VOLUME
33
䡠
NUMBER
2
䡠
JANUARY
10
2015
JOURNAL OF CLINICAL ONCOLOGY
Myelodysplastic Syndrome Successfully Treated With Adalimumab Case Report A 60-year-old male was referred in September 2009 with mild macrocytic anemia and thrombocytopenia. Past medical history was remarkable for Crohn’s disease treated with colectomy and colostomy, and the patient was on no active therapy at the time. At the time of presentation, the patient’s hemoglobin was 107 g/L, MCV was 106 fL, and platelet count was 25 ⫻ 109/L. His WBC was 6.3 ⫻109/L with an absolute neutrophil count of 4.5 ⫻ 109/L. Work-up for secondary nutritional, metabolic, hemolytic, infectious, and toxic causes was negative. A bone marrow aspirate and biopsy revealed evidence of dyserythropoiesis (⬎ 10% cells; left arrow), dysmegakaryopoiesis (⬎ 10% cells) and hypolobated neutrophils (right arrow), as seen in Figure 1. There were no ring sideroblasts, blasts were 2%, and the karyotype 46XY. He was diagnosed with myelodysplastic syndrome (MDS), WHO subtype refractory cytopenias with multilineage dysplasia. The patient achieved a hematologic improvement-erythroid according to International Working Group (IWG) 2006 criteria1 on darbepoetin 500 mcg every 2 weeks, with an increase of hemoglobin from 107 g/L to 123 g/L. His platelet counts remained low, generally less than 20 ⫻ 109/L; thus, he was entered into a randomized doubleblind romiplostim clinical trial 1 year postdiagnosis while continuing on darbepoetin.2 A repeat bone marrow aspirate and biopsy at the time of study entry revealed cytogenetic progression with a new trisomy 21 mutation. On study, his platelet count increased from 18 ⫻ 109/L to 42 ⫻ 109/L. Because of safety concerns, the therapy was halted early, and he was taken off study 1 year later. Interestingly, his hemo-
Fig 1. e4
© 2014 by American Society of Clinical Oncology
D I A G N O S I S
I N
O N C O L O G Y
globin levels progressively improved through this time, and his darbepoetin requirements declined to 300 mcg every 4 weeks. Six months after study discontinuation he was able to stop the erythropoietic stimulating agent (ESA), maintaining a hemoglobin of 130 g/L. However, his platelet counts remained in the 40 to 50 ⫻ 109/L range (Fig 2). Two months after discontinuing darbepoetin, he was started on adalimumab, an anti–tumor necrosis factor alpha (TNF␣) antibody, for his recurrently symptomatic Crohn’s disease (diarrhea and pain), at 40 mg subcutaneously every 2 weeks. He tolerated the medication well with excellent control of his Crohn’s disease symptoms. During the next 6 months, his platelet counts slowly increased. When seen in follow-up in the hematology clinic 6 months later, his platelet count had essentially normalized at 144 ⫻ 109/L with a hemoglobin of 143 g/L. One year post-start of adalimumab, his hemoglobin is 141 g/L with an MCV of 104 fL, his platelets are 248 ⫻ 109/L, and his WBC is 5.1 ⫻ 109/L. He remains on treatment with adalimumab, with normal blood counts and stable Crohn’s disease. Discussion MDSs are common hematologic disorders in adults and may affect as many as two in 1,000 anemic people over the age of 65.3 They are characterized by ineffective hematopoiesis and peripheral blood cytopenias. Genomic instability of the MDS clone often leads to disease progression and overt leukemia. Although azacitidine and lenalidomide are approved treatments for particular subsets of patients with this disease, there is still a paucity of treatments for lower-risk patients. We believe this case highlights two important findings: one, the potential nonmegakaryocytic hematologic benefits of thrombomimetic agents, and two, the benefit of TNF-␣ blockage in MDS. While on and even after the thrombopoietin (TPO)-receptor agonist romiplostim, our patient was able to discontinue the ESA before starting the adalimumab, with normalization of his hemoglobin level. His erythropoietic response was more likely due to romiplostim and not just continued darbepoetin. Given that ESAs are not diseasemodifying treatments in MDS, erythropoietic responses are not typically durable once they are discontinued, but this was not the case in our patient.4 Trilineage hematologic responses have been observed on romiplostim,2 and some anticlonal activity was observed with eltrombopag beyond simply the expected platelet improvements.5 In aplastic anemia, eltrombopag has been observed to induce improvements in both hemoglobin levels (in 24%, with half of those becoming transfusion independent) and neutrophil responses in 36% of patients. Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response.6 These findings suggest that TPO agonists may stimulate hematopoiesis at the level of primitive hematopoietic cells, consistent with the results of previous lab studies.7 One mechanism of ineffective hematopoiesis in early MDS may be the increased apoptosis of hematopoietic cells induced by cytokines. TNF-␣ is a pro-inflammatory cytokine that acts as a potent inhibitor of normal hematopoiesis through increased apoptosis.8 A number of studies9-11 have suggested the dysregulation of TNF-␣ and Journal of Clinical Oncology, Vol 33, No 2 (January 10), 2015: pp e4-e6
