A JH
SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES
AJH Educational Material A physician or group of physicians considers presentation and evolution of a real clinical case, reacting to clinical information and data (boldface type). This is followed by a discussion/commentary
Two cases of concomitant diffuse large B-cell lymphoma and myelodysplastic syndrome Massimo Dozzo, Francesco Zaja,* Stefano Volpetti, Marianna Chiozzotto, Simona Puglisi, Maddalena Mazzucco, Giulia Perali, and Renato Fanin
䊏 Case Report 1 A 64-year-old gentleman was diagnosed in 2011 with myelodisplastic syndrome (MDS)-type refractory cytopenia with monolinear dysplasia (thrombocytopenia), according to the World Health Organization (WHO) classification, International Prognostic Scoring System (IPSS) low risk [1], and was managed only with an observational program. In February 2013, he started complaining of left axillary and supraclavicular adenopathies, together with abdominal pain, abundant night sweats, and weight loss. A supraclavicular lymphnode biopsy performed in March 2013 led to the diagnosis of diffuse large B-cell lymphoma (DLBCL), stage III B [Ann Arbor, International Prognostic Index (IPI) low-intermediate]. Bone marrow aspirate and biopsy performed at the time of DLBCL staging revealed the picture of a multilineage dysplasia with blast excess (Refractory anemia with excess of blast (RAEB) type 2 according to the WHO classification), with normal cytogenetic analysis (46 XY) and intermediate-1 IPSS risk. Total white blood cell and neutrofils counts were 8.3 3 109/L and 4.8 3 109/L, retrospectively; hemoglobin and platelet counts were 104 g/L and 88 3 109/L, respectively. The development of MDS secondary to chemotherapy or radiotherapy is a well known and rather common phenomenon, while the coexistence of de novo MDS and non-Hodgkin lymphomas (NHL) prior to any exposure to chemo-radiotherapy is rare [2]; even if some case reports described the simultaneous occurrence of MDS and NHL, the real incidence of these coexisting diseases has not been established yet [3]. DLBCL is an aggressive disorder that represents nearly 40% of all NHL and can occur with a wide range of clinical presentations [4]. In consideration of the higher incidence of DLBCL in advanced age, it is not unusual that patients with DLBCL present with significant comorbidities, including other oncological diseases; for these cases, treatment should be tailored with a curative intent to the individual patient, unless comorbidities prevent a full therapeutic approach. Concomitant cytopenia is a significant consideration in individualizing the treatment of DLBCL. In particular, the coexistence of a primary MDS negatively interferes with the outcome of lymphoproliferative disease, worsening, in general, the patient’s clinical status and limiting the possibility of a full therapeutic approach [3,5]. In particular, the hematological toxicity of several cytotoxic agents indicated for lymphoma as alkilators or antracyclines may produce prolonged cytopenias and potentially favor leukemic progression; for this
reason, a careful evaluation of the treatment choice for patients in whom there is the coexistence of MDS and NHL is necessary [3,5]. The patient was started on standard R-CHOP chemoimmunotherapy program (Rituximab, Vincristine, Adriamicin, Cyclophosphamide, and Prednisone) every 21 days for six cycles, followed by two further Rituximab administrations; given the coexistence of MDS, the dosage of Doxorubicin and Cyclophosphamide was reduced to 50% of the total dose. The patient’s treatment compliance was fairly good and the therapy was administrated as originally planned. The hematological toxicity experienced during the therapy was moderate; in particular, we observed grade 3 anemia only after course 3, while grade 3 neutropenia and grade 4 thrombocytopenia were observed after each R-CHOP course. The patient received 3–6 administrations of granulocyte colony-stimulating factor (G-CSF), for every cycle except the first one, and a total of three red blood cell transfusions. No infectious complication or episode of neutropenic fever occurred. Restaging after the end of R-CHOP therapy documented a complete remission (CR) status of the lymphoma (according to Cheson 2007 [6]); the bone marrow re-evaluation and, in particular, the percentage of myeloid blasts, were comparable to that observed at baseline. After 11 months of follow-up, the clinical status of the patient remains unchanged for DLBCL and MDS.
䊏 Case Report 2 A 57-year-old woman with a previous medical history (since 2005) of leucopenia and neutropenia, affected by DLBCL, stage IV A with important involvement of dorsal vertebral column, IPI high-intermediate, presented on May 2013. Bone marrow aspiration and biopsy performed at staging found the picture of multilineage dysplasia (RAEB type 2 according to the WHO classification), with intermediate-1 IPSS risk and normal cytogenetic analysis (46 XX). Total white blood cell and neutrofils counts were 1.6 3 109/L and 0.6 3 109/L, respectively, while hemoglobin level and platelet count were 115 g/L and 236 3 109/L, respectively. After initial surgical decompressive laminectomy with D5– D10 stabilization, the patient underwent local radiotherapy at the level of D7–D8 (33 Gy in 11 fractions); subsequently, a standard R-CHOP chemoimmunotherapy program was planned every 21 days for a total of six cycles, followed by two additional Rituximab administrations and concomitant central nervous system prophylaxis with intratecal Methotrexate (12 mg).
