Complete response	• Complete resolution of skin patches, plaques and tumors (or erythroderma) • No evidence of abnormal lymph nodes • Absence of circulating Sézary cells • No evidence of new tumors (cutaneous or non-cutaneous) • Requires confirmation by skin biopsy
Partial response	•≥ 50% improvement in the composite end point (Δ skin^† + Δ lymph node^‡ + Δ peripheral blood^§) with ≥ 30% improvement in skin • No worsening in lymph nodes or circulating Sézary cells • No evidence of new tumors (cutaneous or non-cutaneous)
Stable disease	• Patients who do not have enough improvement or worsening to qualify for PR or PD, respectively
Progressive disease	•> 25% worsening in composite end point (Δ skin^† + Δ lymph node^‡ + Δ peripheral blood^§) with > 15% worsening in skin, or • Evidence of new tumors (cutaneous or non-cutaneous)

CT, computed tomography; MRI, magnetic resonance imaging; PD, progressive disease; PR, partial response.

*Confirmed responses must be repeated at least 1 month after initial assessment.

^†Δ skin = percentage change in total score from baseline of weighted body surface area (patients without erythroderma) or erythroderma scale (patients with erythroderma).

^‡Δ lymph node = percentage change in size of abnormal lymph nodes (sum of longest diameter) from baseline based on physical examination and/or CT/MRI.

^§Δ peripheral blood = percentage change in absolute number of circulating malignant T-cells (Sézary cells) from baseline.

Table II. Demographics and baseline characteristics.

	All patients (n = 96)	Only skin involvement (n = 25)*	Erythroderma (n = 40)	Lymphadenopathy (n = 55)^†	Blood involvement (n = 37)^‡	Higher blood tumor burden (n = 13)^§
Male sex, n (%)	59 (62)	18 (72)	21 (53)	27 (49)**	22 (60)	4 (31)**
Age in years, mean (SD)	56.9 (12)	58.9 (11)	59.6 (14)	56.5 (13)	57 (13)	58 (17)
ECOG PS, n (%)
0	49 (51)	15 (60)	18 (45)	22 (40)**	21 (57)	5 (39)
1	47 (49)	10 (40)	22 (55)	33 (60)**	16 (43)	8 (62)
Disease stage at study entry^¶, n (%)
IB	15 (16)	10 (40)**	1 (3)**	1 (2)**	4 (11)	0**
IIA	13 (14)	4 (16)**	1 (3)**	7 (13)**	4 (11)	0**
IIB	21 (22)	6 (24)**	0**	8 (15)**	8 (22)	0**
III	23 (24)	5 (20)**	21 (53)**	16 (29)**	9 (24)	5 (39)**
IVA	24 (25)	0**	17 (43)**	23 (42)**	12 (32)	8 (62)
Prior no. of systemic therapies, median (range)	2 (1–8)	3 (1–7)	2 (1–6)	2 (1–8)	3 (1–8)	3 (1–6)**
Chemotherapy, n (%)	73 (76)	21 (84)	27 (68)	40 (73)	24 (65)	7 (54)
Bexarotene, n (%)	32 (33)	8 (32)	14 (35)	17 (31)	17 (46)**	7 (54)
Immunotherapy, n (%)	36 (38)	7 (28)	15 (38)	23 (42)	18 (49)	7 (54)
Steroids, n (%)	13 (14)	6 (24)	4 (10)	6 (11)	2 (5)	0
Denileukin diftitox, n (%)	14 (15)	3 (12)	4 (10)	8 (15)	5 (14)	1 (8)
Photopheresis, n (%)	18 (19)	0**	11 (28)	12 (22)	14 (38)**	5 (39)

SD, standard deviation; ECOG PS, Eastern Cooperative Oncology Group performance status.

*Patients without definitive lymphadenopathy and blood involvement.

^†Patients with ≥ 1 lymph node ≥ 1.5 cm by conventional measurements or ≥ 1.0 cm by spiral computed tomography scan.

^‡Sézary cells > 5% of lymphocytes.

^§Sézary cell counts > 1000 cells/μL and/or Sézary cells > 20% of lymphocytes.

^¶American Joint Committee on Cancer staging system used at the time of this study was not impacted by blood involvement.