Downloaded from jco.ascopubs.org on April 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
160
300
140
Darbepoetin stopped
Darbepoetin 500 mcg every 2 weeks
200
150
130
120
150 Adalimumab started
110 100 Romiplostim study stopped
Hemoglobin Level (g/L)
Platelet Count (×109/L)
250
Darbepoetin decreased to 300 mcg every 3 weeks Darbepoetin decreased to 300 mcg every 4 weeks Darbepoetin 500 mcg every 3 weeks
100 Romiplostim study entry
50 90 Platelets Hemoglobin
80
0 0
3
5
6
7
8
9
13
14
20
24
26
27
28
29
32
38
Time Since Diagnosis (months) Platelets Hemoglobin
25 25 18 21 23 28 32 42 33 47 39 39 53 86 99 144 248 107 107 123 118 124 114 120 132 138 132 126 129 125 127 129 143 141
Fig 2.
related proteins Fas and Fas-Ligand in MDS hematopoietic precursors and have explored its role in the pathophysiology of the disease. Gersuk et al12 demonstrated that TNF-␣, Fas and Fas-Ligand were significantly dysregulated in the marrow of 44 patients with MDS, with higher elevations of TNF-␣ observed in the WHO category of refractory anemia compared with histologies of excess blasts. In vitro, marrow cultures treated with Fas or TNF-␣ blockade showed significant increases in numbers of hematopoietic colonies compared with untreated cells. This provided preliminary evidence for the potential benefit of TNF-␣ blockade as a therapeutic intervention. Clinical studies have shown that TNF-␣ inhibition with etanercept (recombinant soluble TNF receptor) and infliximab (a chimeric human/murine antibody to TNF-␣) may have activity in MDS. Initial early clinical studies with etanercept as monotherapy showed evidence of trilineage responses with modest response rates of 0% to 33%.13-15 The combination of antithymocyte globulin (ATG) and etanercept was studied in 25 low-risk patients with MDS, yielding a response rate of 56% by the 2006 IWG criteria.1,16 This rate is higher than the published response rates of ATG alone, which range between 26% and 42%, but similar to the combination of ATG and cyclosporine with response rates of 48%.17-19 Scott et al also tested the combination of etanercept with azacitidine in patients with higher-risk MDS/chronic myelomonocytic leukemia, either intermediate-2/high risk by the International Prognostic Scoring System, or low/intermediate-1 disease with cytopenias. They reported an overall response rate of 72% by 2000 IWG criteria, with a median duration of response not reached at 2 years.20,21 These results suggest an improvement compared with azacitidine alone; however, the patient populations were heterogeneous, and most of the responses were bone marrow responses without www.jco.org
hematologic improvement.22 Infliximab has also been studied in MDS. Sustained erythroid responses to infliximab infusions were originally noted in two patients with lower-risk MDS and isolated anemia with elevated circulating TNF-␣ levels.23 Raza et al24 tested two different doses of infliximab (5 v 10 mg/kg) in a mixed population of 37 patients with MDS, which achieved hematologic response in eight patients. Unfortunately,arandomizedphaseIItrialinlow-riskpatientswithMDScomparing two different doses (3 v 5 mg/kg) yielded disappointing results, with only three of 22 patients in the 3 mg/kg responding per 2006 IWG criteria, and zero of 21 patients in the 5 mg/kg group.25 The results of these phase II studies do suggest a beneficial effect of TNF-␣ blockade in MDS when used in combination with other standard treatments for this disease. Adalimumab is a thirdgeneration recombinant human IgG1 antibody to TNF-␣ widely used in Crohn’s disease. It is more convenient than intravenous infliximab as it is subcutaneously administered, it is more effective than placebo in infliximab failures (complete remission 21% v 7%),26 and there is less antibody formation than with infliximab (3% v 28%).27 Etanercept has not been shown to be effective in Crohn‘s disease.28 This is the first report to suggest that adalimumab as a potent inhibitor of TNF-␣ may also have significant activity in MDS. As well, this report adds to the evidence that TPO-receptor agonists may have positive effects on trilineage hematopoiesis. Given the limited number of efficacious treatments in this disease, adalimumab may warrant future investigation in lower-risk MDS.