Clinica Ematologica, Centro Trapianti e Terapie Cellulari “Carlo Melzi”, DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy
Conflict of interest: Nothing to report *Correspondence to: Francesco Zaja, Clinica Ematologica, Centro Trapianti e Terapie Cellulari “Carlo Melzi”, Azienda Ospedaliero Universitaria S. M. Misericordia, p.le S. Maria Misericordia 15, 33100 Udine, Italy. E-mail: [email protected] Received for publication: 7 May 2014; Revised: 31 May 2014; Accepted: 6 June 2014 Am. J. Hematol. 89:1011–1013, 2014. Published online: 10 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23783 C 2014 Wiley Periodicals, Inc. V
doi:10.1002/ajh.23783
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[3]
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[7]
[8] [9] [10] [11] [12] [13]
[14] [15]
[16] [17]
[18] [19]
[20]
[21]
[22]
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PTCL 1 RAEB
PTCL 1 RARS del (20 q) Hepatosplenic gd T-cell NHL 1 RA
HL 1 RA PTCL 1 RCMD PTCL 1 RA/RAEB
Plasmocytic NHL 1 RA PTCL 1 RA Lymphoplasmocytic NHL 1 CMML B-NHL NOS 1 RARS HL 1 GS 1 RAEB
PTCL 1 RA/RAEB
B-NHL PTCL 1 RARS
DLBCL 1 RA del (9 q) PTCL 1 RAEB ALCL 1 MDS PTCL 1 MDS PTCL 1 RAEB B-NHL 1 RAEB
ALCL 1 RCMD del(20 q) PTCL 1 secondary AML PTCL 1 RCMD del(20 q) DLBCL 1 RAEB
Diagnosis
2 CHOP
Splenectomy, LSG-15 regimen (6 VCAP, AMP and VECP) CHOP
4 ABVD Topical corticosteroids Gemcitabine, Prednisone 1 palliative radiotherapy 3 CHOP
ABVD Cyclophosphamide Chemotherapy (not specified) Local radiotherapy, combined chemotherapy (not specified) Chlorambucil Combined chemotherapy (not specified) Combined chemotherapy (not specified) Local radiotherapy Supportive therapy Plasmapheresys, Clorambucil 1 steroids Supportive therapy 4 MOPP/ABVD
VNCOP-B
Steroids
FLAG protocol 1 maintenance therapy with methotrexate COP, CHOP, MINE
CHOP
First line therapy
Death after 2 months
Improvement in clinical condition; death from severe hemorrhagic diathesis PR; transient complete remission after allogeneic SCT and relapse after 11 months
Death after 5 days from disease Transient complete remission and evolution into AML; death from progressive disease Evolution into AML; death from renal failure and stroke PR; death from progressive disease PR; death from progressive disease
Death (not specified) Death from respiratory failure after 23 days PR; death from progressive disease
Death (not specified)
Death (not specified) Death (not specified)
Resistance; death for severe gastrointestinal hemorrhagic bleeding Rapid evolution into AML and death one week later from progressive disease Death from progressive disease after 3 weeks of treatment CR CR; relapse after 8 months in the ethmoid and paranasal sinuses PR Death from deterioration of general conditions Death (not specified)
Resistance; after second line therapy transient response and death from progressive disease CR
Response to first line therapy
2
351
8
9 4 14
1 9
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15
7 8
1 221 Not evaluable 141 Not evaluable 16
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Overall survival (months)
CR: complete remission; PR: partial remission; allogeneic SCT: allogeneic stem cell transplantation; DLBCL: diffuse large B-cell lymphoma; B-NHL-NOS: B-cell non-Hodgkin lymphoma not otherwise specified; HL: Hodgkin’s lymphoma; PTCL: peripheral T-cell lymphoma; ALCL: anaplastic large-cell lymphoma; GS: granulocytic sarcoma; MDS: myelodysplastic syndrome; RARS: refractory anemia with ringed sideroblasts; RA: refractory anemia; RAEB: refractory anemia with excess of blast; RCMD: refractory cytopenia with multilineage dysplasia; AML: acute myeloid leukemia; ABVD: Adriamycin, Bleomycin, Vinblastine, Dacarbazine; ARA-C/HD ARA-C: Cytosine Arabinoside/ High-dose Cytosine Arabinoside; MOPP: Mechlorethamine, Vincristine, Prednisone, Procarbazine; FLAG: Fludarabine, Cytosine Arabinoside, G-CSF; CHOP: Cyclophosphamide, Adriamicin, Vincristine, Prednisone; VCAP: Vincristine, Cyclophasphamide, Doxorubicin, Prednisolone; AMP: Doxorubicin, Ranimustine, Prednisone; VECP: Vindesine, Etoposide, Carboplatin, Prednisolone; COP: Cyclophosphamide, Vincristine, Prednisone; MINE: Ifosfamide, Mithoxantrone, Etoposide, Mesna; VNCOP-B: Vincristine, Mithoxantrone, Cyclophosphamide, Etoposide, Prednisone, Bleomycin; CMML: chronic myelomonocytic leukemia.
