Int J Hematol (2014) 99:777–781 DOI 10.1007/s12185-014-1563-5
CASE REPORT
Pure red cell aplasia complicating the course of long-standing mantle cell lymphoma Alexander Kanellopoulos • Katrina Koutsi • George Georgiou • Themis Ntalagiorgos • Kyriaki Petevi • George Boutsikas • Loula Papageorgiou • Gabriela Gainaru • Pagona Flevari • Maria K. Angelopoulou • John Meletis • Theodoros P. Vassilakopoulos
Received: 2 October 2013 / Revised: 22 February 2014 / Accepted: 23 February 2014 / Published online: 26 March 2014 Ó The Japanese Society of Hematology 2014
Abstract Pure red cell aplasia (PRCA) is a rare cause of severe hypoplastic anemia characterized by profound depletion of erythroid precursors. Although PRCA may be associated with lymphoproliferative diseases, it has never been described in mantle cell lymphoma (MCL). We report what to our knowledge is the first case of a patient with indolent, non-nodal MCL complicated by PRCA. The patient presented with severe hypoproliferative anemia in the setting of a long-standing diagnosis of B-cell chronic lymphocytic leukemia. Bone marrow studies revealed the complete absence of erythroid progenitors. Cyclin D1 positivity on immunohistochemistry, confirmed by a positive FISH for t(11;14) (q13;q32), established the final diagnosis of MCL in conjunction with PRCA. Rituximab monotherapy led to rapid remission of splenomegaly and the leukemic picture, but the patient achieved transfusion independency only with subsequent administration of cyclosporine-A, and remained so during the subsequent 15 months despite the gradual disease recurrence.
Pure red cell aplasia (PRCA) is a syndrome characterized by selective and complete absence of bone marrow erythroblasts, resulting in hypoplastic, normochromic, and normocytic anemia [1]. PRCA is caused by humoral suppressors of erythropoiesis or an abnormal marrow microenvironment and may develop in many hematologic malignancies, most commonly in B-cell chronic lymphocytic leukemia (B-CLL) or T-cell large granular lymphocyte leukemia (T-LGL) [2]. PRCA has been rarely described to complicate the clinical course of non-Hodgkin’s lymphomas, especially in low-grade histologies [3–5]. To the best of our knowledge, an association of PRCA with mantle cell lymphoma (MCL) has not been reported so far [6, 7]. We report a case of non-nodal, indolent MCL complicated by PRCA, regressing only after cyclosporine-A (CsA) administration, despite the prompt response of disease to rituximab monotherapy.
Keywords Pure red cell aplasia Mantle cell lymphoma Rituximab Cyclosporine-A
Case report
A. Kanellopoulos K. Koutsi G. Georgiou T. Ntalagiorgos K. Petevi G. Boutsikas L. Papageorgiou G. Gainaru P. Flevari M. K. Angelopoulou J. Meletis T. P. Vassilakopoulos (&) Department of Haematology, School of Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece e-mail: [email protected]
An 84-year-old woman with a reported history of B-CLL since 1990 was referred to our department on August 2011 due to severe, transfusion-dependent anemia of 12-month duration. Since then, the patient was asymptomatic with indolent disease characterized by moderate, stable lymphocytosis without symptomatic organomegaly/lymphadenopathy or cytopenias. Therefore, she had never received cytostatic treatment or steroids, while anemia was resistant to darbepoetin alfa. Her medical history was remarkable for hypertension, generalized anxiety disorder, and transient ischemic attack treated with valsartan/hydrochlorothiazide, escitalopram, and clopidogrel, respectively.
Introduction
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778 Table 1 Patient laboratory characteristics linking MCL with PRCA
A. Kanellopoulos et al.
CT scan
Splenomegaly and absent lymphadenopathy
BM biopsy
[70 % CD20?CD5?CD23?CD21?CD43?DBA44?Cyclin D1? lymphoid cells
BM smear
82 % lymphocytes/18 % myeloid cells/megakaryocytes present/ virtually absent erythroid cells
BM immunophenotype
Predominant k?CD20intFMC-7dim/intCD79bdim/ int CD5dimCD23dimCD11c? population 81 %
PB FISH for t(11;14) (% positivity)
MCL mantle cell lymphoma, CT computed tomography, BM bone marrow, PB peripheral blood, NMC nucleated marrow cells, int intermediate positivity, PR partial response, MR no response, Pos positive, Neg negative, DAT direct antiglobulin test, IAT indirect antiglobulin test, and SPEP serum protein electrophoresis
Ht (%)/Hb (g/L)
21.0/69
RBC count (per L)
2.66 9 1012
Reticulocyte count (per L)
3 9 109
MCV (fl)/MCH (pg)/MCHC (g/dL)
81.6/25.9/31.8
WBC count (per L)/differential (%)
20.01 9 109 (poly 14, lymphs 80, monos 5, eos 1)
PLT count (per L) BM PCR for TcR clonality
204 9 109 Neg.