Anca Prica and Rena Buckstein Sunnybrook Health Sciences Centre/Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on April 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e5
Prica and Buckstein
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Cheson BD, Greenberg PL, Bennett JM, et al: Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108:419-425, 2006 2. Kantarjian HM, Mufti GJ, Fenaux P, et al: Treatment with the thrombopoietin (TPO)-receptor agonist romiplostim in thrombocytopenic patients (PTS) with low or intermediate-1 (INT-1) risk myelodysplastic syndrome (MDS): Follow-up AML and survival results of a randomized, double-blind, placebo (PBO)-controlled study. Blood 120, 2012 (suppl; abstr 421) 3. Buckstein R, Jang K, Friedlich J, et al: Estimating the prevalence of myelodysplastic syndromes in patients with unexplained cytopenias: A retrospective study of 322 bone marrows. Leuk Res 33:1313-1318, 2009 4. Santini V: Clinical use of erythropoietic stimulating agents in myelodysplastic syndromes. Oncologist 16 suppl 3:35-42, 2011 5. Oliva EN, Santini V, Zini G, et al: Efficacy and safety of eltrombopag for the treatment of thrombocytopenia of low and intermediate-1 IPSS risk myelodysplastic syndromes: Interim analysis of a prospective, randomized, single-blind, placebo-controlled trial (EQOL-MDS). Blood 120:21, 2012 6. Olnes MJ, Scheinberg P, Calvo KR, et al: Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med 367:11-19, 2012 7. Qian H, Buza-Vidas N, Hyland CD, et al: Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell 1:671-684, 2007 8. Selleri C, Sato T, Anderson S, et al: Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol 165:538-546, 1995 9. Musto P, Matera R, Minervini MM, et al: Low serum levels of tumor necrosis factor and interleukin-1 beta in myelodysplastic syndromes responsive to recombinant erythropoietin. Haematologica 79:265-268, 1994 10. Stasi R, Brunetti M, Bussa S, et al: Serum levels of tumour necrosis factor-alpha predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome. Clin Lab Haematol 19:197-201, 1997 11. Verhoef GE, De Schouwer P, Ceuppens JL, et al: Measurement of serum cytokine levels in patients with myelodysplastic syndromes. Leukemia 6:12681272, 1992 12. Gersuk GM, Beckham C, Loken MR, et al: A role for tumour necrosis factor-alpha, Fas, and Fas-Ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 103:176-188, 1998 13. Deeg HJ, Gotlib J, Beckham C, et al: Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: A pilot study. Leukemia 16:162-164, 2002 14. Maciejewski JP, Risitano AM, Sloand EM, et al: A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome. Br J Haematol 117:119-126, 2002
15. Rosenfeld C, Bedell C: Pilot study of recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) in patients with low risk myelodysplastic syndrome. Leuk Res 26:721-724, 2002 16. Scott BL, Ramakrishnan A, Fosdal M, et al: Anti-thymocyte globulin plus etanercept as therapy for myelodysplastic syndromes (MDS): A phase II study. Br J Haematol 149:706-710, 2010 17. Yazji S, Giles FJ, Tsimberidou AM, et al: Antithymocyte globulin (ATG)based therapy in patients with myelodysplastic syndromes. Leukemia 17:21012106, 2003 18. Lim ZY, Killick S, Germing U, et al: Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia 21:1436-1441, 2007 19. Sloand EM, Wu CO, Greenberg P, et al: Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 26:2505-2511, 2008 20. Scott BL, Ramakrishnan A, Storer B, et al: Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept. Br J Haematol 148:944-947, 2010 21. Cheson BD, Bennett JM, Kantarjian H, et al: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671-3674, 2000 22. