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Blastic plasmacytoid dendritic cell neoplasm with acute myeloid leukemia successfully treated to a remission currently of 26 months duration
Leukemia Research 35 (2011) e61–e63
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor Blastic plasmacytoid dendritic cell neoplasm with acute myeloid leukemia successfully treated to a remission currently of 26 months duration Recently, CD4+/CD56+ hematodermic neoplasias have been recognized as a distinct entity among hematologic malignancies. There is increasing evidence of a close histogenetic relationship to plasmacytoid dendritic cells so that they are classified as blastic plasmacytoid dendritic cell neoplasms. These typically present with characteristic skin manifestations often accompanied by cytopenias in peripheral blood. Fulminant leukemia commonly evolves during the clinical course of disease representing the main reason for poor overall prognosis of CD4+CD56+ blastic plasmacytoid dendritic cell neoplasm. Long-term remissions and sporadic cures have so far only been reported after intensive chemotherapy regimens followed by allogenic stem cell transplantation. Here, we report on an elderly patient with blastic plasmacytoid dendritic cell neoplasm and acute myeloid leukemia (AML) who received dose intensive multiagent chemotherapy leading to a sustained complete hematological remission. This demonstrates that dose intensive polychemotherapy in elderly patients is feasible, and on occasions long-term remissions may be achieved. This could be of particular interest for patients with blastic plasmacytoid dendritic cell neoplasm not eligible for allogenic stem cell transplantation.
1. Introduction Over the last decade blastic plasmacytoid dendritic cell neoplasms have been recognized as a rare, but distinct entity among hematologic malignancies. Based on CD56 expression in the absence of T cell markers and myeloid lineage antigens CD4+/CD56+ neoplasms were provisionally classified as blastic natural killer cell lymphoma in the 1999 WHO classification of hematopoietic tumors [1]. Recent evidence, however, suggests that the majority of hematodermic tumors are closely related to plasmacytoid dendritic cell lineage [2,3] and therefore are now classified as blastic plasmacytoid dendritic cell neoplasms [4]. They typically present with asymptomatic solitary or multifocal skin lesions (nodules, patch-plaque or bruise-like areas) as the only clinical manifestation of disease when systemic B symptoms are rare. A common finding at diagnosis are (occasionally severe) peripheral cytopenias sometimes misleading to the exclusive diagnosis of myelodysplastic syndrome which in cases coincides. Fulminant leukemia (>90%), especially of myelomonocytic pattern (10–20%), is a common feature in the natural course during progression or relapse [5,6]. The overall prognosis of CD4+/CD56+ blastic plasmacytoid dendritic cell neoplasm is poor with a median overall survival of 12–14 months with advanced age as an adverse prognostic factor [5]. Although most cases respond to initial polychemotherapy (80–90%), treatment-refractory relapses generally occur after a median of only 9–11 months. Long-term remissions 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.11.019
and sporadic cures have so far only been reported after intensive chemotherapy regimens followed by allogenic stem cell transplantation in first remission [7,8]. Here, we report the case of an elderly patient presenting with blastic plasmacytoid dendritic cell neoplasm and subsequent evolution of AML. The patient received extensive multiagent chemotherapy leading to a sustained complete hematological remission of currently 26 months duration. 2. Case report A 66-year old patient presented in June 2008 to a dermatologic practitioner with suddenly appearing generalised maculopapulous exanthema without pruritus (Fig. 1). After 4 weeks of unsuccessful topical treatment with corticoids, the patient was admitted to the dermatologic hospital of the University of Munich for further investigation. His medical history, including history of travelling, sexual behaviour and drug intake, held no clue. Several infectious causes, such as rickettsiosis, lues and parvovirus, could be ruled out by serologic tests. Skin biopsy finally revealed lymphoid infiltration of the dermis, focally reaching into the subcutis, consisting of monomorphic lymphocytes. Immunostaining showed neoplastic cells positive for CD4, CD56 and CD68 (cytoplasmatic, low) but negative for CD3, CD20, TdT, MPO and CD117, consistent with CD4+/CD56+ blastic plasmacytoid dendritic cell neoplasm (Fig. 2). Laboratory findings then depicted an isolated thrombocytopenia and increased inflammation markers (CRP) and LDH levels, so that the patient was transferred to our department of hematology at the University Hospital of Munich. At the time of admission, the patient reported on night sweats with otherwise well-being, no fever, weight loss or diarrhea. The rash displayed unchanged with otherwise normal physical status. A bone marrow aspirate could initially not be attained due to a punctio sicca. Within the
Fig. 1. Maculopapulous exanthema at initial presentation.
