T-large granular lymphocyte
leukemia (T-LGLL) is a chronic clonal proliferation
of effector memory cytotoxic CD3+CD57+CD56- T
cells and the current guidelines suggest
immunosuppressive therapy as first-line therapy, but
the treatment of refractory/relapsed patients is still
challenging due to the lack of prospective studies.
We describe a series of two refractory/relapsed
T-LGLL patients successfully treated with
bendamustine, a chemotherapeutic agent largely used
for B-cell neoplasms, but poorly investigated for the
treatment of T-cell diseases. Complete remission
(CR) was achieved in 3 and 6 months, respectively,
and maintained for at least 20 months. One patient
relapsed after a 20-month CR, but she was
responsive to bendamustine therapy again, obtaining
a further prolonged CR.
Bendamustine as single agent or in combination
could be a feasible therapeutic option in
refractory/relapsed T-LGLL, especially for elderly
patients because of its safety profile

Annunziata, Silvana

Baldi, Carlo Eugenio

Ferrara, Idalucia

Giudice, Valentina

Guariglia, Roberto

Pezzullo, Luciano

Rocco, Mattia

Rosamilio, Rosa

Selleri, Carmine

Villani, Gaetano

PubMed

EleA@UniSA - Università degli Studi di Salerno

Translational Medicine @ UniSa - ISSN 2239-9747 2016, 15(11): 80-83  80 Università degli Studi di Salerno  Abstract - T-large granular lymphocyte leukemia (T-LGLL) is a chronic clonal proliferation of effector memory cytotoxic CD3+CD57+CD56- T cells and the current guidelines suggest immunosuppressive therapy as first-line therapy, but the treatment of refractory/relapsed patients is still challenging due to the lack of prospective studies.  We describe a series of two refractory/relapsed T-LGLL patients successfully treated with bendamustine, a chemotherapeutic agent largely used for B-cell neoplasms, but poorly investigated for the treatment of T-cell diseases. Complete remission (CR) was achieved in 3 and 6 months, respectively, and maintained for at least 20 months. One patient relapsed after a 20-month CR, but she was responsive to bendamustine therapy again, obtaining a further prolonged CR.  Bendamustine as single agent or in combination could be a feasible therapeutic option in refractory/relapsed T-LGLL, especially for elderly patients because of its safety profile.   Keywords: LGL leukemia, bendamustine, chemotherapy, salvage therapy, immunosuppression   I.  INTRODUCTION   Large granular lymphocyte leukemias (LGLL) are chronic clonal lymphoproliferations of mature post-thymic TCRαβ+ CD3+CD4-CD5dimCD8+CD27-CD28-CD45RO-CD57+ T cells (T-LGLL, 85% of cases) or CD3-CD56+ natural killer cells (NK-LGLL) [1-5]. T-LGLL usually affects old subjects (> 60 years) with an indolent course and a median overall survival > 10 years [1,5]. At diagnosis, T-LGLL patients show peripheral blood (PB) cytopenias, splenomegaly, bone marrow (BM) infiltration by clonal large granular lymphocytes (LGLs), frequently associated with autoimmune or hematologic disorders (40% of cases) (Table 1) [1,3,5]. Current guidelines of T-LGLL suggest to start               treatment  only in patients with symptomatic  or life- threatening  cytopenias (Table 2) [3,4]. Immuno- suppressive therapy (IST), with single agent methotrexate (MTX), cyclophosphamide (CTX), or cyclosporin-A (CyA), is the first-line therapy of T-LGLL.  Table 1. LGLL diagnostic criteria  [3,5]  Clinical presentation: PB cytopenia(s)  Splenomegaly Autoimmune diseases  LGL > 0.5 x 109 cells/L   LGL morphology: Large dimensions (15-18 um of diameter) Round or reniform nucleus Abundant cytoplasm with azurophilic granules   LGL phenotype:  T: TCRαβ+CD3+CD4-CD5dimCD8+CD27-CD28-CD45RO-CD57+ NK: CD3-CD16+CD56+CD57+   Presence of clonal TCR rearrangement by PCR or flow cytometry Abbreviations. LGLL = large granular lymphocyte leukemia; PB = peripheral blood; LGL = large granular lymphocytes; TCR = T cell receptor; NK = natural killer cell; PCR = polymerase chain reaction.  Overall response rate with IST ranges from 40% to 70%, but no standard treatments are clearly defined due to the lack of prospective studies [3-5].  Relapsed patients after  IST stop or tapering, as defined in Table 3, are eligible for a second course of immunosuppression with similar or different IST [6]. In T-LGLL patients with IST failure after 4 months, a switch to a second-line treatment is recommended [5,7]. Bendamustine is an alkylating agent that may act as a purine analogue, but the precise mechanism of action is still unclear [8]. This drug is largely used in B-cell non-Hodgkin lymphoma (NHL), but recent studies have focused on refractory/relapsed T cell neoplasm patients, suggesting a role of this drug also in T-cell NHL [9-10].  