Parvovirus serology IgM, IgG
Neg.
Ferritin level (ng/mL)
925
DAT/IAT
Neg.
Serum protein (albumin/ c-Globulin; g/L)-SPEP
57 (41/6)-no paraprotein peaks
On admission, physical examination revealed pallor and moderate splenomegaly 5 cm below the left costal margin (blcm). Laboratory tests demonstrated hematocrit 21.0 %, hemoglobin 6.9 g/dL, red blood cell count 2.66 9 1012/L (MCV 81.6 fl, MCH 25.9 pg, MCHC 31.8 g/dL), white blood cell count 20.01 9 109/L with absolute lymphocytosis (poly 14 %, lymphs 80 %, monos 5 %, eosinophils 1 %), platelet count 204 9 109/L, markedly low reticulocyte count of 3 9 109/L, elevated LDH levels of 439 U/L (upper normal limit 220 U/L), moderately elevated serum ferritin of 925 ng/Ml, and normal kidney and liver function tests, except for slightly elevated blood urea nitrogen. In peripheral blood, there was a variation in lymphocyte morphology, with predominant mature small lymphocytes with a thin rim of cytoplasm and mature-appearing round nuclei while other neoplastic cells had more abundant cytoplasm and irregular indented nuclei. The total serum protein level was 57 g/L with hypogammaglobulinemia (albumin 41 g/L, c-globulins 6 g/L); no paraprotein peaks were observed, and the direct and indirect Coombs’ tests were negative with no laboratory evidence of hemolysis. Parvovirus B19 serology (IgM, IgG) was negative. A whole body CT scan confirmed the presence of splenomegaly without lymphadenopathy. The main laboratory findings are summarized in Table 1. Bone marrow smears revealed extensive infiltration by small, mature lymphocytes at a percentage of 82 %. Myeloid cells accounted for 18 % of total bone marrow
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cells, and megakaryocytes were present, while erythroblasts were virtually absent. No significant dysplastic changes were evident. Bone marrow biopsy demonstrated extensive nodular and interstitial involvement by CD5?, CD20?, CD23?, and Cyclin D1? lymphoid cells. The immunophenotype revealed the presence of a predominant k-clonal CD5?, CD23dim, CD20dim, FMC-7dim/intermediate, CD79bdim/intermediate, and CD11c? lymphoid population. In the extensive lymphocytic infiltrate that consisted 91 % of nucleated marrow cells, CD3?CD8?, CD3-CD16?/ CD56?, and CD3?CD16?/CD56? cells were 3, 3, and 1 %, respectively. Furthermore, PCR fragment analysis for T-cell clonality in the bone marrow was negative. These data support the exclusion of concomitant T-large granular lymphocytic leukemia (T-LGL) in this patient. Cyclin D1 positivity prompted us to perform FISH analysis on peripheral blood cells, which was positive for the presence of t(11;14)(q13;q32) translocation. Therefore, the diagnosis was modified from B-CLL to the splenic form of MCL, complicated by PRCA (Table 1). The patient received 4 weekly courses of rituximab with complete disappearance of both lymphocytosis and palpable splenomegaly. Despite this rapid tumor response, anemia was marginally improved as long as hemoglobin levels increased by only 1 g/dl under a heavy transfusion programme. At that point, 10 weeks after the start of rituximab treatment, she was started on cyclosporine at 3 mg/kg daily in two divided doses. One month after the initiation of
PRCA in mantle cell lymphoma
779
Fig. 1 Hemogram and treatment regimens of patient. Arrow (down arrow) depicts rituximab weekly cycle, (right arrow) represents duration of cyclosporine-A (CsA) administration and (inverted triangle) stands for a unit of packed red blood cells
cyclosporine treatment, the patient achieved transfusion independency with hemoglobin level of approximately 10 g/dL. A bone marrow aspiration and biopsy, performed 4 months after the start of CsA treatment, revealed restoration of erythropoiesis with persistence of neoplastic lymphoid population, albeit at the much lower percentage of 20 %. Nine months afterwards, the patient developed again a relatively stable leukemic picture and subtle, but clinically evident splenomegaly of 2 cm blcm. However, she remained transfusion independent during the subsequent 15 months (Fig. 1).
