BEAM Regimen Research Articles

90Yttrium Ibritumomab Tiuxetan (Zevalin) Combined with BEAM (Z -BEAM) Conditioning Regimen Plus Autologous Stem Cell Transplantation in Relapsed or Refractory Follicular Lymphoma. GELA Phase II Study.

Autologous stem cell transplantation (ASCT) is widely used in relapsed or refractory low grade lymphoma with conditioning regimen including chemotherapy with or without total body irradiation (TBI). Radiolabelled immunotherapy 90Yttrium ibritumomab tiuxetan (Zevalin) is effective in B-cell lymphoma and delivers targeted radiation without TBI toxicity. To take advantage of this antilymphoma effect, conventional dose of 90Yttrium ibritumomab tiuxetan 15 MBq/kg (maximum 1200 MBq, total dose) was given without dosimetry day -14 before ASCT and combined to standard BEAM regimen starting at day -7. The goal of this phase II study was to evaluate efficacy and toxicity of Z BEAM. Patients < 65 years with CD20+ low grade B cell Lymphoma in 1st or 2nd relapses, or not achieving complete remission after first line treatment were included in the trial. They had to be chemosensitive to last salvage therapy, no more than three lines of treatment and eligible for ASCT. The primary end point was to detect a 2 yrs EFS at least 80%. Hematological reconstitution was evaluated after transplant and during the first year follow up. From 3/2005 to 8/2006, 77 patients were included. Patients characteristics at inclusion: 90% follicular lymphoma, median age 53 yr. (31–64), FLIPI <3, 74%, bone marrow involvement, 22%. Median delay between first line and ASCT was 31 months and median last salvage and ASCT 4.4 months. Response rate before ASCT were CR 36%, CRu 41%, PR 22%, stable 1%. As first line treatment, all pts received mostly CHOP associated in 29 cases with rituximab; 29 patients had relapsed and received a second line chemotherapy with rituximab in 22 cases; 48 patients who did not achieved remission after first line treatment received another line of chemotherapy before ASCT. Overall, among the 77 pts last salvage chemotherapy regimen included rituximab in 74 pts. The haematological reconstitution after Z-BEAM followed by ASCT in 75 pts was: time to neutrophils > 1G/L 12 days (9–35), time to platelets >20 G/L 12 days (3–42). Median number of platelets transfusions 4; red blood cell transfusions 2. Grade 3-4 toxicities were: infection 83%, mucositis 47%, pulmonary 4%. Safety data indicated 35 serious adverse events in 24 patients that did not appear to significantly differ from those usually seen after ASCT. No toxic death was observed. At week 12 and 42 after ASCT, median haemoglobin level were 11.6 g/dl and 11.3 g/dl, median platelets counts was 111G/L and 148 G/L, leucocytes counts 3.48 G/L and 4.80 G/L respectively. Only 5 events were reported. After a minimum follow up of one year for all patients, estimated 2 years EFS is 93%. Updated results on survival will be reported. Conclusion: Z BEAM is a safe conditioning regimen which can be used for B cell lymphoma. Longer follow up is necessary to evaluate long term toxicity and efficacy. Further randomized study are warranted.

Autologous Hematopoietic Stem Cell Transplantation in Severe Multiple Sclerosis. The Brazilian Experience with Two Conditioning Regimes: BEAM and High-Dose Cyclophosphamide.

Introduction: Multiple sclerosis (MS) is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS) leading to gradual axonal degeneration. It is a classical auto-immune disease, thus high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) could “reset” the immune disorder by controlling autoreactive clones and by restoring self-tolerance after immunological recovery.Objectives: Describe the experience of the Brazilian Cooperative Group of AHSCT for Autoimmune Diseases in 41 MS patients followed-up to five years.Methods: Stem cells were mobilized from the bone marrow with Cy (2g/m2) and Filgrastim (10μg/kg/d SC), collected by leukapheresis and cryopreserved. Patients were conditioned with BEAM (BCNU 300 mg/m2, cytarabine 200 mg/m2, etoposide 200 mg/m2 ×4, melphalan 140 mg/m2) and horse antilymphocyte globulin (ATG) 90 mg/kg) or cyclophosphamide (CY) 50 mg/kg ×4 and rabbit ATG (rATG) 4.5 mg/kg, followed by stem cell infusion. Quality of life was assessed by the Short Form-36 Health Survey Questionnaire (SF-36).Results: Between January 2001 and June 2006, 21 patients received BEAM/ATG and 20 received CY/ATG. Medium age was 42 years (27–53 years), 24 (58.5%) were females, 33 (80.4%) had secondary progressive MS form, 80.95% had EDSS (Expanded Disability Status Scale) 6.0 or higher. No significant difference was seen between the groups regarding age, sex, disease presentation and EDSS. The mean number of CD34+ infused cells was 8.8×106/kg (2,5– 25.13×106/kg). Mean engraftment was 9,3 days (7–10 days) for neutrophils and 13 days (7–24 days) for platelets. 18 patients (46%) had neutropenic fever, 8 (20.0%) had pneumonia and 5 (12.5%) had allergic reactions to lymphoglobulin. Three patients (14.3%) died in the BEAM group due to conditioning regiment toxicity, sepsis and alveolar hemorrhage. Mean hospital stay was 35.47 days (20–168 days) in the BEAM group and 20.15 days (14–32 days) in the CY group (p<0,0001). EDSS-based disease progress in six months to a year was similar in both groups (p = 0.54). Disease worsening was detected in 6/18 patients in the BEAM group and 4/14 in the Cy group. Median follow-up was 17 months. Disease-free survival 4 years post-transplant was 65%. 31/41 patients completed SF-36 after transplantation and they exhibited improvement in their general health status at 100 days post-transplant (p = 0.02).Conclusion: In our study, a less intensive conditioning regimen (CY + rATG) was associated with similar neurological outcomes but also with less toxicity when compared to BEAM regimen. The majority of patients had an improvement in their quality of live. Longer follow-up is required to assess the therapeutic effectiveness of both regimens in MS progression.