Here, we report two cases of elderly refractory T-LGLL patients who achieved a prolonged complete remission using bendamustine as salvage therapy.  Table 2. Treatment indications in LGLL [3,5]  Severe neutropenia (absolute neutrophil count <0.5 x109 cells/L)  Moderate neutropenia (absolute neutrophil count <1 x109 cells/L) with recurrent infections  Symptomatic or transfusion dependent anemia  Severe thrombocytopenia (<0.5 x 109/L)   Associated autoimmune conditions requiring therapy Abbreviations. LGLL = large granular lymphocyte leukemia. Prolonged complete hematologic response in relapsed/refractory T-large granular lymphocyte leukemia after bendamustine treatment  R. Rosamilio1, V. Giudice1, I. Ferrara1, S. Annunziata1, L. Pezzullo1, G. Villani1, C. Baldi1,          R. Guariglia1, M. Rocco1, C. Selleri1  1Department of Medicine and Surgery, University of Salerno, Baronissi, Italy (cselleri@unisa.it)      Translational Medicine @ UniSa - ISSN 2239-9747 2016, 15(11): 80-83  81 Università degli Studi di Salerno II.  PATIENTS AND METHODS   In this study, two T-LGLL patients were enrolled after informed consent in accordance with the Declaration of Helsinki [11] and the institutional review boards of the Hematology and Transplant Center, Department of Medicine and Surgery, University of Salerno, Italy. The authors retrospectively reviewed all available medical records.   Table 3. Response criteria in LGLL [3]  Complete response: Hemoglobin >12 g/dL  Platelet count ≥150 x 109/L  ANC  >1.5 x 109 cells/L ALC <4 x 109 cells/L with circulating LGLs < 0.5 x 109 cells/L  Partial response: Improvements of blood count that do not meet criteria for CR ANC >0.5 x109 cells/L or decreasing transfusion requirements  Treatment failure: Failure to achieve partial or complete response  Progressive disease: Worsening of cytopenias, hepatomegaly or splenomegaly Abbreviations. LGLL = large granular lymphocyte leukemia; ANC = Absolute neutrophil count;  ALC = Absolute lymphocyte count;  LGLs = large granular lymphocytes; CR = complete remission.   III.  RESULTS  Case 1  A 73-year-old woman received diagnosis of T-LGLL in 2003 from other institution. Treatment with low-dose oral MTX, (10 mg/m2 weekly) and prednisone (PDN) was started in 2008, due to anemia and moderate thrombocytopenia. After a 4-month therapy, in the absence of a clinical response, oral CTX (100 mg/day)  and PDN for 4 months were used as second-line treatment without any response, although this therapy was associated with erythropoiesis-stimulating agents (ESAs). In August 2012, the patient referred to our institution for fatigue, transfusion-dependent severe anemia and neutropenia. The basic clinical characteristics, laboratory data on admission and clinical records of the patient are detailed in Table 4.  In September 2012, oral CyA, (2 mg/Kg/day) and PDN were administered as third-line therapy, but the patient experienced the worsening of cytopenias, the increase in the transfusion support (8-10 packed red blood cell transfusions/month), and positivity of indirect and direct antiglobulin tests. After 8 months of no clinical response, the patient performed a salvage therapy with bendamustine (70 mg/m2 for 2 consecutive days every 28 days). Pneumocystis jiroveci prophylaxis was carried out with trimethoprim/sulfamethoxazole (TMP/SMX), while ESAs were administered to improve erythropoiesis. After the first bendamustine course, our patient experienced a rapid hemoglobin improvement and transfusion independence, achieving complete remission (CR) within three months. Grade 4 neutropenia was documented after the second course of chemotherapy and treated with granulocyte colony-stimulating factors (G-CSFs). The patient experienced also other complications such as Escherichia coli-related urinary tract infection (treated with 500 mg/day oral levofloxacin for 6 days) and hypertransaminasemia associated with vasculitis-like rush of the limbs after the third cycle, which led to the treatment discontinuation  and patient re-evaluation. Given that the patient was in CR and showed a minimal BM infiltration (LGLs <10% of total cellularity), bendamustine was definitely discontinued. CR was maintained for 20 months, when the patient showed again anemia; for this reason, a second course of 4 cycles of bendamustine was administered, without any clinical toxicity. At last follow-up, 12 months after the end of therapy, the patient was still in CR.  