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 10:223-232, 2009 23. Stasi R, Amadori S: Infliximab chimaeric anti-tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes. Br J Haematol 116:334-337, 2002 24. Raza A, Candoni A, Khan U, et al: Remicade as TNF suppressor in patients with myelodysplastic syndromes. Leuk Lymphoma 45:2099-2104, 2004 25. Baron F, Suciu S, Amadori S, et al: Value of infliximab (Remicade) in patients with low-risk myelodysplastic syndrome: Final results of a randomized phase II trial (EORTC trial 06023) of the EORTC Leukemia Group. Haematologica 97:529-533, 2012 26. Sandborn WJ, Rutgeerts P, Enns R, et al: Adalimumab induction therapy for Crohn disease previously treated with infliximab: A randomized trial. Ann Intern Med 146:829-838, 2007 27. Hanauer SB, Sandborn WJ, Rutgeerts P, et al: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: The CLASSIC-I trial. Gastroenterology 130:323-333, 2006 28. Sandborn WJ, Feagan BG, Hanauer SB, et al: An engineered human antibody to TNF (CDP571) for active Crohn’s disease: A randomized double-blind placebo-controlled trial. Gastroenterology 120:1330-1338, 2001
DOI: 10.1200/JCO.2013.49.4948; published online ahead of print at www.jco.org on February 24, 2014
■ ■ ■
e6
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on April 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
33
䡠
NUMBER
2
䡠
JANUARY
10
2015
JOURNAL OF CLINICAL ONCOLOGY
Myelodysplastic Syndrome Successfully Treated With Adalimumab Case Report A 60-year-old male was referred in September 2009 with mild macrocytic anemia and thrombocytopenia. Past medical history was remarkable for Crohn’s disease treated with colectomy and colostomy, and the patient was on no active therapy at the time. At the time of presentation, the patient’s hemoglobin was 107 g/L, MCV was 106 fL, and platelet count was 25 ⫻ 109/L. His WBC was 6.3 ⫻109/L with an absolute neutrophil count of 4.5 ⫻ 109/L. Work-up for secondary nutritional, metabolic, hemolytic, infectious, and toxic causes was negative. A bone marrow aspirate and biopsy revealed evidence of dyserythropoiesis (⬎ 10% cells; left arrow), dysmegakaryopoiesis (⬎ 10% cells) and hypolobated neutrophils (right arrow), as seen in Figure 1. There were no ring sideroblasts, blasts were 2%, and the karyotype 46XY. He was diagnosed with myelodysplastic syndrome (MDS), WHO subtype refractory cytopenias with multilineage dysplasia. The patient achieved a hematologic improvement-erythroid according to International Working Group (IWG) 2006 criteria1 on darbepoetin 500 mcg every 2 weeks, with an increase of hemoglobin from 107 g/L to 123 g/L. His platelet counts remained low, generally less than 20 ⫻ 109/L; thus, he was entered into a randomized doubleblind romiplostim clinical trial 1 year postdiagnosis while continuing on darbepoetin.2 A repeat bone marrow aspirate and biopsy at the time of study entry revealed cytogenetic progression with a new trisomy 21 mutation. On study, his platelet count increased from 18 ⫻ 109/L to 42 ⫻ 109/L. Because of safety concerns, the therapy was halted early, and he was taken off study 1 year later. Interestingly, his hemo-
Fig 1. e4
© 2014 by American Society of Clinical Oncology
D I A G N O S I S
I N
O N C O L O G Y