Pre-Transplant Rituximab Therapy Is Associated with Improved Progression-Free and Overall Survival in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma (DLBCL).

Outcomes following first-line therapy for patients (pts) with DLBCL have improved significantly with the availability of the chimeric anti-CD20 monoclonal antibody rituximab (R). Despite this progress, many pts develop refractory or recurrent DLBCL and are considered candidates for autologous hematopoietic stem cell transplantation (AuHCT). For such pts, it is possible that R given pre-transplant and/or during conditioning therapy affects the natural history of DLBCL, such that traditional methods of risk assessment and patient selection for AuHCT may need revision. We therefore studied the outcomes of 1,006 pts who underwent peripheral blood AuHCT for DLBCL between 1996 and 2003 reported to the CIBMTR, analyzed according to whether R was (n=188, “+R” group) or was not (n=818, “-R” group) administered prior to AuHCT. Using the chi-square statistic for categorical and the Kruskal-Wallis for continuous variables, there were no significant differences between the +R and -R groups with regard to gender, pre-transplant performance status, disease status at transplant, pre-transplant chemosensitivity, second-line aa-IPI score distribution, Ann Arbor stage at transplant, interval from diagnosis to transplant, bulky disease, bone marrow involvement, post-transplant radiation therapy, or post-transplant myeloid growth factor therapy. The +R group had a higher proportion of pts age 61 or older (40% vs. 23%, p<0.001). AuHCT occurred between 1999–2003 in 96% of pts in the +R group, and between 1996–2001 in 93% of the -R pts (p<0.001). For the +R pts, 94% received R only with pretransplant chemotherapy, 3% only with conditioning therapy, and 3% with both pretransplant chemotherapy and conditioning therapy. Conditioning regimens were similar in the +R and -R groups, with the majority receiving the BEAM regimen. In univariate analysis, platelet and neutrophil engraftment were not affected by use of R. Treatment-related mortality (TRM) at 1, 3, or 5 years did not differ significantly between the +R and -R groups. Progression-free survival (PFS) at 1 and 3 years was superior in the +R group (62% vs. 49% at 1 year, p=0.002; 49% vs. 38% at 3 years, p=0.010). Overall survival (OS) was superior in the +R group (68% vs. 60% at 1 year, p=0.032; 57% vs. 45% at 3 years, p=0.003). In multivariate analysis, later year of transplant (2000–2003) and age <55 were associated with lower TRM, but pre-transplant R was not. Conversely, pre-transplant R, age <55, and fewer than 3 lines of chemotherapy were associated with improved PFS, while year of transplant was not. Finally, pre-transplant R, age <55, fewer than 3 lines of chemotherapy, and year of transplant 2000–2003, were all associated with improved OS. We conclude that pre-transplant rituximab is associated with improved PFS and OS following AuHCT for DLBCL, with no evidence of impaired engraftment or increased TRM.

Phase I Study for Poor Prognosis Lymphoma: Modification of the “BEAM” (BCNU +Etoposide+ARA-C+Melphalan) Regimen with Escalating-Dose Melphalan (MEL) Using Amifostine (AF) Cytoprotection and Autologous Hematopoietic Stem Cell Transplantation (AHSCT).