Case 2  A 72-year-old man was admitted to our department in October 2013 for severe anemia associated with atypical circulating and marrow LGLs (Figure 1A). Physical examination did not detected lymphadenopathies and hepatomegaly, but revealed splenomegaly, confirmed by ultrasonography (longitudinal diameter, 150 mm; anteroposterior diameter, 156 mm; transverse diameter, 66 mm). Other clinical characteristics, laboratory data on admission and clinical records of the patient are summarized in Table 4. Immunosuppression was started with CyA (5 mg/Kg/day) and PDN (0.5 mg/kg/day). After a 4-month therapy, the persistence of transfusion-dependent anemia and the worsening of neutropenia (0.29 x 109 cells/L) required a second line therapy. Bendamustine was administrated for a total of 6 cycles at 70 mg/m2 for 2 days every 28 days. Bacterial, fungal and Pneumocystis jiroveci prophylaxis was carried out using oral levofloxacin (500 mg/day), oral fluconazole (200 mg/day), and TMP/SMX (160-800 mg/twice per week). ESAs and G-CSFs were also administered to reduce myelosuppression and to prevent febrile neutropenia. Grade 3 neutropenia and two episodes of transient hypertransaminasemia with indirect hyperbilirubinemia were documented, but they did not require drug discontinuation. CR was achieved after 6 cycles of bendamustine and, after that, the patient no longer needed transfusions or ESAs administration (Figure 1B). BM aspiration performed at the end of treatment did not show evidence of lymphoproliferative disorder, confirmed by BM flow cytometry immunophenotype and BM biopsy. After 26-month of follow-up, the patient was still in CR.  IV.  DISCUSSION  T-LGLL is a chronic lymphoproliferative disorder with an indolent course, mostly diagnosed after the sixtieth decade of life1. T-LGLL patients are a fragile population because of their older age (>60-year-old), the presence of comorbidities (frequently autoimmune disorders) and symptoms which   negatively  influence the  Translational Medicine @ UniSa - ISSN 2239-9747 2016, 15(11): 80-83  82 Università degli Studi di Salerno Table 4. Patients characteristics   Case 1 Case 2  Age 73 72  Sex Female Male  Laboratory data on admission Hemoglobin g/dL White blood cell (x 109 cells/L) Absolute lymphocyte count (x 109 cells/L) Absolute neutrophil count (x 109 cells/L) Platelet count (x 109cells/L)  Mean corpuscular volume (fL) Lactate dehydrogenase (U/L) Rheumatoid factor Anti-nuclear antibodies titer Direct antiglobulin test  7.7 7.01 5.41 1.10 224 112 644 Negative 1:640 Negative  8.8 11.19 10.17 0.615 117 104 776 n.e. n.e. Negative  Peripheral blood LGLs Percentage (%) Flow cytometric phenotype   75 CD3+CD8+CD7+CD5-CD4-CD56-TCRαβ+  78 CD3+CD8+CD2+CD7+CD4-CD5-CD56- TCRαβ+  Indications for treatment Transfusion dependent anemia Transfusion dependent anemia, splenomegaly  Immunosuppressive therapies  MTX+ PDN, CTX+PDN, CyA+ PDN CyA+PDN  Response to  immunosuppressive  therapies  Treatment failure Treatment failure  Time to-BENDA treatment  10 years 4 months  BENDA dosage     70 mg/m2 for 2 days every 28 days                       70 mg/m2 for 2 days every 28 days  Number of BENDA cycles  3 and 4* 6  Response to BENDA Complete response Complete response  Follow up (months) after BENDA treatment 20 and 12° 26 Abbreviations. n.e. = not evaluated; LGLs = large granular lymphocytes; MTX = methotrexate; PDN = prednisone; CTX = cyclophosphamide;    CyA = cyclosporine-A; BENDA = bendamustine.   Symbols. * = 3 cycles of BENDA and 4 after relapse; ° = 20 months after first BENDA treatment and 12 after the second BENDA treatment.  quality of life and the outcome [12,13]. Nowadays, there are no “curative” therapeutic options for T-LGLL. For this reason, the goals are the stabilization of the disease and the correction of cytopenias. IST is the mainstay of treatment for T-LGLL [3,5], but the optimal therapeutic strategy for refractory/relapsed patients is still challenging, even though purine analogues and alemtuzumab are currently used as second-line therapy4.  Bendamustine, a molecule developed more than 50 years ago, is an alkylating agent with a complex mechanism of action, sharing characteristics with purine analogues [8,11]. Several mechanisms of action have been hypothesized, as the induction of extensive and durable DNA damage and impairment of DNA repair [8]. The inhibition of the DNA repair mechanism could be enhanced by the in vitro combination of bendamustine with cladribine or fludarabine, commonly used for B-cell and T-cell NHL [8,14]. Bendamustine can induce apoptosis through traditional and non-traditional pathways [8]. In particular, the activation of mitotic catastrophe is caspase-2-dependent and cannot be inhibited by overexpression of Bcl-2 [8]. Moreover, the p53-dependent DNA-damage response pathways can be activated not only by bendamustine-induced DNA interstrand crosslinks, but also by oxidative stress and increased release of apoptosis-inducing factor from mitochondria [8]. Based on the interesting results of Zaja et