globin levels progressively improved through this time, and his darbepoetin requirements declined to 300 mcg every 4 weeks. Six months after study discontinuation he was able to stop the erythropoietic stimulating agent (ESA), maintaining a hemoglobin of 130 g/L. However, his platelet counts remained in the 40 to 50 ⫻ 109/L range (Fig 2). Two months after discontinuing darbepoetin, he was started on adalimumab, an anti–tumor necrosis factor alpha (TNF␣) antibody, for his recurrently symptomatic Crohn’s disease (diarrhea and pain), at 40 mg subcutaneously every 2 weeks. He tolerated the medication well with excellent control of his Crohn’s disease symptoms. During the next 6 months, his platelet counts slowly increased. When seen in follow-up in the hematology clinic 6 months later, his platelet count had essentially normalized at 144 ⫻ 109/L with a hemoglobin of 143 g/L. One year post-start of adalimumab, his hemoglobin is 141 g/L with an MCV of 104 fL, his platelets are 248 ⫻ 109/L, and his WBC is 5.1 ⫻ 109/L. He remains on treatment with adalimumab, with normal blood counts and stable Crohn’s disease. Discussion MDSs are common hematologic disorders in adults and may affect as many as two in 1,000 anemic people over the age of 65.3 They are characterized by ineffective hematopoiesis and peripheral blood cytopenias. Genomic instability of the MDS clone often leads to disease progression and overt leukemia. Although azacitidine and lenalidomide are approved treatments for particular subsets of patients with this disease, there is still a paucity of treatments for lower-risk patients. We believe this case highlights two important findings: one, the potential nonmegakaryocytic hematologic benefits of thrombomimetic agents, and two, the benefit of TNF-␣ blockage in MDS. While on and even after the thrombopoietin (TPO)-receptor agonist romiplostim, our patient was able to discontinue the ESA before starting the adalimumab, with normalization of his hemoglobin level. His erythropoietic response was more likely due to romiplostim and not just continued darbepoetin. Given that ESAs are not diseasemodifying treatments in MDS, erythropoietic responses are not typically durable once they are discontinued, but this was not the case in our patient.4 Trilineage hematologic responses have been observed on romiplostim,2 and some anticlonal activity was observed with eltrombopag beyond simply the expected platelet improvements.5 In aplastic anemia, eltrombopag has been observed to induce improvements in both hemoglobin levels (in 24%, with half of those becoming transfusion independent) and neutrophil responses in 36% of patients. Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response.6 These findings suggest that TPO agonists may stimulate hematopoiesis at the level of primitive hematopoietic cells, consistent with the results of previous lab studies.7 One mechanism of ineffective hematopoiesis in early MDS may be the increased apoptosis of hematopoietic cells induced by cytokines. TNF-␣ is a pro-inflammatory cytokine that acts as a potent inhibitor of normal hematopoiesis through increased apoptosis.8 A number of studies9-11 have suggested the dysregulation of TNF-␣ and Journal of Clinical Oncology, Vol 33, No 2 (January 10), 2015: pp e4-e6
Downloaded from jco.ascopubs.org on April 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
160
300
140
Darbepoetin stopped
Darbepoetin 500 mcg every 2 weeks
200
150
130
120
150 Adalimumab started
110 100 Romiplostim study stopped
Hemoglobin Level (g/L)
Platelet Count (×109/L)
250
Darbepoetin decreased to 300 mcg every 3 weeks Darbepoetin decreased to 300 mcg every 4 weeks Darbepoetin 500 mcg every 3 weeks
100 Romiplostim study entry
50 90 Platelets Hemoglobin
80
0 0
3
5
6
7
8
9
13
14
20
24
26
27
28
29
32
38
Time Since Diagnosis (months) Platelets Hemoglobin
25 25 18 21 23 28 32 42 33 47 39 39 53 86 99 144 248 107 107 123 118 124 114 120 132 138 132 126 129 125 127 129 143 141
Fig 2.
