Two cases of concomitant diffuse large B‐cell lymphoma and myelodysplastic syndrome
Authors: Massimo Dozzo, Francesco Zaja, Stefano Volpetti, Marianna Chiozzotto, Simona Puglisi, Maddalena Mazzucco, Giulia Perali, Renato Fanin
Journal: American Journal of Hematology (2014)

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 × 109/L and 4.8 × 109/L, retrospectively; hemoglobin and platelet counts were 104 g/L and 88 × 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. 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 × 109/L and 0.6 × 109/L, respectively, while hemoglobin level and platelet count were 115 g/L and 236 × 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). 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 peg-filgrastim 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. 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 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.