Discussion MCL represents 6 % of all non-Hodgkin’s lymphomas. It is an incurable B-cell malignancy, which frequently presents with generalized lymphadenopathy, hepatosplenomegaly, and extranodal disease, mainly consisting of bone marrow and subclinical gastrointestinal tract involvement [8]. The primary genetic event is the cytogenetic abnormality t(11;14)(q13;q32) that leads to cyclin D1 overexpression, providing an excellent marker for diagnosis. Compared with other indolent lymphomas, MCL usually runs a more aggressive clinical course. However, there is a marked heterogeneity regarding response to treatment and final outcome, which may in part reflect the presence or absence of biological markers [9, 10]. The initially reported median survival of 3–5 years may have been improved with the advent of modern treatment approaches. Although intensive approaches including high-dose cytarabine or the use of autologous transplantation as consolidation therapy
may provide good results in younger patients [11, 12], many patients have a more indolent disease. Indeed, satisfactory results have also been reported with the combination of rituximab with mild chemotherapy, such as oral intermittent chlorambucil [13]. Furthermore, recent data highlight the role of maintenance rituximab in prolonging not only progression-free survival, but also overall survival [14, 15]. Cases of MCL presenting with leukemic picture and/or splenomegaly without lymphadenopathy probably constitute a separate subset of the disease with more indolent clinical course [16]. Non-nodal leukemic MCL is recognized as a dinstict clinical entity. Although it shares a similar gene expression profile with classical MCL, it bears unique features, most notably the mutated immunoglobulin heavy chain genes (IgVH), downregulated cell adhesion/ invasion property, underexpression of SOX-11 gene and expression of CD23 [17–19]. Indolent MCL displays a less aggressive clinical behavior than classical MCL, with a significantly longer survival, often exceeding 7–10 years, and can be managed with a ‘watch and wait’ approach or with less intensive treatment approaches [13, 20]. In the above mentioned patient, the indolent clinical course along with neoplastic cell morphology and CD5/ CD23 positivity resulted in a long-standing diagnosis of B-CLL. However, as leukemic cells were CD11c positive and had dim to moderate expression of FMC-7 and CD79b, alternative diagnoses of SMZL and MCL were also considered, given that CD23 tends to be positive in SMZL as well as in the splenic and non-nodal subset of MCL [19]. Finally, the expression of cyclin D1 on bone marrow biopsy, which was confirmed by a positive FISH analysis
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for the presence of t(11;14) on peripheral blood neoplastic cells, established the diagnosis of MCL. Autoimmune hemolytic anemia and PRCA are rare but well-described complications of non-Hodgkin’s lymphomas. The most frequent lymphoproliferative disorders complicated by PRCA are T-LGL, CLL, angioimmunoblastic T-cell lymphoma (AITL), and diffuse large B-cell lymphoma (DLBCL) [6, 7]. To the best of our knowledge, PRCA has never been described in association with MCL [6]. It should be stressed that PCR for TCR clonality excluded T-LGL as a potential cause of PRCA in this patient. Among her medications (including darbepoetin), only clopidogrel has been implicated in the development of PRCA in a single case report [2, 21]. However, our patient had been taking clopidogrel for many years and the drug was not ceased after the diagnosis of PRCA, due to high risk for recurrent arterial thrombotic disease. The underlying pathogenesis of PRCA complicating lymphoproliferative disorders remains rather intangible. It is an immune process, involving either antibody-induced red cell aplasia (mediated by monoclonal or polyclonal B-cells) or T-cells (and NK-cells) that suppress erythropoiesis not only directly, but also by producing inhibitory mediators that disrupt the expansion of erythroid colonies in the bone marrow [2, 5, 22]. For example, in S-LGL leukemia, erythropoiesis is suppressed either by LHC-I restricted CD8? T-lymphocyte cytotoxicity, or by LHC-Iindependent T-cell cytotoxicity related to the existence of killer cell inhibitory receptors (JIRs) [23, 24]. Instead, in other lymphoma subtypes, such as angioimmunoblastic T-cell lymphoma, the inhibition of erythroid precursors appears to be mediated by humoral factors [25]. Furthermore, PRCA has been reported in the context of follicular lymphoma (FL), splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) [5, 6]. It is noteworthy that in many cases, the condition is both B- and T-cell mediated. This applies to PRCA induced by red cell progenitor-specific antibodies that cross-link the Fc receptor of T-LGL with the target cell, when S-LGL and B-NHL coexist [26]. The therapeutic armamentarium of PRCA consists mainly of immunosuppressive treatments such as corticosteroids, cyclophosphamide, CsA, antithymocyte globulin, and splenectomy with an overall response rate of about 68 % [2]. Dungarwalla et al. [27] described three patients with idiopathic PRCA unresponsive to rituximab, but few case reports suggest that rituximab may benefit patients with indolent lymphomas (B-CLL, SMZL) complicated by immunosuppression-resistant PRCA [2, 5]. Hirokawa et al. [7] suggested that chemotherapy improves PRCA in parallel with lymphoma. In our patient, non-nodal MCL was complicated by PRCA that persisted irrespective of disease burden reduction, because rituximab led to rapid and
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A. Kanellopoulos et al.