Patients
Ref.
TABLE 1. Patients with Concomitant Lymphoma and Myelodysplastic Syndrome
Dozzo et al.
SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES
doi:10.1002/ajh.23783
SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES Due to the association of MDS with moderate decreases of hemoglobin and neutrophils count and peripheral neuropathy (secondary to the lymphoma vertebral involvement), the dosage of Doxorubicin, Cyclophosphamide, and Vincristine was reduced to 50% of the total dose. Overall treatment compliance was rather good, and the hematological toxicity experienced during the therapy reached a grade 2 anemia only after course 2, while grade 4 neutropenia and grade 2 thrombocitopenia were documented after courses 2 and 5. The patient required from 4 to 7 supplementations of G-CSF 300 mcg during the first four cycles; a single administration of pegfilgrastim 6 mg was given after courses 5 and 6. The patient did not necessitate any transfusion support. No extrahematological toxicity and no infectious complications or episodes of neutropenic fever occurred. The restaging at the end of the therapy program documented CR (Cheson 2007), while the bone marrow evaluation resulted superimposable to that of debut. After 10 months of follow-up, the clinical status is of stable CR for DLBCL and unchanged blood cell count. The peculiarity of our cases may be summarized in the following two points: (a) both patients had a diagnosis of DLBCL, which seems to represent a minority among patients with concomitant NHL and MDS; (b) both patients were managed with an adapted specific therapeutic approach (dose reduced R-CHOP), which was performed in the absence of major complications, and this allowed both patients to achieve CR, maintaining a stable situation for MDS.
䊏 Discussion Limited case reports are available on the coexistence of lymphoid malignancies with MDS, with a predominance of T-cell versus B-cell NHL, and mostly with unremarkable outcome and treatment related complications. Table 1 summarizes the patients’ main characteristics, and treatments and outcomes of cases described in the literature; 24 patients have been described so far: four received only palliative treatments, five received CHOP or CHOP-like regimens; overall and complete responses were achieved in 8 and 3, respectively, with a median overall survival of 8 months (range 1–35 months). Only two cases of
䊏 References
1. Komrokji RS, Padron E, Lancet JE, et al. Prognostic factors and risk models in myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk 2013;13 Suppl 2:S295–S299. 2. Tanaka H, Ohwada C, Hashimoto S, et al. Leukemic presentation of ALK-negative anaplastic large cell lymphoma in a patient with myelodysplastic syndrome. Intern Med 2012;51:199–203. 3. Breccia M, Petti MC, D’Elia GM, et al. Cutaneous pleomorphic T-cell lymphoma coexisting with myelodysplastic syndrome transforming into acute myeloid leukemia: Successful treatment with a fludarabine-containing regimen. Eur J Hematol 2002;68:1–3. 4. Ghielmini M, Vitolo U, Kimby E, et al. On behalf of the Panel Members of the 1st ESMO Consensus Conference on Malignant Lymphoma. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia (CLL). Ann Oncol 2013;24:561–576. 5. Huang HH, Zhu JY, Han JY, et al. Co-existent de novo myelodysplastic syndrome and T-cell non-Hodgkin lymphoma: A common origin or not? J Int Med Res 2009;37:270–276. 6. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586. 7. Jaalouk G, Avvisati G, Latagliata R, et al. Simultaneous occurrence of large B-cell non-Hodgkin lymphoma and myelodysplastic syndrome rapidly evolving into acute myeloblastic leukemia. Leuk Lymphoma 1996;21:339–341.