al. in 2013 in a small cohort of T-cell NHL refractory/relapsed patients, we decided to start bendamustine administration in two cases of refractory T-LGLL patients, according to the dosage previously reported [9]. Furthermore, bendamustine was chosen as salvage therapy due to its mechanism of action, hypothesizing that the mitotic catastrophe could avoid the constitutively activated anti-apoptotic pathways in LGLs [8]. Indeed, our series of refractory T-LGLL patients experienced a rapid clinical response and achieved the CR within 3 and 6 months, respectively. One patient relapsed after 20 months of CR with a minimal BM LGL infiltration. Interestingly, she was still responsive to a second course of bendamustine which allowed a 12-months disease-free survival at the time of writing. Moreover, bendamustine was confirmed as a drug with a good safety profile [14], because the myelosuppression was easily managed with G-CSFs and ESAs.  V.  CONCLUSION  Standard salvage treatment for relapsed/refractory T-LGLL patients has not been defined yet due to the lack of prospective studies. Bendamustine-based regimens are increasingly used in both B-cell and T cell neoplasms, but few studies are available for T-LGLL. Our case series shows the efficacy and safety of bendamustine in the treatment of elderly relapsed/refractory T-LGLL patients. Even though these Translational Medicine @ UniSa - ISSN 2239-9747 2016, 15(11): 80-83  83 Università degli Studi di Salerno results require further validation in prospective randomized studies, bendamustine as single agent or in combination should be considered a feasible second-line option for relapsed or refractory T-LGLL.   Figure 1. Bone marrow morphological features and clinical course in case 2 T-LGLL. (A) Marrow large granular lymphocytes with abundant cytoplasm and the characteristic azurophilic granules (May–Giemsa assay, Nikon Microscope, Ci-L model; original magnification 20X left panel, and 100X right panel).  (B) Hemoglobin levels during and after bendamustine treatment.  Red blood cell transfusions are displayed as dark red arrow, according to the time of administration.   REFERENCES  [1] Lamy T, Loughran TP Jr. Clinical features of large granular lymphocyte leukemia. Semin Hematol 2003;40(3):185-195. [2] Loughran TP Jr. Clonal diseases of large granular lymphocytes. Blood 1993;82(1):1-14. [3] Lamy T, Loughran TP Jr. How I treat LGL leukemia. Blood 2011;117(10):2764-2774. [4] Dearden C. Large granular lymphocytic leukaemia pathogenesis and management. Br J Haematol 2011;152(3):273-283. [5] Steinway SN, LeBlanc F, Loughran TP Jr. The pathogenesis and treatment of large granular lymphocyte leukemia. Blood Rev 2014;28(3):87-94.  [6] Loughran TP Jr, Zickl L, Olson TL, Wang V, Zhang D, Rajala HLM, Hasanali Z, Bennett JM, Lazarus HM, Litzow MR, Evens AM, Mustjoki S, Tallman MS. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia 2015;29(4):886-894 [7] Dearden CE, Johnson R, Pettengell R, Devereux S, Cwynarski K, Whittaker S, McMillan A, British Committee for Standards in Haematology. Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma). Br J Haematol 2011;153(4):451-485. [8] Leoni LM, Hartley JA. Mechanism of action: the unique pattern of bendamustine-induced cytotoxicity. Semin Hematol 2011; 48 (Suppl 1):12-23.  [9] Zaja F, Baldini L, Ferreri AJ, Luminari S, Grossi A, Salvi F, Zambello R, Goldaniga M, Volpetti S, Fanin R. Bendamustine salvage therapy for T cell neoplasms. Ann Hematol 2013; 92(9):1249-1254. [10] Reboursiere E, Le Bras F, Herbaux C, Gyan E, Clavert A, Morschhauser F, Malak S, Sibon D, Broussais F, Braun T, Fornecker LM, Garidi R, Tricot S, Houot R, Joly B, Abarah W, Choufi B, Pham AD, Gac AC, Fruchart C, Marin E, Safar V, Parcelier A, Maisonneuve H, Bachy E, Cartron G, Jaccard A, Tournilhac O, Rossi C, Schirmer L, Martignoles JA, Gaulard P, Tilly H, Damaj G, Lymphoma Study Association (LYSA) centers. Bendamustine for the treatment of relapsed or refractory peripheral T cell lymphomas: A French retrospective multicenter study. Oncotarget 2016 Jul 21 [Epub ahead of print]. [11] World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310(20):2191-2194. [12] Sokol L, Loughran TP Jr. Large granular lymphocyte leukemia. Oncologist 2006;11(3):263-273. [13] Zambello R, Teramo A, Gattazzo C, Semenzato G. Are T-LGL Leukemia and NK-Chronic Lymphoprolifera-tive Disorder really two distinct diseases? Transl Med UniSa 2014;8(1):4-11.  [14] Cheson BD, Brugger W, Damaj G, Dreylingd M, Kahle B, Kimbyf E, Ogurag M, Weidmannh E, Wendtneri CM, Zinzani PL. Optimal use of bendamustine in hematologic disorders: Treatment recommendations from an international consensus panel - an update. Leuk Lymphoma 2016; 57(4):766-782. 