**Indicates significantly different (p ≤ 0.05) distribution from the alternative category: patients with or without only skin involvement, erythroderma, lymphadenopathy, blood involvement or higher blood tumor burden.

Table III. Composite responses.

	All patients (n = 96)	Only skin involvement (n = 25)*	Erythroderma (n = 40)	Lymphadenopathy (n = 55)^†	Blood involvement (n = 37)^‡	Higher blood tumor burden (n = 13)^§
ORR, n (%)	33 (34)	10 (40)	14 (35)	15 (27)	12 (32)	4 (31)
CR, n (%)	6 (6)	2 (8)	2 (5)	2 (4)	2 (5)	0
PR, n (%)	27 (28)	8 (32)	12 (30)	13 (24)	10 (27)	4 (31)
Time to response in months, median (range)	1.9 (0.9–4.8)	2.1 (0.9–3.0)	1.9 (1.0–4.8)	1.9 (1.0–4.8)	1.9 (1.0–4.8)	1.2 (1.0–4.8)
Duration of response in months, median (range)	15.0 (< 0.1++19.8+)	15.0 (1.9++18.7+)	15.0 (< 0.1++15.0)	NE (< 0.1++9.2+)	NE (1.6++19.8+)	NE (3.6++8.6+)

ORR, objective response rate; CR, complete response; PR, partial response; NE, not evaluable (rate of response ending did not reach 50%).

*Patients without definitive lymphadenopathy and blood involvement.

^†Patients with ≥ 1 lymph node ≥ 1.5 cm by conventional measurements or ≥ 1.0 cm by spiral computed tomography scan.

^‡Sézary cells > 5% of lymphocytes.

^§Sézary cell counts > 1000 cells/μL and/or Sézary cells > 20% of lymphocytes.

Table IV. Responses by compartment.

	Skin response		Lymph node response in patients with baseline lymphadenopathy (n = 55)*	Blood response
	Patients without erythroderma (n = 56)	Patients with baseline erythroderma (n = 40)		Patients with blood involvement (n = 37)^†	Patients with higher blood tumor burden (n = 13)^‡
ORR, n (%)	23 (41)	15 (38)	18 (33)	21 (57)	7 (54)
CR, n (%)	4 (7)	4 (10)	4 (7)	3 (8)	1 (8)
PR, n (%)	19 (34)	11 (28)	14 (25)	18 (49)	6 (46)
Time to response in months, median (range)	1.9 (0.9–6.5)	1.9 (1.0–6.2)	1.9 (1.0–5.6)	1.1 (0.9–7.6)	3 (1.0–7.6)
Duration of response in months, median (range)	NE (< 0.1+–18.7+)	8.1 (< 0.1+–11.5)	2.6 (< 0.1+–4.3)	3.8 (< 0.1+–13.2)	NE (< 0.1+–5.8+)

ORR, objective response rate; CR, complete response; PR, partial response; NE, not evaluable.

*Patients with ≥ 1 lymph node ≥ 1.5 cm by conventional measurements or ≥ 1.0 cm by spiral computed tomography scan.

^†Sézary cells > 5% of lymphocytes.

^‡Sézary cell counts > 1000 cells/μL and/or Sézary cells > 20% of lymphocytes.

Table V. Most common (> 10%) drug-related (possibly, probably or definitely related) treatment-emergent adverse events.

	All patients (n = 96)	Only skin involvement (n = 25)*	Erythroderma (n = 40)	Lymphadenopathy (n = 55)^†	Blood involvement (n = 37)^‡	Higher blood tumor burden (n = 13)^§
Nausea	54 (56)	14 (56)	19 (48)	31 (56)	22 (60)	6 (46)
Asthenic conditions^¶	43 (45)	12 (48)	14 (35)	24 (44)	16 (43)	6 (46)
Vomiting NOS	27 (28)	7 (28)	8 (20)	15 (27)	11 (30)	4 (31)
Anorexia	19 (20)	6 (24)	4 (10)	9 (16)	8 (22)	2 (15)
Thrombocytopenia^††	14 (15)	5 (20)	4 (10)	7 (13)	4 (11)	1 (8)
Diarrhea NOS	13 (14)	2 (8)	6 (15)	6 (11)	10 (27)**	6 (46)**
Headache	13 (14)	3 (12)	3 (8)	8 (15)	5 (14)	2 (15)
Ageusia	12 (13)	2 (8)	3 (8)	9 (16)	5 (14)	1 (8)
Dysgeusia	11 (12)	2 (8)	3 (8)	4 (7)	9 (24)**	3 (23)
Anemia^‡‡	10 (10)	1 (4)	5 (13)	8 (15)	4 (11)	1 (8)

NOS, not otherwise specified; MedDRA, medical dictionary for regulatory activities.

