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. 2019 Jan 26;8(2):143. doi: 10.3390/jcm8020143

Table 1.

Summary profiles of clinical trials that reported capillary leak syndrome as an adverse event of anti-cancer drugs.

Ref. No. Author, Year of Publication Period of Study Country Total Number CLS Incidence (%) Diagnosis Drug Treatment Dose
IL-2
[12] Atkins et al., 1999 1985–1993 USA 270 92 34.1 Melanoma IL-2 720,000 IU/kg every 8 h
[13] Sparano et al., 1993 1988–1992 USA 44 40 90.9 Melanoma IL-2 6 × 106 IU/m2 every 8 h
[14] Tarhini et al., 2007 2000–2003 USA 26 7 26.9 Melanoma IL-2 600,000 IU/kg every 8 h for up to 14 doses for 2 cycles
[15] Talpur et al., 2012 2003–2008 USA 8 6 75.0 Cutaneous peripheral T-cell lymphoma IL-2 Dose level 18 μg/kg
[16] Gallagher et al, 2007 2006 Israel 14 14* 100.0 Melanoma, renal cell carcinoma IL-2 Dose level 8–14 μg/kg
[17] Shusterman et al., 2010 NA USA 39 12 30.8 Neuroblastoma IL-2 Dose level 12 mg/m2
[18] Shaughnessy et al., 2005 NA USA 2 1 50.0 Non-Hodgkin lymphoma, Hodgkin disease, acute leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, multiple myeloma, aplastic anemia IL-2 Dose level 9.0 μg/kg
[18] Shaughnessy et al., 2005 NA USA 20 2 10.0 Non-Hodgkin lymphoma, Hodgkin disease, acute leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, multiple myeloma, aplastic anemia IL-2 Dose level 4.5 μg/kg
[19] Frankel et al., 2003 NA USA 18 2 11.1 Chronic lymphocytic leukemia IL-2 Dose level 9 or 18 μg/kg
[20] Duvic et al., 2002 NA USA 71 18 25.4 Cutaneous T-cell lymphoma IL-2 Dose level 9 or 18 μg/kg
[21] Foss et al., 2001 NA USA 15 2 13.3 Cutaneous T-cell lymphoma IL-2 Dose level 9 or 18 μg/kg
[22] Sievers et al., 2000 NA USA 60 7 11.7 Acute myelogenous leukemia IL-2 9,000,000 IU/m2 for 4 days and 16,000,000 IU/m2 for 10 days
[23] Duvic et al., 1998 NA USA 4 1 25.0 Cutaneous T cell lymphoma IL-2 Dose level 9 or 18 μg/kg
[24] Meehan et al., 1997 1993–1995 USA 57 3 5.3 Breast cancer IL-2 MTD 6 × 106 IU/m2/day
[25] Chang et al., 1993 NA Japan 20 15 75.0 Melanoma, renal cell cancer IL-2 Using vaccine-primed lymph node cell with IL-2 (180,000 IU/kg)
[26] van Haelst Pisani C
et al., 1991		 NA France 5 4 80.0 Melanoma, renal cell cancer IL-2 Human recombinant IL-2 3 × 10⁶ IU/m²/24 h for 4 or 5 days
[27] Philip et al., 1989 1987–1988 France 20 8 40.0 Renal cell cancer IL-2 IL-2 3 × 10⁶ IU/m² with lymphapheresis(17), IL-2 3 × 10 ⁶IU/m²(3)
[28] Carey et al., 1997 NA UK 10 10* 100.0 Malignant melanoma, renal cell cancer IL-2 Using 3 × 10⁶ IU/m²/day for 5 days
IL-2 with other agents
[16] Gallagher et al., 2007 2006 Israel 4 4 100.0 Renal cell carcinoma IL-2
+ bevacizumab		 IL-2 dose level 9–14 μg/kg
[29] Pautier et al., 2013 NA France 3 0 0.0 Melanoma, ovarian adenocarcinoma, Merkel-cell carcinoma, gastrointestinal stromal tumor, rectal adenocarcinoma, cervical adenocarcinoma IL-2