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Letter to the Editor / Leukemia Research 35 (2011) e61–e63
Fig. 2. Immunhistologic staining performed on skin biopsy showing lymphoid infiltration of the dermis by monomorphic neoplastic cells (CD4+CD56+CD3−). (a) HE-staining, (b) anti-CD4, (c) anti-CD56, (d) anti-CD3.
next days the patient rapidly developed fever accompanied by extensive feeling of illness and blood tests showed an increasing leukocytosis with predominant monocytosis in differential blood count and a further increase in LDH levels. Blood smear now revealed an acute myeloid leukemia with monocytic differentiation consistent with the histological findings from bone marrow. Beyond, flow cytometry from peripheral blood detected aberrant expression of CD4 and CD56 (immune phenotype CD13+CD33+CD14+CD64+CD61+HLA−DR+CD4+CD56+). Cytogenetics showed no numeric or structural abnormalities. Altogether, these findings and the clinical course led to the diagnosis of a CD4+/CD56+ blastic plasmacytoid dendritic cell neoplasm with subsequently rapid development of fulminant myelomonocytic leukemia. Therefore, intensive polychemotherapy according to HAM-protocol (high-dose ara-c, mitoxantrone) [9] was initiated, which prompted a complete disappearance of skin manifestations and histologically a complete remission in bone marrow. As long-term remissions of acute leukemia evolving from blastic plasmacytoid dendritic cell neoplasm in literature were so far only
reported after allogenic stem cell transplantation, we introduced the patient to our transplantation department at the University Hospital of Munich. However, after due deliberation he finally rejected a potential allogenic stem cell transplantation. So, with regard to the high-risk situation, a second induction cycle with high dose chemotherapy according to TAD-9 protocol (thioguanine, cytarabine, daunorubicin) [9] plus concomitant intrathecal prophylaxis (methotrexate, cytarabine, dexamethasone) followed by consolidation with a second HAM cycle was applied. After the second induction, peripheral blood stem cells were collected in case of refractory or relapsing disease. Our patient received polychemotherapy from July to October 2008. Now, 26 months after completion of chemotherapy, the patient is still free from recurrence of AML. 3. Discussion Our patient showed a typical clinical presentation of blastic plasmacytoid dendritic cell neoplasm followed by rapid
Letter to the Editor / Leukemia Research 35 (2011) e61–e63
progression to myelomonocytic leukemia. In general, blastic plasmacytoid dendritic cell neoplasms are associated with an extremely poor prognosis because virtually all patients experience quick relapses after polychemotherapy [5]. Despite the fulminant course at initial presentation and the advanced age as an independent adverse prognostic factor our patient responded very well to extensive multiagent chemotherapy without any higher grade toxicities. This demonstrates that dose intensive polychemotherapy in elderly patients is feasible and on occasions long-term, or at least sustained remissions may be achieved. So we report on one of the rare cases with blastic plasmacytoid dendritic cell neoplasm that experience long-lasting (>2 yrs) complete hematological remissions after conventional chemotherapy without subsequent allogenic stem cell transplantation. This emphasizes, that also elderly patients where therapeutic options are often limited, may benefit from aggressive treatment of blastic plasmacytoid dendritic cell neoplasm with associated AML. Conflict of interest All authors declare no conflict of interest. Acknowledgement No professional writing assistance. No funding source. Contributions. M.F. performing dermatohistology, review of article; T.R. and N.A. documentation of clinical course, assistance in writing of article and R.S. and F.O. conception of manuscript, review and final approval of article. References [1] Chan JKC, Jaffe ES, Ralfikiaer E. Blastic NK-cell lymphoma. In: Jaffe ES, Harris N, Stein H, et al, editors. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2001. p. 214–5. World Health Organization Classification of Tumours. [2] Petrella T, Comeau MR, Maynadie M, et al. Agranular CD4+ CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)originates from a population of CD56+ precursor cells relatedto plasmacytoid monocytes. Am J Surg Pathol 2002;26:852–62. [3] Herling M, Teitell MA, Shen RR, et al. TCL1 expression in plasmacytoid dendritic cells (DC2s) and the related CD4+ CD56+ blastic tumors of skin. Blood 2003;101:5007–9.