Background: AHSCT is standard therapy for recurrent or progressive, yet chemosensitive lymphoma, both non-Hodgkin's (NHL) and Hodgkin's (HL). However, relapse is frequent, and augmentation of existing conditioning regimens (e.g. BEAM) is one approach to reducing these relapses. Since BEAM has considerable regimen related toxicity (RRT), methods to allow safe dose augmentation are needed. Prior experience (BBMT 2004; 10(7): 473–83) indicates that AF may be useful in protecting vs RRT produced by high-dose MEL used alone; thus, we postulated a cytoprotective effect in this situation as well.Goals: Determine the maximum tolerated dose (MTD) of escalated dose MEL in BEAM, using AF and AHSCT, in a classical Phase I trial.Methods: We utilized AF 740mg/m2 daily before and during BEAM (i.e., −7 to −1) with MEL, starting at 140 mg/m2 (level A) and escalating by 20 mg/m2 per 4 - pt. cohorts. AHSCT and other supportive care measures were routine. (Thiotepa was used in patients with a history or at high risk of central nervous system (CNS) disease.) The Berman (JCO 1989; 7(9): 1288–94) scale of grading RRT was used to determine the MTD in 4- pt. cohorts; those who died of non-RRT causes were deemed non-evaluable and replaced.Results: Between 07/30/2003 and 06/28/2006, we entered 18 patients (NHL13 /HL 5), med age 60 (range 23 to 72) years. All had progressed or relapsed; 12 were chemosensitive. To date, 6 patients at level A (140mg/m2), 4 patients at B (160mg/m2), 5 patients at C (180mg/m2) and 3 patients at D (200mg/m2) have been evaluated >D +30. Three patients (2 at level A and 1 at level C) were non-evaluable due to:Removal (pt's request) during BEAM,Death due to CNS bleeding; andMI (with known pre-existing coronary artery disease), and were replaced.None of the remaining 15 had Bearman RRT >II; 2 had none and 10 had only grade I RRT. All (save one case of hepatic II RRT) were stomatitis and/or gastrointestinal. All had CD34+ > 2.0 x 10e6/kg and prompt hematopoietic reconstitution: ANC >0.5 and platelets >20K at median D+ 11 (range +9 to +12) and D+ 12 (range +9 to +24), respectively. No late (i.e., >D+ 30) hematologic or non-hematologic toxicities were noted. At present, 11 patients are alive, 7 in CR, one too early to evaluate at median D+ 469, range + 27 to 999. Conversely, 7 are dead, due to relapse (5), MI (one), and CNS bleeding (1). Responses occurred at all dose levels. In evaluable patients < CR before AHSCT, 9/14 achieved CR (mostly confirmed by imaging studies, notably PET scans) by D +100; 6 remain in CR at median D +593, range +36 to +614, including one patient who had a “consolidation” allogeneic HSCT. Another patient in CR at AHSCT remains in CR at D +514.Conclusion: Although not strictly proven, we believe the use of AF allows the safe use of escalated doses of MEL in the BEAM regimen >/= 180mg/m2. Dose escalation will continue until a MTD is found.

Palifermin Treatment in Patients Receiving High Dose Melphalan or BEAM Prior to Autologous Peripheral Blood Stem-Cell Transplantation.

Background. Oral mucositis (OM) is a common complication of high-dose (HD) chemotherapy conditioning regimens used with peripheral blood stem-cell transplantation (PBSCT). Severe grades of OM are associated with higher morbidity such as infections, need for total parenteral nutrition (TPN), opioid analgesics and prolonged hospitalization and has been historically underreported. Recent epidemiology reveals an incidence of severe OM of 50–60%. Moreover, OM is reported by patients as the worst and most debilitating complication of PBSCT. The keratinocyte growth factor, palifermin, stimulates the growth, differentiation, migration, and survival of epithelial cells. Palifermin is now approved in the US and the EU to decrease the incidence, duration, and severity of OM in patients (pts) with hematological malignancies requiring autologous PBSCT.Objective. This report describes the treatment of 60 pts who received palifermin through an early access program in Belgium. We evaluated the effect of palifermin on OM in pts with multiple myeloma or non-Hodgkin's lymphoma receiving HD melphalan (HD Mel) or BEAM conditioning regimen, respectively, prior to autologous PBSCT.Methods. The pts received palifermin (IV bolus: 60 μg/kg/day) for 3 days before and 3 days after HD Mel or BEAM. The common OM prevention strategy included basic oral hygiene, mouth washes and oral cryotherapy during HDM administration (n=9). For each patient, follow-up data were collected on mucositis grading, duration of hospitalization, neutropenic fever, treatment with G-CSF, IV antibiotics, opioids, and TPN. The grade of OM during treatment was assessed according to the WHO oral-toxicity scale (grade 0 to 4). Drug-related adverse events were also recorded.Results. Thirty pts received HD Mel and 30 pts received BEAM before PBSCT. All 60 pts received at least 3 palifermin bolus injections; the scheduled doses (6 bolus) were administered to 55 (91%) of 60 pts. Analysis of the follow-up data revealed that 10 (16%) pts experienced no OM. Furthermore, a low incidence (31%) of severe (grade 3 and 4) OM was observed with each conditioning regimen. The median duration of severe OM with the HD Mel regimen was 7 days (range 3–27) contrasting with a median OM duration of 3 days (range 2–12) with the BEAM regimen. Two pts in each regimen required prolonged hospitalization due to OM. With either regimen, neutropenic fever and use of IV antibiotics were common (70% of pts), while bacteremia was infrequent (20% of pts). Myeloid growth factors were administered post PBSCT to the majority of pts. Forty percent (40%) of HD Mel-treated pts and 26% of BEAM-treated pts required opioid analgesics. The percentages of pts receiving TPN were similar in the 2 conditioning regimens (66% of all pts). TPN was used in 16 (84%) pts with severe OM and in 24 (58%) pts with no or grade 1–2 OM. Adverse events clearly related to palifermin were reported in 25 (41%) of 60 pts. The most common adverse events included rash (18 events, 8 severe), disorders of tongue and oral mucosa (13 events, 2 severe), edema (10, no severe) and pruritus (7, no severe).Conclusions. These results indicate that palifermin use prior to HD Mel or BEAM and immediately following the transplantion may provide effective support in the prophylaxis of severe OM in pts undergoing autologous PBSCT, without major toxicity.

