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Autologous Hematopoietic Stem Cell Transplantation As Salvage Leukemia (1998) 12, 1699–1707 1998 Stockton Press All rights reserved 0887-6924/98 $12.00 http://www.stockton-press.co.uk/leu Autologous hematopoietic stem cell transplantation as salvage treatment for advanced B cell chronic lymphocytic leukemia L Sutton1, K Maloum2, H Gonzalez1, H Zouabi1, N Azar3, C Boccaccio3, F Charlotte4, J-M Cosset5, J Gabarre1, V Leblond1, H Merle-Beral2 and J-L Binet1,2 Departments of 1Clinical Hematology, 2Biological Hematology, 3Hemobiology, and 4Pathology, Hoˆpital Pitie´-Salpeˆtrie`re; and 5Department of Radiotherapy, Institut Curie, Paris, France Given the generally poor outcome of advanced B cell chronic known radiosensitivity of CLL lymphocytes.13 The aim of the lymphocytic leukemia, experimental approaches are warranted, study was to determine whether an adequate response for especially for younger patients in whom classical treatments have failed. We therefore conducted a prospective single- hematopoietic stem cell collection could be obtained and to center study, using polychemotherapy (ESHAP) to prepare study the outcome of autologous transplantation in patients patients for hematopoietic stem cell collection and autologous with advanced CLL. Despite the limited number of patients, stem cell transplantation as consolidation therapy. Twenty this study shows that it can be impossible to collect adequate patients entered the study. An adequate response to ESHAP stem cells for autografting in multitreated patients, and argues was obtained in 13 patients, and sufficient stem cells for graft- in favor of stem cell harvest immediately after the first ing were obtained in eight of the 12 patients who underwent the collection procedure. Six of these grafted patients are alive remission is obtained. in complete clinical remission a median of 30 months after transplantation. It should be noted that we were only able to graft 40% of the patients enrolled in this study, either because a new remission could not be obtained or because not enough Patients and methods hematopoietic stem cells could be collected. This argues for stem cell collection as soon as a first remission is obtained, even if the autograft is done later in the course of the disease. Patient eligibility Keywords: B-CLL; advanced disease; autologous transplantation; hematopoietic stem cell B-CLL was diagnosed on the basis of classical criteria, using blood cell counts, cytology, immunophenotyping and bone Introduction marrow cell morphology. Patients with B-CLL were eligible for the study if they had received at least two different chemo- Hematopoietic stem cell transplantation has been widely used therapy regimens and were refractory to or had relapsed after in treating chronic lymphocytic leukemia (CLL), and is cur- the last treatment. Binet’s staging and new cytologic, pheno- rently one of the only approaches yielding immunophenotypic typic and bone marrow biopsy studies were performed at and molecular remission.1–3 However, the use of stem cell enrolment. Tumor burden was assessed by physical examin- transplantation as first-line treatment is debatable, as fludara- ation and by chest and abdominal-pelvic computed tomogra- bine and CHOP give 80% and 77% of responses, respectively, phy. From September 1992 to January 1997, all consecutive in previously untreated patients and a survival time tending patients aged up to 66 years, and those under 50 lacking an towards 10 years in patients entering clinical remission.4–7 HLA-identical sibling, were offered the protocol. Informed However, standard treatments are usually only palliative, and consent was obtained from all the patients. The treatment pro- curative treatments for younger patients are clearly needed.8 tocol was reviewed by the scientific committee of the French The prognosis is worse when the disease relapses or does not Cooperative Group on Chronic Lymphocytic Leukemia and respond to first-line therapies. Fludarabine only induces short- approved by the local Institutional Review Board. lived remission in such patients; in addition, the disease is rapidly life-threatening when it is resistant to this second-line therapy.4,8 Consequently, younger patients who relapse or are refractory after several lines of treatment need a salvage pro- Treatment plan cedure. We conducted a prospective study aimed at inducing remission with the combination of etoposide, cisplatin, high- dose cytarabine and high-dose methylprednisolone (ESHAP), Patients were first treated with ESHAP chemotherapy every 4 as originally proposed by Velasquez et al,9 as it has given weeks, combining intravenous infusions of methylpredniso- 2 interesting results in relapsing and refractory lymphoma. The lone (500 mg/day) for 5 days, etoposide (40 mg/m /day) and 2 need for myeloablative treatment for consolidation was sug- cisplatin (25 mg/m /day as a 24-h continuous infusion) for 4 2 gested by results in other lymphoproliferative disease.10–12 days, and cytarabine (2 g/m at the end of the last infusion of 9 Autologous hematopoietic stem cell transplantation (ASCT) cisplatin). The