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[4] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. World health organization classification of tumours, vol. 2. IARC. [5] Marco Herling, Dan Jones. CD4+/CD56+ hematodermic tumor. The features of an evolving entity and its relationship to dendritic cells. Am J Clin Pathol 2007;127:687–700. [6] Khoury JD, Medeiros LJ, Manning JT, et al. CD56(+) TdT(+) blastic natural killer cell tumor of the skin: a primitive systemic malignancy related to myelomonocytic leukemia. Cancer 2002;94:2401–8. [7] Feuillard J, Jacob MC, Valensi F, et al. Clinical and biologic features of CD4(+)CD56(+) malignancies. Blood 2002;99:1556–63. [8] Petrella T, Bagot M, Willemze R, et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol 2005;123:662–75. [9] Buchner T, Hiddemann W, Wormann B, Loffler H, Gassmann W, Haferlach T, et al. Double induction strategy for acute myeloid leukemia: the effect of highdose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 1999;93:4116–24.
Andreas Voelkl ∗ Department of Hematology and Oncology, Medizinische Klinik Innenstadt, University Hospital of Munich, Ziemssenstrasse 1, D-80336 Munich, Germany Michael Flaig Dermatologic Hospital of the University of Munich, Munich, Germany Tim Roehnisch Nurcan Alpay Ralf Schmidmaier Fuat Oduncu Department of Hematology and Oncology, Medizinische Klinik Innenstadt, University Hospital of Munich, Munich, Germany ∗ Corresponding
author. Tel.: +49 89 5160 3923/2167; fax: +49 89 5160 4180. E-mail address: [email protected] (A. Voelkl) 24 October 2010 Available online 16 December 2010
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor Blastic plasmacytoid dendritic cell neoplasm with acute myeloid leukemia successfully treated to a remission currently of 26 months duration Recently, CD4+/CD56+ hematodermic neoplasias have been recognized as a distinct entity among hematologic malignancies. There is increasing evidence of a close histogenetic relationship to plasmacytoid dendritic cells so that they are classified as blastic plasmacytoid dendritic cell neoplasms. These typically present with characteristic skin manifestations often accompanied by cytopenias in peripheral blood. Fulminant leukemia commonly evolves during the clinical course of disease representing the main reason for poor overall prognosis of CD4+CD56+ blastic plasmacytoid dendritic cell neoplasm. Long-term remissions and sporadic cures have so far only been reported after intensive chemotherapy regimens followed by allogenic stem cell transplantation. Here, we report on an elderly patient with blastic plasmacytoid dendritic cell neoplasm and acute myeloid leukemia (AML) who received dose intensive multiagent chemotherapy leading to a sustained complete hematological remission. This demonstrates that dose intensive polychemotherapy in elderly patients is feasible, and on occasions long-term remissions may be achieved. This could be of particular interest for patients with blastic plasmacytoid dendritic cell neoplasm not eligible for allogenic stem cell transplantation.