Palifermin in Patients with Hematological Malignancies Undergoing Autologous Hematopoietic Stem Cell Transplantation (HSCT): The Italian Early Access Program (EAP).

Oral mucositis (OM) is an acute, severe and often dose-limiting toxicity in patients undergoing HSCT. OM significantly affects functional status and patients' quality of life; however no effective therapy was available for this condition. Palifermin (Kepivance®) is a human keratinocyte growth factor (KGF) produced by recombinant DNA technology. KGF binds to its receptor on epithelial cells, stimulating their proliferation, differentiation, and migration. Palifermin has been shown to decrease the incidence and duration of severe OM in patients with hematologic malignancies receiving myelotoxic therapy and HSCT. In Italy, compassionate use protocols are considered EAP and are regulated by a decree issued by the Ministry of Health (MoH) on May 8th 2003. The objective of the Decree is to ensure that patients have access to experimental therapies outside clinical trials, when no valid therapeutic alternative exists. Approval is granted in case of serious or rare diseases or life-threatening conditions. After Ethical Committee (EC) approval and notification to MoH, the drug can be supplied in response to an unsolicited request from a physician. The drug is then administered under the physician's direct responsibility. During EAP, the Decree allows collection of the patient's data similar to an observational trial. From July 2005 through July 2006 a total of 26 centers have requested the drug and obtained approval from local EC. Each center collected the following data on a case report form: vital signs, disease status and treatment, palifermin administration, mucositis, analgesic use, parenteral supplementation, common laboratory tests and duration of hospitalization. A total of 175 adults patients with hematological malignancies treated with autologous SCT participated in the EAP. In an interim analysis, data from 41 patients (24 men; 17 women; median age 52.44) were analyzed. The most common diagnoses were multiple myeloma (MM) (n=16) and non-Hodgkin lymphoma (NHL) (n=15). Conditioning therapy and supportive care were administered according to standard institutional practice (high-dose melphalan for MM and the BEAM regimen for NHL). Palifermin 60 mcg/kg/day was given intravenously on 3 consecutive days before the conditioning regimen and on 3 days starting on the day of stem cell infusion. OM was evaluated daily for 28 days after transplantation or until severe OM resolution using the five-grade World Health Organization (WHO) oral-toxicity scale. Safety was assessed on the basis of the incidence of adverse events. The incidence of severe OM (Grade 3–4) was 17% and the mean duration was 2.2 ± 3.5 days (CI, 1.1–3.3) in patients with OM Grade 0–4 while in patients with OM G3-4 the mean duration was 6.9 ± 2.5 (CI, 4.5–9.2). Adverse events (mainly rash, pruritus, erythema, mouth and tongue disorders, and taste alteration) were mild to moderate in severity and were transient. The frequency of adverse events was consistent with those observed in clinical trials. In conclusion, the Italian EAP experience with palifermin suggested that results were consistent with those of pivotal studies in patients with hematologic malignancies undergoing HSCT. From the results of the interim analysis of the Italian EAP, the use of palifermin in this setting appears to be feasible and was widely accepted by participating physicians and patients.

Spontaneous Pregnancy and Fertility Preservation Program in Women Undergoing High Dose Chemotherapy for Hematological Malignancies.

Loss of fertility is a major concern in young women undergoing high dose chemotherapy (HDT). Although it is generally accepted that therapy of the myeloabelative range is related with a high rate of fertility loss, we observed during the last years eight spontaneous pregnancies with normal deliveries in young women after bone marrow transplantation. Seven patients (pt's) were with lymphoma and MM and were conditioned with BEAM regimen (n=6) and melphalan 200mg/sm (n=1) prior to an autologous SCT, while one patient had a secondary AML and underwent BEAM primed autologous SCT and Busulfex/FA primed allogeneic BMT. The median age at transplant of this group was 28y and median time from transplant to pregnancy was 25 months. More than 100 women of 18–40y.o were transplanted in our center during this period; however, obviously the fertility rate cannot be calculated as it is related with additional parameters including survival, post transplant complications and mainly patient's preferences. Naturally we observed during the same period many young patients with ovarian failure post transplant, as well as one successful pregnancy from a cryopreserved embryo.Methods. We Therefore initiated in October 2000 a fertility preservation program in which all women of 18 – 40y.o were offered a pretransplant IVF with embryo preservation, and/or ovarian tissue cryopreservation (OTC), according to their clinical status. 651 pt's were transplanted in our center in the last 44 months, of which 81 were women of 18–41y.o that were all enrolled in this program.Results. Seven pt's of this group (8.6%) underwent IVF. The major causes of denying IVF were the need to delay BMT for more than clinically accepted, prolonged preexisting ovarian failure, lack of a suitable partner and patient's preference. Seventeen pt's (21%) underwent OTC. The major causes of denying OTC were patient's preference (mainly due to no evidence of success with this method) and thrombocytopenia/neutropenia. During this period:One patient of this group was fertilized with her cryopreserved embryos 32 months after transplant and is at her 16 week of pregnancy.One patient underwent a successful transplantation of her cryopreserved ovarian tissue 2.5 years after HDC while in a documented ovarian failure, and gave birth to a healthy baby on June 2005. The OTC of this patient was performed after cis-platinum containing salvage therapy for relapsing NHL, prior to BEAM primed SCT, and immediately after a failure of hormonal stimulation for IVF.One patient underwent a cryopreserved ovarian tissue transplantation on July 2005Conclusions: 1. Spontanous pregnancy after HDT, mainly at the younger age, is not a rare phenomenon. 2. Most young patients prior to HDT are not eligible for IVF. 3. Pretransplant ovarian tissue cryopreservation is a feasible tool in this set-up. The first success with this method is promising.