*Patients without definitive lymphadenopathy and blood involvement.

^†Patients with ≥ 1 lymph node ≥ 1.5 cm by conventional measurements or ≥ 1.0 cm by spiral computed tomography scan.

^‡Sézary cells > 5% of lymphocytes.

^§Sézary cell counts > 1000 cells/μL and/or Sézary cells > 20% of lymphocytes.

¶Includes the MedDRA preferred terms asthenia, fatigue, lethargy and malaise.

**Indicates significantly different (p ≤ 0.05) distribution from the alternative category: patients with or without only skin involvement, erythroderma, lymphadenopathy, blood involvement or higher blood tumor burden.

^††Includes the MedDRA preferred terms thrombocytopenia and platelet count decreased.

^‡‡Includes the MedDRA preferred terms anemia NOS, hemoglobin decreased and red blood cell count decreased.

Table VI. Pruritus at baseline and changes in pruritus visual analog scale.

	All patients (n = 96)	Only skin involvement (n = 25)*	Erythroderma (n = 40)	Lymphadenopathy (n = 55)^†	Blood involvement (n = 37)^‡	Higher blood tumor burden (n = 13)^§
Patients with at least moderately severe pruritus at baseline^¶
n	65	18	30	39	24	9
Baseline VAS, mean (SD)	68.5 (21.0)	67.9 (22.2)	78.6 (18.0)**	69.9 (20.4)	67.7 (18.7)	75.1 (19.0)
Best change in VAS, mean (SD)	−38.4 (27.8)	−43.1 (23.8)	−40.0 (32.8)	−33.9 (30.8)**	−36.3 (27.1)	−37.9 (30.8)
CMRP	28 (43.1)	10 (55.6)	12 (40.0)	11 (28.2)**	10 (41.7)	3 (33.3)
Patients with severe pruritus at baseline^††
n	36	11	22	22	12	7
Baseline VAS, mean (SD)	84.5 (10.7)	82.9 (9.4)	87.5 (10.2)**	84.7 (11.5)	83.7 (9.7)	83.7 (9.1)
Best change in VAS, mean (SD)	−48.9 (27.9)	−52.8 (22.0)	−47.9 (33.4)	−45.9 (31.7)	−48.6 (26.4)	−44.9 (31.8)
CMRP	19 (52.8)	8 (72.7)	11 (50.0)	9 (40.9)	5 (41.7)	3 (42.9)

VAS, visual analog scale; SD, standard deviation; CMRP, clinically meaningful reduction in pruritus (defined as a decrease in VAS score of ≥ 30 for ≥ 2 consecutive cycles for patients with moderate-to-severe pruritus at baseline).

*Patients without definitive lymphadenopathy and blood involvement.

^†Patients with ≥ 1 lymph node ≥ 1.5 cm by conventional measurements or ≥ 1.0 cm by spiral computed tomography scan.

^‡Sézary cells > 5% of lymphocytes.

^§Sézary cell counts > 1000 cells/μL and/or Sézary cells > 20% of lymphocytes.

^¶Baseline score of ≥ 30 mm.

**Indicates significantly different (p ≤ 0.05) distribution from the alternative category: patients with or without only skin involvement, erythroderma, lymphadenopathy, blood involvement or higher blood tumor burden.

^††Baseline score of ≥ 70mm.

Table VII. Consensus guidelines from the ISCL, USCLC and Cutaneous Lymphoma Task Force of the EORTC [14].