related proteins Fas and Fas-Ligand in MDS hematopoietic precursors and have explored its role in the pathophysiology of the disease. Gersuk et al12 demonstrated that TNF-␣, Fas and Fas-Ligand were significantly dysregulated in the marrow of 44 patients with MDS, with higher elevations of TNF-␣ observed in the WHO category of refractory anemia compared with histologies of excess blasts. In vitro, marrow cultures treated with Fas or TNF-␣ blockade showed significant increases in numbers of hematopoietic colonies compared with untreated cells. This provided preliminary evidence for the potential benefit of TNF-␣ blockade as a therapeutic intervention. Clinical studies have shown that TNF-␣ inhibition with etanercept (recombinant soluble TNF receptor) and infliximab (a chimeric human/murine antibody to TNF-␣) may have activity in MDS. Initial early clinical studies with etanercept as monotherapy showed evidence of trilineage responses with modest response rates of 0% to 33%.13-15 The combination of antithymocyte globulin (ATG) and etanercept was studied in 25 low-risk patients with MDS, yielding a response rate of 56% by the 2006 IWG criteria.1,16 This rate is higher than the published response rates of ATG alone, which range between 26% and 42%, but similar to the combination of ATG and cyclosporine with response rates of 48%.17-19 Scott et al also tested the combination of etanercept with azacitidine in patients with higher-risk MDS/chronic myelomonocytic leukemia, either intermediate-2/high risk by the International Prognostic Scoring System, or low/intermediate-1 disease with cytopenias. They reported an overall response rate of 72% by 2000 IWG criteria, with a median duration of response not reached at 2 years.20,21 These results suggest an improvement compared with azacitidine alone; however, the patient populations were heterogeneous, and most of the responses were bone marrow responses without www.jco.org
hematologic improvement.22 Infliximab has also been studied in MDS. Sustained erythroid responses to infliximab infusions were originally noted in two patients with lower-risk MDS and isolated anemia with elevated circulating TNF-␣ levels.23 Raza et al24 tested two different doses of infliximab (5 v 10 mg/kg) in a mixed population of 37 patients with MDS, which achieved hematologic response in eight patients. Unfortunately,arandomizedphaseIItrialinlow-riskpatientswithMDScomparing two different doses (3 v 5 mg/kg) yielded disappointing results, with only three of 22 patients in the 3 mg/kg responding per 2006 IWG criteria, and zero of 21 patients in the 5 mg/kg group.25 The results of these phase II studies do suggest a beneficial effect of TNF-␣ blockade in MDS when used in combination with other standard treatments for this disease. Adalimumab is a thirdgeneration recombinant human IgG1 antibody to TNF-␣ widely used in Crohn’s disease. It is more convenient than intravenous infliximab as it is subcutaneously administered, it is more effective than placebo in infliximab failures (complete remission 21% v 7%),26 and there is less antibody formation than with infliximab (3% v 28%).27 Etanercept has not been shown to be effective in Crohn‘s disease.28 This is the first report to suggest that adalimumab as a potent inhibitor of TNF-␣ may also have significant activity in MDS. As well, this report adds to the evidence that TPO-receptor agonists may have positive effects on trilineage hematopoiesis. Given the limited number of efficacious treatments in this disease, adalimumab may warrant future investigation in lower-risk MDS.