doi:10.1002/ajh.23783
Management of concomitant DLBCL and MDS
concomitant DLBCL and MDS have been described so far: the first had a rapid evolution to acute myeloid leukemia (AML) upon initiation of steroid treatment [7]; the second patient, who received Vincristine, Mithoxantrone, Cyclophosphamide, Etoposide, Prednisone, Bleomycin (VNCOP-B) regimen, died of progressive disease after only 3 weeks of therapy [8]. A better outcome resulted in four patients who were treated with a rather intensive course, targeted in three cases to NHL (CHOP, Adriamicin, Bleomycin, Vinblastine, Dacarbazine [ABVD], and cyclophosphamide monotherapy, respectively), and in one case to MDS (Fludarabine, Cytosine Arabinoside, G-CSF [FLAG] regimen). The concomitant MDS in these cases was an expression of RAEB, trilinear MDS, MDS transforming into Chronic myelomonocytic leukemia (CMML), and RAEB evolving into AML, respectively [3,9–11]. In one case treated with FLAG regimen, both NHL and MDS evolving into AML achieved CR after treatment (patient with trilinear dysplasia at 24th month from diagnosis) [3]. We believe that a concomitant MDS should always be suspected and researched in patients with NHL and concomitant cytopenias; in these cases bone marrow evaluation together with cytogenetic study is mandatory to distinguish between lymphoma marrow infiltration and primary MDS. Three hypotheses have been made to explain the concomitant occurrence of MDS and lymphoprolypherative disorders: (a) random association of two relatively common diseases of the elderly; (b) MDS may predispose patients to lymphoid malignancies due to a decrease of immune surveillance; (c) lymphoid proliferation and MDS might originate from a common progenitor, based on the up-regulation of certain cytokines, such as interleukin-6 and vascular endothelial growth factor, and the evidence of the clonality of lymphocytes in 7–22% of MDS [3,5,10]. The medical approach to patients with concomitant MDS and NHL is complex and affected by the patient’s age, performance status, comorbidities, expectations, and NHL and MDS subtype and severity. It may vary from only supportive care to mild cytoreduction, rather intensive chemotherapy, and possible stem cell transplant. Our two cases, on the basis of age, absence of other important comorbities, and mild to medium levels of cytopenia were considered eligible for an adapted intensive approach and treated succesfully with curative intent.
8. Gozzetti A, Calabrese S, Crupi R, et al. Deletion 9q in a patient with concomitant myelodysplasia and non-Hodgkin lymphoma. Cancer Genet Cytogenet 2007;175:177. 9. Anzai T, Hirose W, Nakane H, et al. Myelodysplastic syndrome associated with immunoblastic lymphadenopathy-like T-cell lymphoma: Simultaneous clinical improvement with chemotherapy. Jpn J Clin Oncol 1994;24:106–110. 10. Shimamoto T, Hayashi S, Ando K, et al. Anaplastic large-cell lymphoma which showed severe inflammatory status and myelodysplasia with increased VEGF and IL-& serum levels after long-term immunosuppressive therapy. Am J Hematol 2001;66:49–52. 11. Wawrzycki B, Chodorowska G, Pietrzak A, et al. Therapeutic hotline: Primary cutaneous CD41 small/medium sized pleomorphic T cell lymphoma coexisting with myelodysplastic syndrome transforming into chronic myelomonocytic leukemia successfully treated with cyclophosphamide. Dermatol Ther 2010;23:676–681. 12. Auger MJ, Nash JRG, Mackie MJ. Marrow involvement with T cell lymphoma initially presenting as abnormal myelopoiesis. J Clin Pathol 1986;39:134–137. 13. Copplestone JA, Mufti JG, Hamblin TJ, Oscier DG. Immunological abnormalities in myelodysplastic syndromes. II. Coexistent lymphoid or plasma cell neoplasms: A report of 20 cases unrelated to chemotherapy. Br J Haematol 1986; 63:149–159. 14. Sato T, Shiga Y, Takeda H, et al. IBL-like T cell lymphoma with helper T cell phenotype in a case of myelodysplastic syndrome. Rinsho Ketsueki 1986;27:612–616.
15. Schulze R, Schlimok G, Renner D. Coincidence of primary myelodysplastic syndrome and nonHodgkin lymphoma. Clin Invest 1992;70:1082–1084. 16. Uematsu M, Ochi H, Ueda Y, et al. Coexistent myelodysplastic syndrome and non-Hodgkin’s lymphoma. Report of a case and review of the literature. Int J Hematol 1995;62:45–51. 17. Suh YK, Shin SS, Koo CH. Synchronous Hodgkin’s disease and granulocytic sarcoma with no prior therapy. Hum Pathol 1996;27:1103–1106. 18. Elghetany MT. Hodgkin’s disease coexisting with myelodysplastic syndrome prior to therapy: A case report and a review of the association of Hodgkin’s disease with stem cell disorders. Ann Hematol 1997;75:231–234. 19. Kazakov DV, Mentzel T, Burg G, et al. Blastic natural killer-cell lymphoma of the skin associated with myelodysplastic syndrome or myelogenous leukaemia: A coincidence or more? Br J Dermatol 2003;149:869–876. 20. Dalamaga M, Karmaniolas K, Chavelas C, et al. Coexistence of primary refractory anemia with ringed sideroblast and T cell-lymphoblastic nonHodgkin lymphoma. Acta Haematol 2004;111: 171–172. 21. Takaku T, Miyazawa K, Sashida G, et al. Hepatosplenic alphabeta T-cell lymphoma with myelodysplastic syndrome. Int J Hematol 2005;82: 143–147. 22. Xu B, Meng FY, Li YQ. T-cell non-Hodgkin lymphoma with myelodysplastic syndrome: A case report. Zhonghua Zhong Liu Za Zhi 2005; 27:230.