Single or Tandem Autologous Stem-Cell Transplantation Given According to Prognostic Factors at Relapse for Hodgkin Lymphoma.

Patients with relapsed hodgkin lymphoma (HL)have a different prognostic after high-dose therapy (HDT)according to time to relapse and extend of relapse. From 1995 to 1997, 48 patients with early relapse or refractory HL were included in a pilot study of tandem transplantation to evaluate the feasibility before the protocol. From 1998 to 2002, 200 patients with refractory disease or first relapse of HL were prospectively treated with induction chemotherapy followed by HDT and autologous stem-cell transplantation (ASCT). Patients were stratified in 2 groups according to prognostic factors at relapse: groupe 1 (unfavorable relapse: primary refractory disease or early/disseminated relapse) and group 2 (favorable relapse: patients with either early or disseminated relapse). Induction chemotherapy consisted of ifosfamide/etoposide with doxorubicin (IVA) in 70% of patients or with vinorelbine and mitoguazone (MINE)for the remainings. Group 1, patients received 2 cycles of chemotherapy, PBSC collection and tandem ASCT, with a CBV mitoxantrone (30 mg/m2) and 2 months later cytarabine (6g/m2), melphalan (140mg/m2)with total body irradiation (40%) or busulfan (12 mg/kg) followed by the second ASCT.Group 2, patients received 3 cycles of chemotherapy, PBSC collection and a BEAM regimen followed by ASCT. Final results, updated, January 2005 are presented with 245 evaluable patients.Results: after induction chemotherapy overall response rate was at 61% in group 1 and 96% in group 2. In group 1, 70% received the two ASCT, the major reason not to receive the procedure was disease progression after induction chemotherapy (10%) or after the first ASCT (15%), than low stem-cell collection (4%) or toxicity (2%). In group 2, 97% of patients received ASCT and 1 patient received a tandem ASCT for refractory relapse. 5 patients died from toxicity in group1 and none in group2, but 2 secondary leukemia were observed in this group. In intent to treat analysis, at a 3 years median follow-up from the relapse, the EFS was at 45% in group 1 versus 75% in group 2 and the survival at 55% in group 1 versus 80% in group 2. Despite a different consolidation between group 1 and 2, results remained better in group 2. In conclusion, these results confirmed the importance of prognostic factors at relapse of HL.No differences were found in the unfavorable group 1 between refractory patients and early/disseminated relapse. HL patients with adverse prognostic factors (group 1) but responding to second line chemotherapy and eligible for tandem ASCT may benefit from this procedure with an EFS at 70%. The major cause of failure was chemoresistance either at induction or after high-dose therapy.

Transplantation of Ex Vivo Expanded Lin− Cells Selected from Autologous PBSC Grafts in Patients with Diagnosis of Lymphoma.