Response in skin (based on modified SWAT score)
CR	• 100% clearance of skin lesions*
PR	• 50–99% clearance of skin disease from baseline and no new tumors in patients without tumors at baseline
SD	•< 25% increase to < 50% clearance in skin disease from baseline and no new tumors in patients without tumors at baseline
PD	• ≥ 25% increase in skin disease from baseline or • New tumors in patients without tumors at baseline or • Loss of response in those with CR or PR, increase of skin score of > sum of nadir + 50% baseline score
Relapse	• Any disease recurrence in those with CR

Response in lymph nodes (peripheral and central)
CR	• All lymph nodes ≤ 1.5 cm in greatest transverse diameter (major axis) by method used at baseline or biopsy negative for lymphoma • Lymph nodes that were clinically abnormal with histopathology Dutch grade 3/4 or NCI LN4 with major axis ≤ 1.5 cm or minor axis > 1.0 cm at baseline must now have minor axis ≤ 1.0 cm or biopsy negative for lymphoma
PR	• Cumulative reduction of ≥ 50% of the sum of the SPD of each abnormal lymph node at baseline and no new lymph node with major axis > 1.5 cm or minor axis > 1.0 cm if the major axis is 1.0–1.5 cm
SD	• Fails to attain the criteria for CR, PR and PD
PD	• ≥ 50% increase in SPD from baseline or • Any new node with major axis > 1.5 cm of minor axis > 1.0 cm or major axis 1.0–1.5 cm if proven to be clinically abnormal with histopathology Dutch grade 3/4 or NCI LN4 or • Loss of response: > 50% increase from nadir in SPD or lymph nodes in those with PR
Relapse	• Any new lymph node with major axis > 1.5 cm in those with CR proven to be N3 (clinically abnormal with histopathology Dutch grade 3/4 or NCI LN4)

Response in blood (based on absolute numbers of Sézary cells per μL)
CR	• ≤ 5% of peripheral blood lymphocytes are Sézary cells^†
PR	• > 50% decrease in quantitative measurements of blood tumor burden from baseline in those with high tumor burden at baseline^‡
SD	• Fails to attain criteria for CR, PR or PD
PD	•≤ 5% of peripheral blood lymphocytes are Sézary cells at baseline to high tumor burden^‡ or • > 50% increase from baseline and ≥ 5000 Sézary cells/μL or • Loss of response: in those with PR, > 50% increase from nadir and ≥ 5000 Sézary cells/μL
Relapse	• Increase of Sézary cells to > 5% of peripheral blood lymphocytes in those with CR

Response in viscera
CR	• Liver, spleen or any other organ involved at baseline not enlarged on physical exam and considered normal by imaging (no liver or spleen nodules, any post-treatment mass biopsy-negative for lymphoma)
PR	•≥ 50% regression in SPD in splenic nodules, liver nodules or measurable disease in any organs abnormal at baseline • No increase in size of liver or spleen and no new sites of involvement
SD	• Fails to attain the criteria for CR, PR or PD
PD	• > 50% increase in SPD of any organs involved at baseline, or • New organ involvement, or • Loss of response: > 50% increase from nadir in SPD of any previous organ involvement in those with PR
Relapse	• New organ involvement in those with CR

Global response score (based on above compartment scores)
CR	• Skin: CR; lymph nodes/blood/viscera: all CR/NI
PR	• Skin: CR or PR; lymph nodes/blood/viscera: none with PD, if PR in skin ≥ 1 involved at baseline with PR or CR
SD	• Skin: PR; lymph nodes/blood/viscera: none with PD, SD for all involved at baseline
PD	• PD in any compartment (skin/lymph nodes/blood/viscera) or SD in skin
Relapse	• Relapse in any category

ISCL, International Society for Cutaneous Lymphoma; USCLC, United States Cutaneous Lymphoma Consortium; EORTC, European Organisation of Research and Treatment of Cancer; SWAT, Severity-Weighted Assessment Tool; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NCI, National Cancer Institute; SPD, sum of the major axis × minor axis; NI, not involved.

*Skin biopsy is unnecessary for normal appearing skin, but should be performed in representative area if there is any question of residual disease (persistent erythema or pigmentary change) where otherwise a complete response would exist. If histologic features are suspicious or suggestive of mycosis fungoides or Sézary syndrome response should be considered PR.

^†If bone marrow biopsy at baseline unequivocally indicated lymphamatous involvement, a repeat bone marrow biopsy must show no residual disease or the response should be considered PR.

^‡≥ 1000 Sézary cells/μL with positive clone matching that of the skin; one of the following can be substituted for Sézary cells: CD4/CD8≥10, CD4+CD7− cells ≥ 40% or CD4 + CD26− cells ≥ 30%.

Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011;29:2598–2607.

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