+ imatinib mesylate		 IL-2: 3,000,000 IU/day, imatinib mesylate 400 mg/day
[29] Pautier et al., 2013 NA France 11 1 9.0 Melanoma, ovarian adenocarcinoma, Merkel-cell carcinoma, gastrointestinal stromal tumor, rectal adenocarcinoma, cervical adenocarcinoma IL-2
+ imatinib mesylate		 IL-2: 6,000,000 IU/day, imatinib mesylate 400 mg/day
[29] Pautier et al., 2013 NA France 3 1 33.3 Melanoma, ovarian adenocarcinoma, Merkel-cell carcinoma, gastrointestinal stromal tumor, rectal adenocarcinoma, cervical adenocarcinoma IL-2
+ imatinib mesylate		 IL-2: 9,000,000 IU/day, imatinib mesylate 400 mg/day
[30] O’Brien et al., 2006 NA Ireland 10 0 0.0 Melanoma IL-2
+ taurolidine		 IL-2 72 MIU/m2 for 120 h
Taurolidine 2% w/v via continuous infusion
[31] Pichert et al., 1991 1988–1989 Switzerland 14 14* 100.0 Renal cell carcinoma, melanoma IL-2
+ IFN-alfa 2a		 IL-2 3 MIU/m2 for 4 days
IFN-alpha 6 MIU/m2 for 2 days (1, 4 day)
[13] Sparano et al., 1993 1988–1992 USA 41 33 80.5 Melanoma IL-2
+ IFN-alfa		 IL-2 4.5 × 106 IU/m2 per dose
IFN-alpha 2 4.5 × 106 IU/m2
[32] Gilman et al., 2009 1997–2002 USA 19 3 15.8 Neuroblastoma IL-2 + ch14.18 Ch14.18 20 and 40 mg/m2/day
IL-2 4.5 × 106 IU/m2/day
[33] Meehan et al., 2010 NA USA 12 2 16.7 Multiple myeloma, non-Hodgkin
lymphoma		 IL-2 + GM-CSF + G-CSF IL-2 6 × 105–1.5 × 106 IU/m2
G-CSF 5 μg/kg
GM-CSF 7.5 μg/kg
[34] Yu et al., 2010 2001–2009 USA 226 51 22.6 Neuroblastoma IL-2
+ GM-CSF
+ anti-GD2
+ isotretionoin		 IL-2 3.0 × 106 IU/m2 (week 1), 4.5 × 106 IU/m2 (week 2)
GM-CSF 250 μg/m2
isotretionoin 160mg/m2
[35] Hamblin et al., 1993 1988–1989 UK 16 1 6.3 Metastatic colorectal cancer IL-2 + 5-FU IL-2 18 × 10 IU/m2/day over 120 h
5FU 600 mg/m2
[36] Savage et al., 1997 NA UK 24 6 25.0 Metastatic renal cancer IL-2 + 5-FU IL-2 9 × 106 IU
5-FU 200 mg/m2
IL-1 with other agents
[37] Smith et al., 1993 1990–1992 USA 15 6 40.0 Colon cancer, melanoma, renal cell cancer, lung cancer, pancreatic cancer, liposarcoma, adenocarcinoma with unknown primary site IL-1 alpha + carboplatin IL-1 alpha 0.03, 0.1, 0.3 μg/kg
carboplatin 800 mg/m2
[38] Worth et al., 1997 1994 USA 9 4 44.4 Osteosarcoma IL-1 alpha + etoposide IL-1 alpha 0.1 μg/kg
etoposide 100 mg/m2
IL-4
[39] Sosman et al., 1994 NA USA 17 2 11.8 Renal cell carcinoma, melanoma, colon carcinoma, cholangiocarcinoma IL-4+IL-2 IL-4 40–600 μg /m2/day
IL-2 11.2 MIU/m2/day
GM-CSF
[40] Gorin et al., 1992 1988–1990 France 44 3 6.8 Non-Hodgkin lymphoma GM-CSF Dose level 250 μg/m2
[41] Liberati et al., 1991 NA Italy 14 1 7.1 Non-Hodgkin lymphoma GM-CSF Dose level 5 μg/kg
[42] Steward et al., 1989 NA USA &UK 20 3 15.0 Metastatic solid tumors GM-CSF Using dose 0.3, 1.0, 3.0, 10, 30, and 60 μg/kg/day
Dose level 32 μg /kg