complete regression of splenomegaly and marrow involvement, with only 20 % residual lymphoma cells, but its role in the improvement of PRCA was rather questionable. Although we cannot exclude a late effect of rituximab, the patient became transfusion independent only with CsA. This might reflect the potential predominant role of T- or NK-cells in the pathogenesis of PRCA in this patient. The elimination of erythroid precursors could be mediated by a polyclonal expansion of CD8? cytotoxic T-cells. Alternatively, it could be mediated by cd S-cells via an MHC-unrestricted manner. According to a recent study, such cd S-cells display non-clonal expansion of Vd1 and depletion of Vd2 populations in chronic acquired PRCA [28]. The MCL patient reported here has many clinical similarities to B-CLL, whereas the response of our case to immunosuppressive therapy after failure to control satisfactorily PRCA with tumor burden reduction may resemble to B-CLL PRCA, which is not an indication for diseasespecific treatment, unless immunosuppression has failed [29, 30]. Further, the notion that in B-CLL PRCA is mediated by autoantibodies against erythroid progenitors, is challenged by data highlighting the role of T and NK-cells that exert direct cytolysis on erythroid progenitors [24, 30]. In conclusion, this is the first report of PRCA in conjuction with MCL and specifically its indolent subset, which initially presented as primary leukemic disease and then progressed to its splenic form. This provides some insight into the heterogeneity of MCL and highlights the need to expand our understanding in the complexity of interactions between the lymphoma cells and the immune system. Conflict of interest of interest.
The authors declare that they have not conflict
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PRCA in mantle cell lymphoma 6. Hauswirth AW, Skrabs C, Schutzinger C, Gaiger A, Lechner K, Jager U. Autoimmune hemolytic anemias, Evans’ syndromes, and pure red cell aplasia in non-Hodgkin lymphomas. Leuk Lymphoma. 2007;48:1139–49. 7. Hirokawa M, Sawada K, Fujishima N, Kawano F, Kimura A, Watanabe T, et al. Acquired pure red cell aplasia associated with malignant lymphomas: a nationwide cohort study in Japan for the PRCA Collaborative Study Group. Am J Hematol. 2009;84:144–8. 8. Swerdlow SH, Campo E, Seto M, Mu¨ller-Hermelink HK. Mantle cell lymphoma. In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Shiele J, Vardiman JW, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th edn. International Agency for Research on Cancer (IARC), 2008. 9. Korkolopoulou P, Vassilakopoulos TP. Topoisomerase IIalpha as a prognostic factor in mantle cell lymphoma. Leukemia. 2004;18:1347–9. 10. Von Hohenstaufen KA, Conconi A, de Campos CP, Franceschetti S, Bertoni F, Margiotta Casaluci G, et al. Prognostic impact of monocyte count at presentation in mantle cell lymphoma. Br J Haematol. 2013;162:465–73. 11. Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23:7013–23. 12. Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C, Schmits R, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105:2677–84. 13. Sachanas S, Pangalis GA, Vassilakopoulos TP, Korkolopoulou P, Kontopidou FN, Athanasoulia M, et al. Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen. Leuk Lymphoma. 2011;52:387–93. 14. Dreyling M, Kluin-Nelemans HC, Bea` S, Klapper W, Vogt N, Delfau-Larue MH, et al. Update on the molecular pathogenesis and clinical treatment of mantle cell lymphoma: report of the 11th annual conference of the European Mantle Cell Lymphoma Network. Leuk Lymphoma. 2013;54:699–707. 15. Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520–31. 16. Angelopoulou MK, Siakantaris MP, Vassilakopoulos TP, Kontopidou FN, Rassidakis GZ, Dimopoulou MN, et al. The splenic form of mantle cell lymphoma. Eur J Haematol. 2002;68:12–21. 17. Ferna`ndez V, Salamero O, Espinet B, Sole´ F, Royo C, Navarro A, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70:1408–18.