Background: Hematopoietic stem cells are able to regenerate hematopoiesis in all of its lineages. They are clinically used in transplantation of bone marrow or peripheral blood stem cells (PBSC) in patients with diagnosis of leukemia or lymphoma. While amount of hematopoietic stem cells is critical for the long-term engraftment, the amount of progenitor and precursor cells can influence time to engraftment, and it is critical for duration of neutropenia after transplantation. The methods of expansion of hematopoietic stem cells could reduce time to engraftment and decrease the risk of early post-transplant complications.Methods: Authors analyzed expansion of enriched hematopoietic stem cells (HSC), selected by immunomagnetic separation of Lin− cells from PBSC, in the culture of serum-free medium in vitro with all combinations of 5 cytokines (SCF, Flt-3-L, IL-3, IL-6, TPO) with and without G-CSF. Cell counts, morphology, immunophenotyping, and CFU-GM and CFU-Meg cultures were performed. Clinical transplantation protocol based on these results was developed. 10 patients with diagnosis of non-Hodgkin's or Hodgkin's lymphoma indicated for autologous transplantation, who signed the informed consent, were enrolled into the protocol. Except of standard PBSC graft, additional cells were collected, Lin− cells were selected by immunomagnetic separation, frozen and stored at Tissue bank. At day -14, Lin− cells were thawed and expanded in culture of serum-free medium with cytokines SCF, Flt-3-L, IL-3, IL-6 and G-CSF. Patients received high-dose chemotherapy regimen BEAM from day −7 to day −2. Progenitor cells expanded ex vivo in culture from Lin− cells were infused at day 0, following transplantation of PBSC. Patients were monitored, blood counts were performed, side effects were observed, and times to engraftment in granulocytes and platelets were calculated.Results: In experiments, the highest number of CFU-GM colonies was observed at day +14 with cytokine combination SCF+IL-3+Flt-3-L+ IL-6. The highest number of CFU-Meg colonies was observed in cytokine combination SCF+IL-3+TPO. G-CSF increased count and maturation of cells. Number of total cells grew 200 to 350 times at day +14. In the clinical protocol, 2 patients were excluded for technical reasons and 1 patient was excluded because of disease progression. 7 patients completed the protocol. The clinical procedure was free of serious adverse effects in all patients. Patients received doses from 5•107 to 3•109 cells. The group of patients was compared with historical controls - 142 patients treated at our department with autologous PBSC transplantation after BEAM regimen for diagnosis of lymphoma. Control group received higher average dose of CD34+ cells than experimental group: 7.7•106 / kg versus 6.6•106 / kg. Engraftment in granulocytes > 1000 / μl was shortened from 11 to 7.3 days in experimental group. Engraftment in platelets was not changed significantly (12 versus 11 days). Duration of neutropenia was shortened from 8 to 5.6 days. In patients, who received higher doses of infused cells > 2•109, average engraftment in granulocytes occurred at 6.3 days and duration of neutropenia was 5 days.Conclusions: HSC can be enriched from PBSC grafts, cultured and expanded ex vivo, and safely used in the cellular therapy protocols. The procedure resulted in significant shortening of critical period of neutropenia.

BEAM vs BuMelTT high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell infusion (HSCT) in the treatment of non-Hodgkin’s lymphoma

6676 HDC with HSCT is widely used in the treatment of chemosensitive relapses of NHL. There are only limited data comparing toxicities and efficacy of particular HDC regimens used in NHL. We retrospectively compared two conditioning regimens: BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan) and BuMelTT (busulphan, melphalan, thiotepa). Patients and Methods: Between January 1998 and May 2004 32 patients at a median age of 59 years (range 35–70 years) were treated with BEAM, and 54 patients (median age 51 years, range 35–65 years) with BuMelTT. Treatment groups were not significantly different with regard to histopathology and grade, sex, and former treatment, which consisted of 1 to 6 (median 3) chemotherapy regimens and a median of 9 cycles in both groups. There were significantly more patients with advanced disease (stage III and/or IV) in BEAM (81%) vs BuMelTT (58%). Radiotherapy had been given to 38% of BEAM vs 70% of BuMelTT patients. Age adjusted IPI 0–1 was diagnosed in 34% vs 47% patients, IPI 2 - 31% vs 19%, IPI 3 - 22% vs 15%, IPI 4 - 9% vs 6%, and unknown 3% vs 13% in BEAM vs BuMelT, respectively. Results: 16 of 53 (30%) patients treated with BuMelTT died, 4 due to treatment-related toxicity, one due to systemic aspergillosis, one due to stroke, and 10 (19%) of progressive disease. In contrast, 10 of 32 patients (31%) from the BEAM group died, one of treatment-related toxicity, and 9 (28%) of progressive disease. Median survival has not yet been reached, K-M estimates of 3-year OS for BEAM vs BuMelTT were 54% vs 63%, respectively. Conclusion: BEAM regimen appears less toxic than BuMelTT. It’s efficacy, however, may be inferior to BuMelTT. This observation needs to be confirmed in a randomized study. No significant financial relationships to disclose.

Front-Line High-Dose Chemotherapy (HDT) Combined with Rituximab for Adults with Aggressive Large B-Cell Lymphoma (DLBCL) : Goelams 074 Trial.