Gemcitabine
[43] Jidar et al., 2009 NA France 23 1 4.3 Cutaneous T-cell lymphoma Gemcitabine Using dose 700–1000 mg/m2
[44] Kurosaki et al., 2009 2003–2006 Japan 27 1 3.7 Pancreatic cancer Gemcitabine Dose level 1000 mg/m2 biweekly
[45] Dumontet et al., 2001 1988–2000 France 36 1 2.8 Non-Hodgkin lymphoma Gemcitabine Dose level 1 g/m2
SS1P
[46] Kreitman et al., 2009 NA USA 24 13 54.2 Peritoneal mesothelioma, pleural mesothelioma, pleural–peritoneal mesothelioma, ovarian carcinoma, pancreatic carcinoma SS1P Dose level 4–25 μg/kg
[47] Hassan et al., 2007 2000–2006 USA 34 2 5.9 Peritoneal mesothelioma, pleural mesothelioma, pleural–peritoneal mesothelioma, ovarian carcinoma, pancreatic carcinoma SS1P Dose level 18 or 25 μg/kg
Anti-CD agents
[48] Sausville et al., 1995 NA USA 11 4 36.4 B-cell lymphoma Anti-CD22 Dose level 28.8 mg/m2
MTD 19.2 mg/m2
[49] Vitetta et al., 1991 NA USA 15 15* 100.0 B-cell lymphoma Anti-CD22 Using dose 12.5, 25, 50, 75, 100 mg/m2
[50] Wayne et al., 2014 NA USA 7 2 28.6 Acute lymphoblastic leukemia Anti-CD22 Dose level 30 μg/kg
[51] Amlot et al., 1993 NA USA 26 3 11.5 B-cell lymphoma Anti-CD22 Using Maximal single dose 2.5–13.9 mg/m2
[52] Stathis et al., 2014 NA Switzerland 5 1 20.0 Non-Hodgkin lymphoma Anti-CD22 + temsirolimus Using dose Anti-CD22 0.8 mg/m2 + temsirolimus 15 mg/day,
Anti-CD22 0.8 mg/m2 + temsirolimus 10 mg/day
[53] Schindler et al., 2011 NA USA 17 1 5.9 B-cell acute lymphoblastic leukemia Anti-CD19 + anti-CD22 Dose level 8 mg/m2
[54] Bachanova et al., 2015 NA USA 25 7 28.0 Pre-B acute lymphoblastic leukemia, chronic lymphocytic leukemia, Non-Hodgkin lymphoma Anti-CD19 + anti-CD22 Dose level 40–60 μg/kg
[55] Schnell et al., 2003 NA Germany 27 3 11.1 Hodgkin lymphoma Anti-CD25 Dose level 15–20 mg/m2
[56] Schnell et al., 2000 NA Germany 18 18* 100.0 Hodgkin lymphoma Anti-CD25 Dose level 15 mg/m2/cycle
[57] Engert et al., 1997 NA Germany 15 1 6.7 Hodgkin lymphoma Anti-CD25 Dose level 5 mg/m2(3), 10 mg/m2(3), 15 mg/m2(6), 20 mg/m2(3)
[58] Schnell et al., 2002 NA Germany 17 3 17.6 Hodgkin lymphoma, Non-Hodgkin lymphoma Anti-CD30 Dose level 7.5 mg/m2(1), 10 mg/m2(2)
MTD 5 mg/m2
[59] Stone et al., 1996 NA USA 23 16 69.6 Non-Hodgkin lymphoma Anti-CD19
+ IgG-HD37-dgA		 MTD 19.2 mg/m2
[60] Uckun et al., 1999 1996–1998 USA 15 1 6.7 Acute lymphoblastic leukemia, chronic lymphocytic leukemia CD19 receptor directed tyrosine kinase inhibitor B43-Genistein Dose level 0.1 mg/kg
Other agents
[61] Baluna et al., 1996 NA USA 56 12 21.4 Non-Hodgkin lymphoma Ricin A chain-containing immunotoxin Using IgG-HD37-RTA continuous infusion 9.6–19.2 mg/m2(2), bolus infusion range 2–24 mg/m2(2)
IgG-RFB4-RTA continuous infusion 9.6–28.8 mg/m2(4), bolus infusion 23–48 mg/m2(2)
Fab’-RFB4-RTA bolus infusion 25–100 mg/m2(2)