781 18. Orchard J, Garand R, Davis Z, Babbage G, Sahota S, Matutes E, et al. A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, non nodal disease. Blood. 2003;101:4975–81. 19. Ondrejka SL, Lai R, Kumar N, Smith SD, Hsi ED. Indolent mantle cell leukemia: clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, j light chain restriction, and good prognosis. Haematologica. 2011;96:1221–7. 20. Martin P, Chadburn A, Christos P, Weil K, Furman RR, Ruan J, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27:1209–13. 21. Li G, Li ZQ, Yang QY, Yang JD. Acquired pure red cell aplasia due to treatment with clopidogrel: first case report. J Thromb Thrombolysis. 2013 (Epub ahead of print). 22. Alter R, Joshi S, Verdirame JD, Weisenburger DD. Pure red cell aplasia associated with B cell lymphoma: demonstration of bone marrow colony inhibition by serum immunoglobulin. Leuk Res. 1990;14:279–86. 23. Handgretinger R, Geiselhart A, Moris A, Grau R, Teuffel O, Bethge W, et al. Pure red cell aplasia associated with clonal expansion of granular lymphocytes expressing killer-cell inhibitory receptors. N Engl J Med. 1999;340:278–84. 24. Dessypris EN, Lipton JM. Red cell aplasia. In: Greer JP, Foerster J, Lukens JN, Rogers GM, Paraskevas MD, Glader B, editors. Wintrobe’s Clinical Hematology, 12th edn. Philadelphia: Lippincott, Williams & Wilkins, 2009:1196–11. 25. Higuchi T, Mori H, Niikura H, Omine M. Hypocomplementemia and hematological abnormalities in immunoblastic lymphadenopathy and immunoblastic lymphadenopathy-like T cell lymphoma. Acta Haematol. 1996;96:68–72. 26. Loughran TP. Clonal diseases of large granular lymphocytes. Blood. 1993;82:1–14. 27. Dungarwalla M, Marsh JCW, Tooze JA, Lucas G, Ouwehand W, Petengell R, et al. Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology. Ann Hematol. 2007;86:191–7. 28. Michishita Y, Hirokawa M, Fujishima N, Abe Y, Fujishima M, Guo Y-M, et al. CDR3-independent expansion of Vd1 S lymphocytes in acquired chronic pure red cell aplasia. Immunol Let. 2013;150:23–9. 29. Ghazal H. Succesful treatment of pure red cell aplasia with rituximab in patients with chronic lymphocytic leukemia. Blood. 2002;99:1092–4. 30. D’Arena G, Guariglia R, La Rocca F, Trino S, Condelli V, DeMartino L, et al. Autoimmune cytopenias in chronic lymphocytic leukemia. Clin Dev Immunol. 2013;2013:730131.
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CASE REPORT
Pure red cell aplasia complicating the course of long-standing mantle cell lymphoma Alexander Kanellopoulos • Katrina Koutsi • George Georgiou • Themis Ntalagiorgos • Kyriaki Petevi • George Boutsikas • Loula Papageorgiou • Gabriela Gainaru • Pagona Flevari • Maria K. Angelopoulou • John Meletis • Theodoros P. Vassilakopoulos
Received: 2 October 2013 / Revised: 22 February 2014 / Accepted: 23 February 2014 / Published online: 26 March 2014 Ó The Japanese Society of Hematology 2014
Abstract Pure red cell aplasia (PRCA) is a rare cause of severe hypoplastic anemia characterized by profound depletion of erythroid precursors. Although PRCA may be associated with lymphoproliferative diseases, it has never been described in mantle cell lymphoma (MCL). We report what to our knowledge is the first case of a patient with indolent, non-nodal MCL complicated by PRCA. The patient presented with severe hypoproliferative anemia in the setting of a long-standing diagnosis of B-cell chronic lymphocytic leukemia. Bone marrow studies revealed the complete absence of erythroid progenitors. Cyclin D1 positivity on immunohistochemistry, confirmed by a positive FISH for t(11;14) (q13;q32), established the final diagnosis of MCL in conjunction with PRCA. Rituximab monotherapy led to rapid remission of splenomegaly and the leukemic picture, but the patient achieved transfusion independency only with subsequent administration of cyclosporine-A, and remained so during the subsequent 15 months despite the gradual disease recurrence.