American Journal of Hematology, Vol. 89, No. 10, October 2014
1013
SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES
AJH Educational Material A physician or group of physicians considers presentation and evolution of a real clinical case, reacting to clinical information and data (boldface type). This is followed by a discussion/commentary
Two cases of concomitant diffuse large B-cell lymphoma and myelodysplastic syndrome Massimo Dozzo, Francesco Zaja,* Stefano Volpetti, Marianna Chiozzotto, Simona Puglisi, Maddalena Mazzucco, Giulia Perali, and Renato Fanin
䊏 Case Report 1 A 64-year-old gentleman was diagnosed in 2011 with myelodisplastic syndrome (MDS)-type refractory cytopenia with monolinear dysplasia (thrombocytopenia), according to the World Health Organization (WHO) classification, International Prognostic Scoring System (IPSS) low risk [1], and was managed only with an observational program. In February 2013, he started complaining of left axillary and supraclavicular adenopathies, together with abdominal pain, abundant night sweats, and weight loss. A supraclavicular lymphnode biopsy performed in March 2013 led to the diagnosis of diffuse large B-cell lymphoma (DLBCL), stage III B [Ann Arbor, International Prognostic Index (IPI) low-intermediate]. Bone marrow aspirate and biopsy performed at the time of DLBCL staging revealed the picture of a multilineage dysplasia with blast excess (Refractory anemia with excess of blast (RAEB) type 2 according to the WHO classification), with normal cytogenetic analysis (46 XY) and intermediate-1 IPSS risk. Total white blood cell and neutrofils counts were 8.3 3 109/L and 4.8 3 109/L, retrospectively; hemoglobin and platelet counts were 104 g/L and 88 3 109/L, respectively. The development of MDS secondary to chemotherapy or radiotherapy is a well known and rather common phenomenon, while the coexistence of de novo MDS and non-Hodgkin lymphomas (NHL) prior to any exposure to chemo-radiotherapy is rare [2]; even if some case reports described the simultaneous occurrence of MDS and NHL, the real incidence of these coexisting diseases has not been established yet [3]. DLBCL is an aggressive disorder that represents nearly 40% of all NHL and can occur with a wide range of clinical presentations [4]. In consideration of the higher incidence of DLBCL in advanced age, it is not unusual that patients with DLBCL present with significant comorbidities, including other oncological diseases; for these cases, treatment should be tailored with a curative intent to the individual patient, unless comorbidities prevent a full therapeutic approach. Concomitant cytopenia is a significant consideration in individualizing the treatment of DLBCL. In particular, the coexistence of a primary MDS negatively interferes with the outcome of lymphoproliferative disease, worsening, in general, the patient’s clinical status and limiting the possibility of a full therapeutic approach [3,5]. In particular, the hematological toxicity of several cytotoxic agents indicated for lymphoma as alkilators or antracyclines may produce prolonged cytopenias and potentially favor leukemic progression; for this
reason, a careful evaluation of the treatment choice for patients in whom there is the coexistence of MDS and NHL is necessary [3,5]. The patient was started on standard R-CHOP chemoimmunotherapy program (Rituximab, Vincristine, Adriamicin, Cyclophosphamide, and Prednisone) every 21 days for six cycles, followed by two further Rituximab administrations; given the coexistence of MDS, the dosage of Doxorubicin and Cyclophosphamide was reduced to 50% of the total dose. The patient’s treatment compliance was fairly good and the therapy was administrated as originally planned. The hematological toxicity experienced during the therapy was moderate; in particular, we observed grade 3 anemia only after course 3, while grade 3 neutropenia and grade 4 thrombocytopenia were observed after each R-CHOP course. The patient received 3–6 administrations of granulocyte colony-stimulating factor (G-CSF), for every cycle except the first one, and a total of three red blood cell transfusions. No infectious complication or episode of neutropenic fever occurred. Restaging after the end of R-CHOP therapy documented a complete remission (CR) status of the lymphoma (according to Cheson 2007 [6]); the bone marrow re-evaluation and, in particular, the percentage of myeloid blasts, were comparable to that observed at baseline. After 11 months of follow-up, the clinical status of the patient remains unchanged for DLBCL and MDS.
䊏 Case Report 2 A 57-year-old woman with a previous medical history (since 2005) of leucopenia and neutropenia, affected by DLBCL, stage IV A with important involvement of dorsal vertebral column, IPI high-intermediate, presented on May 2013. Bone marrow aspiration and biopsy performed at staging found the picture of multilineage dysplasia (RAEB type 2 according to the WHO classification), with intermediate-1 IPSS risk and normal cytogenetic analysis (46 XX). Total white blood cell and neutrofils counts were 1.6 3 109/L and 0.6 3 109/L, respectively, while hemoglobin level and platelet count were 115 g/L and 236 3 109/L, respectively. After initial surgical decompressive laminectomy with D5– D10 stabilization, the patient underwent local radiotherapy at the level of D7–D8 (33 Gy in 11 fractions); subsequently, a standard R-CHOP chemoimmunotherapy program was planned every 21 days for a total of six cycles, followed by two additional Rituximab administrations and concomitant central nervous system prophylaxis with intratecal Methotrexate (12 mg).