Background: The beneficial effect of adding rituximab to CHOP has been shown for elderly patients with DLBCL (Coiffier et al, N.E.J.M 2002). We have shown that HDT with autologous stem cell transplantation is superior to CHOP in young adults with DLCL ( Milpied et al GOELAMS 072 trial, N.E.J.M 2004). The feasibility of adding rituximab to front-line HDT remains to be established.Methods: A prospective pilot trial was proposed to patients with DLBCL, with intermediate-high or high adjusted IPI, up to the age of 60 y.o. This program consisted of 2 courses of high-dose CHOP-like regimen, 15 days apart, with rituximab (375/mg/m2) on day 1 of each course, followed by rituximab on d 22, harvest of G-CSF mobilised peripheral blood stem cells on d 28,29, then rituximab on d 36 followed by a course of high-dose methotrexate with cytarabin. For patients who achieved at least a PR after these 3 courses, a BEAM regimen started on d 66 to 80 followed by the infusion of stem cells.Results: Between 04/2002 and 05/2003, 42 pts gave their informed consent and were included in that trial. Median age was 50 y.o (18–60 y.o), 23 had WHO PS ≥ 2, the LDH level was >N in 41 pts and 38 had stage III or IV disease. The age-adjusted IPI was intermediate-high in 23 and high in 19 pts. The program was completed in 30 pts (71%), 3 pts died of toxicity before the BEAM regimen, 8 pts failed to achieve at least a PR after the first 3 courses and 1 refused the autologous transplant. On an intent-to-treat basis, the response rate at the end of the treatment was CR/Cru=64%, PR=7%, less than PR or progression= 22% and toxic death=7%. No toxic death was directly attributable to the addition of rituximab. With a median FU of 19 m, the KM 2y probability of OS and EFS are 79% and 59% respectively, these figures compare to those achieved without rituximab in the previous trial as shown on the table:Conclusion : The addition of 4 doses of rituximab to this HDT program is feasible with no unexpected toxicity, allows the harvesting of sufficient numbers of stem cells to support an autologous transplant with a BEAM regimen in responding patients. This treatment is now being randomly prospectively compared with CHOP-14-rituximab in youg adults with DLBCL (Goelams 075 trial).Supported in part by Roche which kindly provided rituximab for that trial and by DRC Nantes programme N°:02/2N 2002.GOELAMS 072 (IPI 2 only)GOELAMS 074 (IPI 2–3)2y OS80%79%2y EFS60%59%

Effect of High-Dose Rituximab on Peripheral Blood Stem Cell Mobilization in Intermediate Grade Non-Hodgkin's Lymphomas.

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered to be standard therapy for patients with intermediate grade NHL (IGNHL) in chemosensitive relapse. In recent years rituximab has been widely used for in vivo purging of lymphoma cells from apheresis products, however its impact on kinetics of stem cell mobilization and engraftment are not well characterized. We studied 69 patients with IGNHL who were mobilized using rituximab plus chemotherapy or with chemotherapy alone. 31 patients (No-R group) were mobilized with ifosfamide (10 g/m2), and etoposide (150 mg/m2 every 12 hours for 6 doses) followed by G-CSF (12 mcg/kg/day). 38 patients (R group) also received 2 doses of rituximab (375 mg/m2 and 1000 mg/m2) on days 1 and 10. Patients underwent HDT following successful stem cell collection. HDT was standard BEAM (+ rituximab for patients in the R group) regimen in most patients. 15 patients received a cycle of CVP (cyclophosphamide, cisplatin, etoposide) prior to BEAM because of failure to achieve at least a PR following mobilization chemotherapy (all in the No-R arm).RESULTS: The baseline characteristics of the 2 groups are summarized in Table 1. Patients in the No-R group were more likely to have stage III/IV disease, and were more likely to have BM involvement with lymphoma, but had received fewer number of chemotherapy regimens received prior to mobilization. Failure to mobilize was defined as failure to reach a circulating CD34 count of 10/mcl. The target cell dose was a minimum of 4 x 106 CD34+ cells/kg. The apheresis data is summarized in Table 2. All 31 patients in the No-R group mobilized the target cell dose (NA-1). In the R group 7.9% did not reach the target cell dose (P=NS). Median time to neutrophil engraftment after ASCT was 10 (8–17) and 11 (9–37) days in the No-R and R groups respectively (P=0.01). The OS and DFS at 2 years were 45% (27–61) and 39% (22–55) and 78% (51–92) and 63% (38–51) respectively in the No-R and R group (P=0.001 and 0.01).CONCLUSION: High dose rituximab added to the mobilization regimen does not affect the ability to collect adequate number of stem cells for ASCT. Incidence of bacteremic episodes was higher in the rituximab group. The OS and DFS were significantly longer in patients receiving rituximab.Table 2. Apheresis DataRituximab group (N=38)No rituximab group (N=31)P=valueMedian days of apheresis (range)2 (1–5)2 (1–7)NSFailure to mobilize10NSFailure to collect 4 x 106CD34+cells/kg30NSMedian CD 34+cells/kg (range)6.5 (0–31.15) x 10613.7 (4.8–148) x 106<.0001PRBC transfusions median (range)1 (0–5)0 (0–8).01Platelet transfusions median (range)2 (0–6)1 (1–3).008No. of patients with infections1380.45Infectious episodes26 (22 bacterial)11 (6 bacterial)0.01Time to ANC > 500/mm3 after mobilization median (range)13 (11–18)14 (6–24) NA 30.7Table 1: Baseline characteristicsRituximab groupNo rituximab groupP valueN=38N=31Age years (range)49.9 (19–70 )48 (26–590.68Stage III/IV (%)9 (23.7%)13 (43.3%).003No. of prior chemoregimens (median, range)2 (1–5)1 (1–3).001IPI score (median, range)0 (0–2)1 (0–2) NA 5.03LDH ≥ normal (%)8 (21%)8 (30.7%)0.78BM involvement (%)0 (0)8 (25.8)

Ann Arbor Stage Is the Most Important Predictor of Survival for Refractory and Relapsed HIV-Associated Lymphoma Enrolled in a Program of High Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation.