Anca Prica and Rena Buckstein Sunnybrook Health Sciences Centre/Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on April 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e5
Prica and Buckstein
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Cheson BD, Greenberg PL, Bennett JM, et al: Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108:419-425, 2006 2. Kantarjian HM, Mufti GJ, Fenaux P, et al: Treatment with the thrombopoietin (TPO)-receptor agonist romiplostim in thrombocytopenic patients (PTS) with low or intermediate-1 (INT-1) risk myelodysplastic syndrome (MDS): Follow-up AML and survival results of a randomized, double-blind, placebo (PBO)-controlled study. Blood 120, 2012 (suppl; abstr 421) 3. Buckstein R, Jang K, Friedlich J, et al: Estimating the prevalence of myelodysplastic syndromes in patients with unexplained cytopenias: A retrospective study of 322 bone marrows. Leuk Res 33:1313-1318, 2009 4. Santini V: Clinical use of erythropoietic stimulating agents in myelodysplastic syndromes. Oncologist 16 suppl 3:35-42, 2011 5. Oliva EN, Santini V, Zini G, et al: Efficacy and safety of eltrombopag for the treatment of thrombocytopenia of low and intermediate-1 IPSS risk myelodysplastic syndromes: Interim analysis of a prospective, randomized, single-blind, placebo-controlled trial (EQOL-MDS). Blood 120:21, 2012 6. Olnes MJ, Scheinberg P, Calvo KR, et al: Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med 367:11-19, 2012 7. Qian H, Buza-Vidas N, Hyland CD, et al: Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell 1:671-684, 2007 8. Selleri C, Sato T, Anderson S, et al: Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol 165:538-546, 1995 9. Musto P, Matera R, Minervini MM, et al: Low serum levels of tumor necrosis factor and interleukin-1 beta in myelodysplastic syndromes responsive to recombinant erythropoietin. Haematologica 79:265-268, 1994 10. Stasi R, Brunetti M, Bussa S, et al: Serum levels of tumour necrosis factor-alpha predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome. Clin Lab Haematol 19:197-201, 1997 11. Verhoef GE, De Schouwer P, Ceuppens JL, et al: Measurement of serum cytokine levels in patients with myelodysplastic syndromes. Leukemia 6:12681272, 1992 12. Gersuk GM, Beckham C, Loken MR, et al: A role for tumour necrosis factor-alpha, Fas, and Fas-Ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 103:176-188, 1998 13. Deeg HJ, Gotlib J, Beckham C, et al: Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: A pilot study. Leukemia 16:162-164, 2002 14. Maciejewski JP, Risitano AM, Sloand EM, et al: A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome. Br J Haematol 117:119-126, 2002
15. Rosenfeld C, Bedell C: Pilot study of recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) in patients with low risk myelodysplastic syndrome. Leuk Res 26:721-724, 2002 16. Scott BL, Ramakrishnan A, Fosdal M, et al: Anti-thymocyte globulin plus etanercept as therapy for myelodysplastic syndromes (MDS): A phase II study. Br J Haematol 149:706-710, 2010 17. Yazji S, Giles FJ, Tsimberidou AM, et al: Antithymocyte globulin (ATG)based therapy in patients with myelodysplastic syndromes. Leukemia 17:21012106, 2003 18. Lim ZY, Killick S, Germing U, et al: Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia 21:1436-1441, 2007 19. Sloand EM, Wu CO, Greenberg P, et al: Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 26:2505-2511, 2008 20. Scott BL, Ramakrishnan A, Storer B, et al: Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept. Br J Haematol 148:944-947, 2010 21. Cheson BD, Bennett JM, Kantarjian H, et al: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671-3674, 2000 22. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 10:223-232, 2009 23. Stasi R, Amadori S: Infliximab chimaeric anti-tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes. Br J Haematol 116:334-337, 2002 24. Raza A, Candoni A, Khan U, et al: Remicade as TNF suppressor in patients with myelodysplastic syndromes. Leuk Lymphoma 45:2099-2104, 2004 25. Baron F, Suciu S, Amadori S, et al: Value of infliximab (Remicade) in patients with low-risk myelodysplastic syndrome: Final results of a randomized phase II trial (EORTC trial 06023) of the EORTC Leukemia Group. Haematologica 97:529-533, 2012 26. Sandborn WJ, Rutgeerts P, Enns R, et al: Adalimumab induction therapy for Crohn disease previously treated with infliximab: A randomized trial. Ann Intern Med 146:829-838, 2007 27. Hanauer SB, Sandborn WJ, Rutgeerts P, et al: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: The CLASSIC-I trial. Gastroenterology 130:323-333, 2006 28. Sandborn WJ, Feagan BG, Hanauer SB, et al: An engineered human antibody to TNF (CDP571) for active Crohn’s disease: A randomized double-blind placebo-controlled trial. Gastroenterology 120:1330-1338, 2001
DOI: 10.1200/JCO.2013.49.4948; published online ahead of print at www.jco.org on February 24, 2014
■ ■ ■
e6
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on April 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