Clinica Ematologica, Centro Trapianti e Terapie Cellulari “Carlo Melzi”, DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy
Conflict of interest: Nothing to report *Correspondence to: Francesco Zaja, Clinica Ematologica, Centro Trapianti e Terapie Cellulari “Carlo Melzi”, Azienda Ospedaliero Universitaria S. M. Misericordia, p.le S. Maria Misericordia 15, 33100 Udine, Italy. E-mail: [email protected] Received for publication: 7 May 2014; Revised: 31 May 2014; Accepted: 6 June 2014 Am. J. Hematol. 89:1011–1013, 2014. Published online: 10 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23783 C 2014 Wiley Periodicals, Inc. V
doi:10.1002/ajh.23783
American Journal of Hematology, Vol. 89, No. 10, October 2014
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[3]
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[8] [9] [10] [11] [12] [13]
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PTCL 1 RAEB
PTCL 1 RARS del (20 q) Hepatosplenic gd T-cell NHL 1 RA
HL 1 RA PTCL 1 RCMD PTCL 1 RA/RAEB
Plasmocytic NHL 1 RA PTCL 1 RA Lymphoplasmocytic NHL 1 CMML B-NHL NOS 1 RARS HL 1 GS 1 RAEB
PTCL 1 RA/RAEB
B-NHL PTCL 1 RARS
DLBCL 1 RA del (9 q) PTCL 1 RAEB ALCL 1 MDS PTCL 1 MDS PTCL 1 RAEB B-NHL 1 RAEB
ALCL 1 RCMD del(20 q) PTCL 1 secondary AML PTCL 1 RCMD del(20 q) DLBCL 1 RAEB
Diagnosis
2 CHOP
Splenectomy, LSG-15 regimen (6 VCAP, AMP and VECP) CHOP
4 ABVD Topical corticosteroids Gemcitabine, Prednisone 1 palliative radiotherapy 3 CHOP
ABVD Cyclophosphamide Chemotherapy (not specified) Local radiotherapy, combined chemotherapy (not specified) Chlorambucil Combined chemotherapy (not specified) Combined chemotherapy (not specified) Local radiotherapy Supportive therapy Plasmapheresys, Clorambucil 1 steroids Supportive therapy 4 MOPP/ABVD
VNCOP-B
Steroids
FLAG protocol 1 maintenance therapy with methotrexate COP, CHOP, MINE
CHOP
First line therapy
Death after 2 months
Improvement in clinical condition; death from severe hemorrhagic diathesis PR; transient complete remission after allogeneic SCT and relapse after 11 months
Death after 5 days from disease Transient complete remission and evolution into AML; death from progressive disease Evolution into AML; death from renal failure and stroke PR; death from progressive disease PR; death from progressive disease
Death (not specified) Death from respiratory failure after 23 days PR; death from progressive disease
Death (not specified)
Death (not specified) Death (not specified)
Resistance; death for severe gastrointestinal hemorrhagic bleeding Rapid evolution into AML and death one week later from progressive disease Death from progressive disease after 3 weeks of treatment CR CR; relapse after 8 months in the ethmoid and paranasal sinuses PR Death from deterioration of general conditions Death (not specified)
Resistance; after second line therapy transient response and death from progressive disease CR
Response to first line therapy
2
351
8
9 4 14
1 9
8 1 3
15
7 8
1 221 Not evaluable 141 Not evaluable 16
1
8
241
7
Overall survival (months)
CR: complete remission; PR: partial remission; allogeneic SCT: allogeneic stem cell transplantation; DLBCL: diffuse large B-cell lymphoma; B-NHL-NOS: B-cell non-Hodgkin lymphoma not otherwise specified; HL: Hodgkin’s lymphoma; PTCL: peripheral T-cell lymphoma; ALCL: anaplastic large-cell lymphoma; GS: granulocytic sarcoma; MDS: myelodysplastic syndrome; RARS: refractory anemia with ringed sideroblasts; RA: refractory anemia; RAEB: refractory anemia with excess of blast; RCMD: refractory cytopenia with multilineage dysplasia; AML: acute myeloid leukemia; ABVD: Adriamycin, Bleomycin, Vinblastine, Dacarbazine; ARA-C/HD ARA-C: Cytosine Arabinoside/ High-dose Cytosine Arabinoside; MOPP: Mechlorethamine, Vincristine, Prednisone, Procarbazine; FLAG: Fludarabine, Cytosine Arabinoside, G-CSF; CHOP: Cyclophosphamide, Adriamicin, Vincristine, Prednisone; VCAP: Vincristine, Cyclophasphamide, Doxorubicin, Prednisolone; AMP: Doxorubicin, Ranimustine, Prednisone; VECP: Vindesine, Etoposide, Carboplatin, Prednisolone; COP: Cyclophosphamide, Vincristine, Prednisone; MINE: Ifosfamide, Mithoxantrone, Etoposide, Mesna; VNCOP-B: Vincristine, Mithoxantrone, Cyclophosphamide, Etoposide, Prednisone, Bleomycin; CMML: chronic myelomonocytic leukemia.