[62] Borghaei et al., 2009 NA USA 39 6 15.4 NSCLC, pancreatic cancer ABR-217620 Dose level 20 μg/kg
[63] Hochhauser et al., 2009 2004–2006 UK 16 10 62.5 Ampulla of vater cancer, cholangiocarcinoma, colorectal cancer, lung cancer, esophagus cancer, pancreatic cancer, sarcoma, malignant melanoma, stomach cancer Pyrrolobenzodiazepine Using dose 15–240 μg/m2
[64] Posey et al., 2002 NA USA 46 1 2.2 Colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, head and neck cancer, stomach cancer, endometrial cancer, thyroid cancer, unknown primary lesion SGN-10
(or BR96 sFv-PE40)		 Dose level > or = 0.384 mg/m2
[65] Elias et al., 2001 NA USA 5 4 80.0 Breast cancer Paclitaxel Dose level 150 mg/m2
[66] Grossbard et al., 1993 1990–1991 USA 12 5 41.7 Non-Hodgkin lymphoma Anti-B4-bR Using dose 20, 40, 50 μg/kg/day for 7 days
MTD 40 μg/kg
[67] Pazdur et al., 1991 NA USA 17 6 35.3 Metastatic cancer FK973 Using dose 30 mg/m2(2), 45 mg/m2(4)
[68] Barrett et al., 1982 1980–1981 UK 36 4 11.1 Acute myeloid leukemia, acute lymphoblastic leukemia, aplastic anemia, mucopolysaccharidosis, metachromic leukodystrophy Dihydro benzoxazine Using dose 12.5 mg/kg(10), 500 g/m2(26)
[69] Zwaan et al., 2014 NA Multicenter in Europe† 36 3 8.3 Acute myeloid leukemia Cyclosporine Using dose plasma concentration <100 μg/L
[69] Zwaan et al., 2014 NA Multicenter in Europe† 29 1 3.4 Acute myeloid leukemia Clofarabine
+ cytarabine
+ liposomal daunorubicin		 Clofarabine 20, 30, 40 mg/m2
Ara-C 2 g/m2/day
dauorubicin 40–60 mg/m2

NA: not available (information was not included in the case series article), CLS: capillary leak syndrome, Using dose: drug dose that was administered to patients, Dose level: serum drug level when the patients show toxicity, DLT: dose limited toxicity, IL: Interleukin, w/v: weight/volume percentage, ch14.18: a chimeric human/murine anti-GD2 antibody, MIU: million international units, GVHD: graft-versus-host disease, INF: interferon, GM-CSF: granulocyte-macrophage colony-stimulating factor, G-CSF: granulocyte-colony stimulating factor, 5-FU: 5-fluorouracil, SS1P: recombinant anti-mesothelin immunotoxin, CD: cluster of differentiation, MTD: maximum tolerated dose, NSCLC: Non small cell lung cancer, ABR-217620: naptumomab estafenatox, SGN-10: a single-chain immunotoxin, Anti-B4-bR: B-cell restricted immunotoxin anti-B4-blocked ricin, FK973: novel, substituted dihydro benzoxazine structurally similar to mitomycin, USA: United States of America, UK: United Kindom; *All study patients developed capillary leak syndrome after receiving anti-cancer agents. There were no capillary leak syndrome features before treatment. † Study population was collected from multiple centers in Europe: Netherlands, Austria, Germany, France, the Czech Republic, and the United Kingdom.