response to this treatment was studied after was thus planned for patients lacking an HLA-identical sibling the first three cycles and patients were moved towards hema- and those over 50 years. Total body irradiation was used as topoietic stem cell (HSC) collection procedures if they quali- a part of the myeloablative conditioning regimen, given the fied. Additional cycles of ESHAP could be performed to improve the response before collection, and also after collec- tion pending ASCT. Trimethoprim/sulphamethoxazole (160 mg/800 mg per day, three times a week) was adminis- Correspondence: L Sutton, Service d’He´matologie Clinique, Hoˆpital Pitie´-Salpeˆtrie`re, 47 boulevard de l’Hoˆpital, 75651 Paris cedex 13, tered from the start of the first ESHAP cycle through the ASCT France; Fax: 33 1 42 16 02 49 procedure as prophylaxis against Pneumocystis carinii Received 8 June 1998; accepted 6 August 1998 infection. ASCT in advanced B-CLL L Sutton et al 1700 Cell collection and processing 109 lymphocytes per liter of blood, and normal BM (except for a few nodules: CRnod). Phenotypic remission was defined Patients were eligible for HSC collection when they fulfilled when less than 5% of PBLy were CD5-CD19 double-positive the criteria of partial response (PR) and in addition had less in which case a molecular analysis of immunoglobulin gene than 4 × 109/1 peripheral blood lymphocytes (PBLy), irrespec- rearrangement was performed to detect minimal residual dis- tive of the PBLy phenotype and the bone marrow pattern of ease.1 The persistence of remission was assessed every 6 infiltration (see below).14 months or more frequently if clinically indicated. Hematologic Bone marrow (BM) and/or peripheral blood stem cells recovery after ASCT was based on daily blood counts, and (PBSC) were used as appropriate. BM was harvested from the defined as a neutrophil count of 0.5 × 109/1 on 2 consecutive iliac crests and treated in vitro with anti-CD19 and anti-CD20 days and a platelet count of 50 × 109/1 without transfusion. monoclonal antibodies plus rabbit complement.15 PBSC were The number of packed red cell and platelet transfusions was mobilized with cyclophosphamide (60 mg/kg/day intra- recorded.17 venously on 2 consecutive days) plus filgrastim (5 ␮g/kg/day) subcutaneously until neutrophil recovery and completion of harvesting; or with filgrastim plus molgramostim (5 ␮g/kg/day Histopathologic studies each); or with filgrastim alone (10 ␮g/kg/day subcutaneously for 6 days), with collection on days 5, 6 and 7.16 Mononuclear BM aspirates and posterior iliac crest biopsies were reviewed cells (MNC) were analyzed for CD19-positive and CD5-CD19 jointly at the Hematobiology and Hematopathology Depart- double-positive cells, CD34-positive cells and granulocyte– ments of Hoˆpital Pitie´-Salpeˆtrie`re. BM biopsies were exam- macrophage colony-forming units (CFU-GM) in the PBSC or ined for cellularity, lymphocyte percentages and the intertra- post-purge BM, and the cells were then cryopreserved.15,16 becular pattern of BM infiltration, which was noted as normal CD19-positive cells were also evaluated in pre-purge BM. (no evidence of lymphoproliferation), nodular (nodules of Patients were eligible for ASCT when CFU-GM and/or CD34- small mature lymphocytes lacking clear germinal centers), positive cell counts reached 5 × 104/kg and 1 × 106/kg, interstitial (replacement of normal hematopoietic tissue by respectively, in BM, or 15 × 104/kg and 2 × 106/kg, respect- small mature lymphocytes infiltrating through fat, with no dis- ively, in PBSC, in a single sample, as currently recommended tortion of the marrow architecture), mixed (both nodular and in our institution. interstitial involvement), or diffuse (disruption of marrow architecture by small mature lymphocytes).18,19 Preparatory regimen and HSC infusion Immunophenotyping Fractionated total body irradiation (TBI), (3.3 Gy every 24 h for 3 days), was first administered at a mean dose rate below Immunophenotyping was performed on peripheral blood, BM 0.25 Gy/min, using a linear accelerator; the total dose to the harvested before and after purging, and PBSC, by flow cyto- lungs was limited to 8 to 9 Gy. TBI was followed by cyclopho- metry with single or dual-color staining on a FACStar device sphamide (60 mg/kg/day for 2 days). After 2 days the cryopre- (Becton Dickinson, San Jose, CA, USA). The following mono- served HSC were rapidly thawed and infused via a central clonal antibodies were always used: CD19 (B4), CD20 (B1), venous line. Filgrastim (5 ␮g/kg/day) was administered from CD10 (J5), and CD23 (B6) from Coultronics (Margency, the day after graft reinfusion until neutrophil recovery. Patients France); and CD5 (OK23), anti-kappa, anti-lambda and anti- were treated in a laminar-flow protected environment until IgM from Dako (Trappes, France).20,21 Residual disease was granulocyte recovery. They received oral prophylactic anti- defined by coexpression of CD5 on CD19-positive B lympho- biotics for gut decontamination. All blood products were fil- cytes.22 When more than 5% of the total lymphocyte popu- tered and irradiated.
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