Patients
Ref.
TABLE 1. Patients with Concomitant Lymphoma and Myelodysplastic Syndrome
Dozzo et al.
SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES
doi:10.1002/ajh.23783
SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES Due to the association of MDS with moderate decreases of hemoglobin and neutrophils count and peripheral neuropathy (secondary to the lymphoma vertebral involvement), the dosage of Doxorubicin, Cyclophosphamide, and Vincristine was reduced to 50% of the total dose. Overall treatment compliance was rather good, and the hematological toxicity experienced during the therapy reached a grade 2 anemia only after course 2, while grade 4 neutropenia and grade 2 thrombocitopenia were documented after courses 2 and 5. The patient required from 4 to 7 supplementations of G-CSF 300 mcg during the first four cycles; a single administration of pegfilgrastim 6 mg was given after courses 5 and 6. The patient did not necessitate any transfusion support. No extrahematological toxicity and no infectious complications or episodes of neutropenic fever occurred. The restaging at the end of the therapy program documented CR (Cheson 2007), while the bone marrow evaluation resulted superimposable to that of debut. After 10 months of follow-up, the clinical status is of stable CR for DLBCL and unchanged blood cell count. The peculiarity of our cases may be summarized in the following two points: (a) both patients had a diagnosis of DLBCL, which seems to represent a minority among patients with concomitant NHL and MDS; (b) both patients were managed with an adapted specific therapeutic approach (dose reduced R-CHOP), which was performed in the absence of major complications, and this allowed both patients to achieve CR, maintaining a stable situation for MDS.
䊏 Discussion Limited case reports are available on the coexistence of lymphoid malignancies with MDS, with a predominance of T-cell versus B-cell NHL, and mostly with unremarkable outcome and treatment related complications. Table 1 summarizes the patients’ main characteristics, and treatments and outcomes of cases described in the literature; 24 patients have been described so far: four received only palliative treatments, five received CHOP or CHOP-like regimens; overall and complete responses were achieved in 8 and 3, respectively, with a median overall survival of 8 months (range 1–35 months). Only two cases of
䊏 References
1. Komrokji RS, Padron E, Lancet JE, et al. Prognostic factors and risk models in myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk 2013;13 Suppl 2:S295–S299. 2. Tanaka H, Ohwada C, Hashimoto S, et al. Leukemic presentation of ALK-negative anaplastic large cell lymphoma in a patient with myelodysplastic syndrome. Intern Med 2012;51:199–203. 3. Breccia M, Petti MC, D’Elia GM, et al. Cutaneous pleomorphic T-cell lymphoma coexisting with myelodysplastic syndrome transforming into acute myeloid leukemia: Successful treatment with a fludarabine-containing regimen. Eur J Hematol 2002;68:1–3. 4. Ghielmini M, Vitolo U, Kimby E, et al. On behalf of the Panel Members of the 1st ESMO Consensus Conference on Malignant Lymphoma. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia (CLL). Ann Oncol 2013;24:561–576. 5. Huang HH, Zhu JY, Han JY, et al. Co-existent de novo myelodysplastic syndrome and T-cell non-Hodgkin lymphoma: A common origin or not? J Int Med Res 2009;37:270–276. 6. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586. 7. Jaalouk G, Avvisati G, Latagliata R, et al. Simultaneous occurrence of large B-cell non-Hodgkin lymphoma and myelodysplastic syndrome rapidly evolving into acute myeloblastic leukemia. Leuk Lymphoma 1996;21:339–341.