1. Introduction Over the last decade blastic plasmacytoid dendritic cell neoplasms have been recognized as a rare, but distinct entity among hematologic malignancies. Based on CD56 expression in the absence of T cell markers and myeloid lineage antigens CD4+/CD56+ neoplasms were provisionally classified as blastic natural killer cell lymphoma in the 1999 WHO classification of hematopoietic tumors [1]. Recent evidence, however, suggests that the majority of hematodermic tumors are closely related to plasmacytoid dendritic cell lineage [2,3] and therefore are now classified as blastic plasmacytoid dendritic cell neoplasms [4]. They typically present with asymptomatic solitary or multifocal skin lesions (nodules, patch-plaque or bruise-like areas) as the only clinical manifestation of disease when systemic B symptoms are rare. A common finding at diagnosis are (occasionally severe) peripheral cytopenias sometimes misleading to the exclusive diagnosis of myelodysplastic syndrome which in cases coincides. Fulminant leukemia (>90%), especially of myelomonocytic pattern (10–20%), is a common feature in the natural course during progression or relapse [5,6]. The overall prognosis of CD4+/CD56+ blastic plasmacytoid dendritic cell neoplasm is poor with a median overall survival of 12–14 months with advanced age as an adverse prognostic factor [5]. Although most cases respond to initial polychemotherapy (80–90%), treatment-refractory relapses generally occur after a median of only 9–11 months. Long-term remissions 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.11.019
and sporadic cures have so far only been reported after intensive chemotherapy regimens followed by allogenic stem cell transplantation in first remission [7,8]. Here, we report the case of an elderly patient presenting with blastic plasmacytoid dendritic cell neoplasm and subsequent evolution of AML. The patient received extensive multiagent chemotherapy leading to a sustained complete hematological remission of currently 26 months duration. 2. Case report A 66-year old patient presented in June 2008 to a dermatologic practitioner with suddenly appearing generalised maculopapulous exanthema without pruritus (Fig. 1). After 4 weeks of unsuccessful topical treatment with corticoids, the patient was admitted to the dermatologic hospital of the University of Munich for further investigation. His medical history, including history of travelling, sexual behaviour and drug intake, held no clue. Several infectious causes, such as rickettsiosis, lues and parvovirus, could be ruled out by serologic tests. Skin biopsy finally revealed lymphoid infiltration of the dermis, focally reaching into the subcutis, consisting of monomorphic lymphocytes. Immunostaining showed neoplastic cells positive for CD4, CD56 and CD68 (cytoplasmatic, low) but negative for CD3, CD20, TdT, MPO and CD117, consistent with CD4+/CD56+ blastic plasmacytoid dendritic cell neoplasm (Fig. 2). Laboratory findings then depicted an isolated thrombocytopenia and increased inflammation markers (CRP) and LDH levels, so that the patient was transferred to our department of hematology at the University Hospital of Munich. At the time of admission, the patient reported on night sweats with otherwise well-being, no fever, weight loss or diarrhea. The rash displayed unchanged with otherwise normal physical status. A bone marrow aspirate could initially not be attained due to a punctio sicca. Within the
Fig. 1. Maculopapulous exanthema at initial presentation.
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Letter to the Editor / Leukemia Research 35 (2011) e61–e63
Fig. 2. Immunhistologic staining performed on skin biopsy showing lymphoid infiltration of the dermis by monomorphic neoplastic cells (CD4+CD56+CD3−). (a) HE-staining, (b) anti-CD4, (c) anti-CD56, (d) anti-CD3.
next days the patient rapidly developed fever accompanied by extensive feeling of illness and blood tests showed an increasing leukocytosis with predominant monocytosis in differential blood count and a further increase in LDH levels. Blood smear now revealed an acute myeloid leukemia with monocytic differentiation consistent with the histological findings from bone marrow. Beyond, flow cytometry from peripheral blood detected aberrant expression of CD4 and CD56 (immune phenotype CD13+CD33+CD14+CD64+CD61+HLA−DR+CD4+CD56+). Cytogenetics showed no numeric or structural abnormalities. Altogether, these findings and the clinical course led to the diagnosis of a CD4+/CD56+ blastic plasmacytoid dendritic cell neoplasm with subsequently rapid development of fulminant myelomonocytic leukemia. Therefore, intensive polychemotherapy according to HAM-protocol (high-dose ara-c, mitoxantrone) [9] was initiated, which prompted a complete disappearance of skin manifestations and histologically a complete remission in bone marrow. As long-term remissions of acute leukemia evolving from blastic plasmacytoid dendritic cell neoplasm in literature were so far only