Prolonged complete hematologic response in relapsed/refractory T-large granular lymphocyte leukemia after bendamustine treatment

T-large granular lymphocyte leukemia (T-LGLL) is a chronic clonal proliferation of effector memory cytotoxic CD3+CD57+CD56- T cells and the current guidelines suggest immunosuppressive therapy as first-line therapy, but the treatment of refractory/relapsed patients is still challenging due to the lack of prospective studies.
We describe a series of two refractory/relapsed T-LGLL patients successfully treated with bendamustine, a chemotherapeutic agent largely used for B-cell neoplasms, but poorly investigated for the treatment of T-cell diseases. Complete remission (CR) was achieved in 3 and 6 months, respectively, and maintained for at least 20 months. One patient relapsed after a 20-month CR, but she was responsive to bendamustine therapy again, obtaining a further prolonged CR.
Bendamustine as single agent or in combination could be a feasible therapeutic option in refractory/relapsed T-LGLL, especially for elderly patients because of its safety profile

Rosamilio R, 9)

Annunziata, S

Pezzullo, L

Villani, G

Baldi, C

Guariglia, R

GIUDICE, VALENTINA

FERRARA, IDALUCIA

ROCCO, MONIA

SELLERI, Carmine

Archivio della Ricerca - Università di Salerno

Prolonged complete hematologic response in relapsed/refractory T-large granular lymphocyte leukemia after bendamustine treatment.

http://elea.unisa.it:8080/xmlui/bitstream/10556/4473/1/11.pdf

Prolonged complete hematologic response in relapsed/refractory T-large granular lymphocyte leukemia after bendamustine treatment

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EleA@UniSA - Università degli Studi di Salerno

Archivio della Ricerca - Università di Salerno