Pure red cell aplasia (PRCA) is a syndrome characterized by selective and complete absence of bone marrow erythroblasts, resulting in hypoplastic, normochromic, and normocytic anemia [1]. PRCA is caused by humoral suppressors of erythropoiesis or an abnormal marrow microenvironment and may develop in many hematologic malignancies, most commonly in B-cell chronic lymphocytic leukemia (B-CLL) or T-cell large granular lymphocyte leukemia (T-LGL) [2]. PRCA has been rarely described to complicate the clinical course of non-Hodgkin’s lymphomas, especially in low-grade histologies [3–5]. To the best of our knowledge, an association of PRCA with mantle cell lymphoma (MCL) has not been reported so far [6, 7]. We report a case of non-nodal, indolent MCL complicated by PRCA, regressing only after cyclosporine-A (CsA) administration, despite the prompt response of disease to rituximab monotherapy.
Keywords Pure red cell aplasia Mantle cell lymphoma Rituximab Cyclosporine-A
Case report
A. Kanellopoulos K. Koutsi G. Georgiou T. Ntalagiorgos K. Petevi G. Boutsikas L. Papageorgiou G. Gainaru P. Flevari M. K. Angelopoulou J. Meletis T. P. Vassilakopoulos (&) Department of Haematology, School of Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece e-mail: [email protected]
An 84-year-old woman with a reported history of B-CLL since 1990 was referred to our department on August 2011 due to severe, transfusion-dependent anemia of 12-month duration. Since then, the patient was asymptomatic with indolent disease characterized by moderate, stable lymphocytosis without symptomatic organomegaly/lymphadenopathy or cytopenias. Therefore, she had never received cytostatic treatment or steroids, while anemia was resistant to darbepoetin alfa. Her medical history was remarkable for hypertension, generalized anxiety disorder, and transient ischemic attack treated with valsartan/hydrochlorothiazide, escitalopram, and clopidogrel, respectively.
Introduction
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778 Table 1 Patient laboratory characteristics linking MCL with PRCA
A. Kanellopoulos et al.
CT scan
Splenomegaly and absent lymphadenopathy
BM biopsy
[70 % CD20?CD5?CD23?CD21?CD43?DBA44?Cyclin D1? lymphoid cells
BM smear
82 % lymphocytes/18 % myeloid cells/megakaryocytes present/ virtually absent erythroid cells
BM immunophenotype
Predominant k?CD20intFMC-7dim/intCD79bdim/ int CD5dimCD23dimCD11c? population 81 %
PB FISH for t(11;14) (% positivity)
MCL mantle cell lymphoma, CT computed tomography, BM bone marrow, PB peripheral blood, NMC nucleated marrow cells, int intermediate positivity, PR partial response, MR no response, Pos positive, Neg negative, DAT direct antiglobulin test, IAT indirect antiglobulin test, and SPEP serum protein electrophoresis
Ht (%)/Hb (g/L)
21.0/69
RBC count (per L)
2.66 9 1012
Reticulocyte count (per L)
3 9 109
MCV (fl)/MCH (pg)/MCHC (g/dL)
81.6/25.9/31.8
WBC count (per L)/differential (%)
20.01 9 109 (poly 14, lymphs 80, monos 5, eos 1)
PLT count (per L) BM PCR for TcR clonality
204 9 109 Neg.
Parvovirus serology IgM, IgG
Neg.
Ferritin level (ng/mL)
925
DAT/IAT
Neg.
Serum protein (albumin/ c-Globulin; g/L)-SPEP
57 (41/6)-no paraprotein peaks
On admission, physical examination revealed pallor and moderate splenomegaly 5 cm below the left costal margin (blcm). Laboratory tests demonstrated hematocrit 21.0 %, hemoglobin 6.9 g/dL, red blood cell count 2.66 9 1012/L (MCV 81.6 fl, MCH 25.9 pg, MCHC 31.8 g/dL), white blood cell count 20.01 9 109/L with absolute lymphocytosis (poly 14 %, lymphs 80 %, monos 5 %, eosinophils 1 %), platelet count 204 9 109/L, markedly low reticulocyte count of 3 9 109/L, elevated LDH levels of 439 U/L (upper normal limit 220 U/L), moderately elevated serum ferritin of 925 ng/Ml, and normal kidney and liver function tests, except for slightly elevated blood urea nitrogen. In peripheral blood, there was a variation in lymphocyte morphology, with predominant mature small lymphocytes with a thin rim of cytoplasm and mature-appearing round nuclei while other neoplastic cells had more abundant cytoplasm and irregular indented nuclei. The total serum protein level was 57 g/L with hypogammaglobulinemia (albumin 41 g/L, c-globulins 6 g/L); no paraprotein peaks were observed, and the direct and indirect Coombs’ tests were negative with no laboratory evidence of hemolysis. Parvovirus B19 serology (IgM, IgG) was negative. A whole body CT scan confirmed the presence of splenomegaly without lymphadenopathy. The main laboratory findings are summarized in Table 1. Bone marrow smears revealed extensive infiltration by small, mature lymphocytes at a percentage of 82 %. Myeloid cells accounted for 18 % of total bone marrow