doi:10.1002/ajh.23783
Management of concomitant DLBCL and MDS
concomitant DLBCL and MDS have been described so far: the first had a rapid evolution to acute myeloid leukemia (AML) upon initiation of steroid treatment [7]; the second patient, who received Vincristine, Mithoxantrone, Cyclophosphamide, Etoposide, Prednisone, Bleomycin (VNCOP-B) regimen, died of progressive disease after only 3 weeks of therapy [8]. A better outcome resulted in four patients who were treated with a rather intensive course, targeted in three cases to NHL (CHOP, Adriamicin, Bleomycin, Vinblastine, Dacarbazine [ABVD], and cyclophosphamide monotherapy, respectively), and in one case to MDS (Fludarabine, Cytosine Arabinoside, G-CSF [FLAG] regimen). The concomitant MDS in these cases was an expression of RAEB, trilinear MDS, MDS transforming into Chronic myelomonocytic leukemia (CMML), and RAEB evolving into AML, respectively [3,9–11]. In one case treated with FLAG regimen, both NHL and MDS evolving into AML achieved CR after treatment (patient with trilinear dysplasia at 24th month from diagnosis) [3]. We believe that a concomitant MDS should always be suspected and researched in patients with NHL and concomitant cytopenias; in these cases bone marrow evaluation together with cytogenetic study is mandatory to distinguish between lymphoma marrow infiltration and primary MDS. Three hypotheses have been made to explain the concomitant occurrence of MDS and lymphoprolypherative disorders: (a) random association of two relatively common diseases of the elderly; (b) MDS may predispose patients to lymphoid malignancies due to a decrease of immune surveillance; (c) lymphoid proliferation and MDS might originate from a common progenitor, based on the up-regulation of certain cytokines, such as interleukin-6 and vascular endothelial growth factor, and the evidence of the clonality of lymphocytes in 7–22% of MDS [3,5,10]. The medical approach to patients with concomitant MDS and NHL is complex and affected by the patient’s age, performance status, comorbidities, expectations, and NHL and MDS subtype and severity. It may vary from only supportive care to mild cytoreduction, rather intensive chemotherapy, and possible stem cell transplant. Our two cases, on the basis of age, absence of other important comorbities, and mild to medium levels of cytopenia were considered eligible for an adapted intensive approach and treated succesfully with curative intent.
8. Gozzetti A, Calabrese S, Crupi R, et al. Deletion 9q in a patient with concomitant myelodysplasia and non-Hodgkin lymphoma. Cancer Genet Cytogenet 2007;175:177. 9. Anzai T, Hirose W, Nakane H, et al. Myelodysplastic syndrome associated with immunoblastic lymphadenopathy-like T-cell lymphoma: Simultaneous clinical improvement with chemotherapy. Jpn J Clin Oncol 1994;24:106–110. 10. Shimamoto T, Hayashi S, Ando K, et al. Anaplastic large-cell lymphoma which showed severe inflammatory status and myelodysplasia with increased VEGF and IL-& serum levels after long-term immunosuppressive therapy. Am J Hematol 2001;66:49–52. 11. Wawrzycki B, Chodorowska G, Pietrzak A, et al. Therapeutic hotline: Primary cutaneous CD41 small/medium sized pleomorphic T cell lymphoma coexisting with myelodysplastic syndrome transforming into chronic myelomonocytic leukemia successfully treated with cyclophosphamide. Dermatol Ther 2010;23:676–681. 12. Auger MJ, Nash JRG, Mackie MJ. Marrow involvement with T cell lymphoma initially presenting as abnormal myelopoiesis. J Clin Pathol 1986;39:134–137. 13. Copplestone JA, Mufti JG, Hamblin TJ, Oscier DG. Immunological abnormalities in myelodysplastic syndromes. II. Coexistent lymphoid or plasma cell neoplasms: A report of 20 cases unrelated to chemotherapy. Br J Haematol 1986; 63:149–159. 14. Sato T, Shiga Y, Takeda H, et al. IBL-like T cell lymphoma with helper T cell phenotype in a case of myelodysplastic syndrome. Rinsho Ketsueki 1986;27:612–616.
15. Schulze R, Schlimok G, Renner D. Coincidence of primary myelodysplastic syndrome and nonHodgkin lymphoma. Clin Invest 1992;70:1082–1084. 16. Uematsu M, Ochi H, Ueda Y, et al. Coexistent myelodysplastic syndrome and non-Hodgkin’s lymphoma. Report of a case and review of the literature. Int J Hematol 1995;62:45–51. 17. Suh YK, Shin SS, Koo CH. Synchronous Hodgkin’s disease and granulocytic sarcoma with no prior therapy. Hum Pathol 1996;27:1103–1106. 18. Elghetany MT. Hodgkin’s disease coexisting with myelodysplastic syndrome prior to therapy: A case report and a review of the association of Hodgkin’s disease with stem cell disorders. Ann Hematol 1997;75:231–234. 19. Kazakov DV, Mentzel T, Burg G, et al. Blastic natural killer-cell lymphoma of the skin associated with myelodysplastic syndrome or myelogenous leukaemia: A coincidence or more? Br J Dermatol 2003;149:869–876. 20. Dalamaga M, Karmaniolas K, Chavelas C, et al. Coexistence of primary refractory anemia with ringed sideroblast and T cell-lymphoblastic nonHodgkin lymphoma. Acta Haematol 2004;111: 171–172. 21. Takaku T, Miyazawa K, Sashida G, et al. Hepatosplenic alphabeta T-cell lymphoma with myelodysplastic syndrome. Int J Hematol 2005;82: 143–147. 22. Xu B, Meng FY, Li YQ. T-cell non-Hodgkin lymphoma with myelodysplastic syndrome: A case report. Zhonghua Zhong Liu Za Zhi 2005; 27:230.
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