reported after allogenic stem cell transplantation, we introduced the patient to our transplantation department at the University Hospital of Munich. However, after due deliberation he finally rejected a potential allogenic stem cell transplantation. So, with regard to the high-risk situation, a second induction cycle with high dose chemotherapy according to TAD-9 protocol (thioguanine, cytarabine, daunorubicin) [9] plus concomitant intrathecal prophylaxis (methotrexate, cytarabine, dexamethasone) followed by consolidation with a second HAM cycle was applied. After the second induction, peripheral blood stem cells were collected in case of refractory or relapsing disease. Our patient received polychemotherapy from July to October 2008. Now, 26 months after completion of chemotherapy, the patient is still free from recurrence of AML. 3. Discussion Our patient showed a typical clinical presentation of blastic plasmacytoid dendritic cell neoplasm followed by rapid
Letter to the Editor / Leukemia Research 35 (2011) e61–e63
progression to myelomonocytic leukemia. In general, blastic plasmacytoid dendritic cell neoplasms are associated with an extremely poor prognosis because virtually all patients experience quick relapses after polychemotherapy [5]. Despite the fulminant course at initial presentation and the advanced age as an independent adverse prognostic factor our patient responded very well to extensive multiagent chemotherapy without any higher grade toxicities. This demonstrates that dose intensive polychemotherapy in elderly patients is feasible and on occasions long-term, or at least sustained remissions may be achieved. So we report on one of the rare cases with blastic plasmacytoid dendritic cell neoplasm that experience long-lasting (>2 yrs) complete hematological remissions after conventional chemotherapy without subsequent allogenic stem cell transplantation. This emphasizes, that also elderly patients where therapeutic options are often limited, may benefit from aggressive treatment of blastic plasmacytoid dendritic cell neoplasm with associated AML. Conflict of interest All authors declare no conflict of interest. Acknowledgement No professional writing assistance. No funding source. Contributions. M.F. performing dermatohistology, review of article; T.R. and N.A. documentation of clinical course, assistance in writing of article and R.S. and F.O. conception of manuscript, review and final approval of article. References [1] Chan JKC, Jaffe ES, Ralfikiaer E. Blastic NK-cell lymphoma. In: Jaffe ES, Harris N, Stein H, et al, editors. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2001. p. 214–5. World Health Organization Classification of Tumours. [2] Petrella T, Comeau MR, Maynadie M, et al. Agranular CD4+ CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)originates from a population of CD56+ precursor cells relatedto plasmacytoid monocytes. Am J Surg Pathol 2002;26:852–62. [3] Herling M, Teitell MA, Shen RR, et al. TCL1 expression in plasmacytoid dendritic cells (DC2s) and the related CD4+ CD56+ blastic tumors of skin. Blood 2003;101:5007–9.
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[4] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. World health organization classification of tumours, vol. 2. IARC. [5] Marco Herling, Dan Jones. CD4+/CD56+ hematodermic tumor. The features of an evolving entity and its relationship to dendritic cells. Am J Clin Pathol 2007;127:687–700. [6] Khoury JD, Medeiros LJ, Manning JT, et al. CD56(+) TdT(+) blastic natural killer cell tumor of the skin: a primitive systemic malignancy related to myelomonocytic leukemia. Cancer 2002;94:2401–8. [7] Feuillard J, Jacob MC, Valensi F, et al. Clinical and biologic features of CD4(+)CD56(+) malignancies. Blood 2002;99:1556–63. [8] Petrella T, Bagot M, Willemze R, et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol 2005;123:662–75. [9] Buchner T, Hiddemann W, Wormann B, Loffler H, Gassmann W, Haferlach T, et al. Double induction strategy for acute myeloid leukemia: the effect of highdose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 1999;93:4116–24.
Andreas Voelkl ∗ Department of Hematology and Oncology, Medizinische Klinik Innenstadt, University Hospital of Munich, Ziemssenstrasse 1, D-80336 Munich, Germany Michael Flaig Dermatologic Hospital of the University of Munich, Munich, Germany Tim Roehnisch Nurcan Alpay Ralf Schmidmaier Fuat Oduncu Department of Hematology and Oncology, Medizinische Klinik Innenstadt, University Hospital of Munich, Munich, Germany ∗ Corresponding
author. Tel.: +49 89 5160 3923/2167; fax: +49 89 5160 4180. E-mail address: [email protected] (A. Voelkl) 24 October 2010 Available online 16 December 2010