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cells, and megakaryocytes were present, while erythroblasts were virtually absent. No significant dysplastic changes were evident. Bone marrow biopsy demonstrated extensive nodular and interstitial involvement by CD5?, CD20?, CD23?, and Cyclin D1? lymphoid cells. The immunophenotype revealed the presence of a predominant k-clonal CD5?, CD23dim, CD20dim, FMC-7dim/intermediate, CD79bdim/intermediate, and CD11c? lymphoid population. In the extensive lymphocytic infiltrate that consisted 91 % of nucleated marrow cells, CD3?CD8?, CD3-CD16?/ CD56?, and CD3?CD16?/CD56? cells were 3, 3, and 1 %, respectively. Furthermore, PCR fragment analysis for T-cell clonality in the bone marrow was negative. These data support the exclusion of concomitant T-large granular lymphocytic leukemia (T-LGL) in this patient. Cyclin D1 positivity prompted us to perform FISH analysis on peripheral blood cells, which was positive for the presence of t(11;14)(q13;q32) translocation. Therefore, the diagnosis was modified from B-CLL to the splenic form of MCL, complicated by PRCA (Table 1). The patient received 4 weekly courses of rituximab with complete disappearance of both lymphocytosis and palpable splenomegaly. Despite this rapid tumor response, anemia was marginally improved as long as hemoglobin levels increased by only 1 g/dl under a heavy transfusion programme. At that point, 10 weeks after the start of rituximab treatment, she was started on cyclosporine at 3 mg/kg daily in two divided doses. One month after the initiation of
PRCA in mantle cell lymphoma
779
Fig. 1 Hemogram and treatment regimens of patient. Arrow (down arrow) depicts rituximab weekly cycle, (right arrow) represents duration of cyclosporine-A (CsA) administration and (inverted triangle) stands for a unit of packed red blood cells
cyclosporine treatment, the patient achieved transfusion independency with hemoglobin level of approximately 10 g/dL. A bone marrow aspiration and biopsy, performed 4 months after the start of CsA treatment, revealed restoration of erythropoiesis with persistence of neoplastic lymphoid population, albeit at the much lower percentage of 20 %. Nine months afterwards, the patient developed again a relatively stable leukemic picture and subtle, but clinically evident splenomegaly of 2 cm blcm. However, she remained transfusion independent during the subsequent 15 months (Fig. 1).
Discussion MCL represents 6 % of all non-Hodgkin’s lymphomas. It is an incurable B-cell malignancy, which frequently presents with generalized lymphadenopathy, hepatosplenomegaly, and extranodal disease, mainly consisting of bone marrow and subclinical gastrointestinal tract involvement [8]. The primary genetic event is the cytogenetic abnormality t(11;14)(q13;q32) that leads to cyclin D1 overexpression, providing an excellent marker for diagnosis. Compared with other indolent lymphomas, MCL usually runs a more aggressive clinical course. However, there is a marked heterogeneity regarding response to treatment and final outcome, which may in part reflect the presence or absence of biological markers [9, 10]. The initially reported median survival of 3–5 years may have been improved with the advent of modern treatment approaches. Although intensive approaches including high-dose cytarabine or the use of autologous transplantation as consolidation therapy
may provide good results in younger patients [11, 12], many patients have a more indolent disease. Indeed, satisfactory results have also been reported with the combination of rituximab with mild chemotherapy, such as oral intermittent chlorambucil [13]. Furthermore, recent data highlight the role of maintenance rituximab in prolonging not only progression-free survival, but also overall survival [14, 15]. Cases of MCL presenting with leukemic picture and/or splenomegaly without lymphadenopathy probably constitute a separate subset of the disease with more indolent clinical course [16]. Non-nodal leukemic MCL is recognized as a dinstict clinical entity. Although it shares a similar gene expression profile with classical MCL, it bears unique features, most notably the mutated immunoglobulin heavy chain genes (IgVH), downregulated cell adhesion/ invasion property, underexpression of SOX-11 gene and expression of CD23 [17–19]. Indolent MCL displays a less aggressive clinical behavior than classical MCL, with a significantly longer survival, often exceeding 7–10 years, and can be managed with a ‘watch and wait’ approach or with less intensive treatment approaches [13, 20]. In the above mentioned patient, the indolent clinical course along with neoplastic cell morphology and CD5/ CD23 positivity resulted in a long-standing diagnosis of B-CLL. However, as leukemic cells were CD11c positive and had dim to moderate expression of FMC-7 and CD79b, alternative diagnoses of SMZL and MCL were also considered, given that CD23 tends to be positive in SMZL as well as in the splenic and non-nodal subset of MCL [19]. Finally, the expression of cyclin D1 on bone marrow biopsy, which was confirmed by a positive FISH analysis
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for the presence of t(11;14) on peripheral blood neoplastic cells, established the diagnosis of MCL. Autoimmune hemolytic anemia and PRCA are rare but well-described complications of non-Hodgkin’s lymphomas. The most frequent lymphoproliferative disorders complicated by PRCA are T-LGL, CLL, angioimmunoblastic T-cell lymphoma (AITL), and diffuse large B-cell lymphoma (DLBCL) [6, 7]. To the best of our knowledge, PRCA has never been described in association with MCL [6]. It should be stressed that PCR for TCR clonality excluded T-LGL as a potential cause of PRCA in this patient. Among her medications (including darbepoetin), only clopidogrel has been implicated in the development of PRCA in a single case report [2, 21]. However, our patient had been taking clopidogrel for many years and the drug was not ceased after the diagnosis of PRCA, due to high risk for recurrent arterial thrombotic disease. The underlying pathogenesis of PRCA complicating lymphoproliferative disorders remains rather intangible. It is an immune process, involving either antibody-induced red cell aplasia (mediated by monoclonal or polyclonal B-cells) or T-cells (and NK-cells) that suppress erythropoiesis not only directly, but also by producing inhibitory mediators that disrupt the expansion of erythroid colonies in the bone marrow [2, 5, 22]. For example, in S-LGL leukemia, erythropoiesis is suppressed either by LHC-I restricted CD8? T-lymphocyte cytotoxicity, or by LHC-Iindependent T-cell cytotoxicity related to the existence of killer cell inhibitory receptors (JIRs) [23, 24]. Instead, in other lymphoma subtypes, such as angioimmunoblastic T-cell lymphoma, the inhibition of erythroid precursors appears to be mediated by humoral factors [25]. Furthermore, PRCA has been reported in the context of follicular lymphoma (FL), splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) [5, 6]. It is noteworthy that in many cases, the condition is both B- and T-cell mediated. This applies to PRCA induced by red cell progenitor-specific antibodies that cross-link the Fc receptor of T-LGL with the target cell, when S-LGL and B-NHL coexist [26]. The therapeutic armamentarium of PRCA consists mainly of immunosuppressive treatments such as corticosteroids, cyclophosphamide, CsA, antithymocyte globulin, and splenectomy with an overall response rate of about 68 % [2]. Dungarwalla et al. [27] described three patients with idiopathic PRCA unresponsive to rituximab, but few case reports suggest that rituximab may benefit patients with indolent lymphomas (B-CLL, SMZL) complicated by immunosuppression-resistant PRCA [2, 5]. Hirokawa et al. [7] suggested that chemotherapy improves PRCA in parallel with lymphoma. In our patient, non-nodal MCL was complicated by PRCA that persisted irrespective of disease burden reduction, because rituximab led to rapid and
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complete regression of splenomegaly and marrow involvement, with only 20 % residual lymphoma cells, but its role in the improvement of PRCA was rather questionable. Although we cannot exclude a late effect of rituximab, the patient became transfusion independent only with CsA. This might reflect the potential predominant role of T- or NK-cells in the pathogenesis of PRCA in this patient. The elimination of erythroid precursors could be mediated by a polyclonal expansion of CD8? cytotoxic T-cells. Alternatively, it could be mediated by cd S-cells via an MHC-unrestricted manner. According to a recent study, such cd S-cells display non-clonal expansion of Vd1 and depletion of Vd2 populations in chronic acquired PRCA [28]. The MCL patient reported here has many clinical similarities to B-CLL, whereas the response of our case to immunosuppressive therapy after failure to control satisfactorily PRCA with tumor burden reduction may resemble to B-CLL PRCA, which is not an indication for diseasespecific treatment, unless immunosuppression has failed [29, 30]. Further, the notion that in B-CLL PRCA is mediated by autoantibodies against erythroid progenitors, is challenged by data highlighting the role of T and NK-cells that exert direct cytolysis on erythroid progenitors [24, 30]. In conclusion, this is the first report of PRCA in conjuction with MCL and specifically its indolent subset, which initially presented as primary leukemic disease and then progressed to its splenic form. This provides some insight into the heterogeneity of MCL and highlights the need to expand our understanding in the complexity of interactions between the lymphoma cells and the immune system. Conflict of interest of interest.
The authors declare that they have not conflict
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