The recent introduction of highly active antiretroviral therapy (HAART) has allowed an aggressive treatment approach in the management of HIV-associated lymphoma (HIV-Ly). Within the Italian Cooperative Group on AIDS and Tumors (GICAT) in 2000 we started a multiinstitutional program of high dose therapy (HDT) and autologous peripheral blood stem cell transplantation (PBSCT) for HIV + patients (pts) with refractory or relapsed lymphoma. CNS lymphoma were excluded. So far, 26 pts entered the study: 10 HD (five 1st relapse, two 2nd relapse, three refractory) and 16 NHL (eight 1st relapse, one 2nd relapse, two partial remission (PR), five refractory). Median age was 38 (28–56); CD4 count 207/cmm (17–506); detectable HIV viremia: 6 pts (23%). Performance status (PS): 0–1, 7 pts (27%); 2, 19 pts (73%). Ann Arbor stage of lymphoma: II, 4 pts (15%); III, 8 pts (31%), IV, 14 pts (54%); B symptoms: 9 pts (35%); bone marrow involvement: 7 pts (27%). Median duration of last remission was 6 months (mo) (1–53). Pts received 2nd line standard dose chemotherapy as debulking treatment. Six pts were refractory and 5 died for disease progression (one is on treatment); 17 of 20 pts with chemosensitive disease successfully mobilized an adequate number of CD34+ after Cyclophosphamide + G-CSF or G-CSF-supported CT. Two pts had early disease progression, and 15 pts received the BEAM regimen and PBSCT, according to the protocol. Engraftment was prompt in all. Pts received HAART during the entire program. Neither treatment-related death nor HIV related death were registered. Fourteen pts achieved complete remission and 1 partial remission. Relapse occurred in 3 (mo +5, +8, +12); 13 are alive and 11 disease-free at 12 mo (2–28) after transplant. The median survival of the entire series (26 pts) from the study entry was 17 mo with 51% of the pts alive after a median f-up of 17 mo. From the analysis of prognostic factor, PS, Ann Arbor stage IV, B symptoms and CD4 count at study entry showed a correlation with survival by univariate, but stage IV disease was the only factor proved to correlate independently with survival on multivariate analysis. The projected overall survival for pts entering the study with stage IV disease (12 pts) or less than stage IV (14 pts) was respectively 90% vs 12% at 2 years (P < 0.001). Our data showed encouraging overall results with an intensive treatment strategy as salvage therapy for HIV-Ly. Ann Arbor stage was the most important predictor of survival. Pts with stage IV disease had poor prognosis, mainly because of chemoresistent disease, suggesting that these pts might benefit from the use of dose intensification earlier in the course of their disease.

Reduced-Intensity Conditioning Regimen with BEAM/Rituximab for Patients with Refractory Non-Hodgkin's Lymphomas.

Non-myeloablative allogeneic stem cell transplantation using the combination of fludarabine/cyclophosphamide/rituximab as a conditioning regimen has been successful in treating patients with relapsed, chemosensitive non-Hodgkin's lymphoma (Blood 98:3595, 2001; J Clin Oncol 21:4407, 2004). A more intense regimen however is required to have an early disease control for patients with refractory disease or in kinetic failure. We used the BEAM regimen for that purpose. Because of potential synergy and without overlapping toxicity, Rituximab (375 mg/m2 on days −6, −1, +7 and +14) was added to the preparative regimen. Transplantation was performed on day 0. Fourteen consecutive patients with refractory lymphoma or in kinetic failure were studied. The study group included 11 males and three females of median age of 46 (range, 19–60) yrs. Underlying histologies include diffuse large cell lymphoma (n= 9), follicular (n=1), mantle cell (n=1), lymphoplasmacytic (n=1), and CLL in Richter transformation to diffuse large cell (n=2). Median # of prior chemoregimens received was 3 (range, 1–8). Twelve patients had a matched sibling donor, one a mismatched sibling, and one a matched unrelated donor. The median # of CD34+ cells infused was 5 x 106 CD34 + cells/kg. Twelve patients received blood and 2 received marrow as the source of the hematopoietic graft. Tacrolimus and methotrexate were used for GVHD prophylaxis. The day-100 mortality was 7%. Eleven patients (79%) had a complete, and 2 (14%) had a partial remission. One patient (7%) had no response. All patients engrafted donor cells (median of 100% at day 30) post transplantation. Median time to ANC > 500 was 13 (11–15) days and median time to platelets > 20K was 14 (9–25) days. The actuarial risk of Gr 2–4 GVHD was 57%, Gr 3–4 GVHD 28%. Eleven of the 13 patients who were alive at day 100 developed chronic GVHD. With a median follow-up time among survivors of 34 (8–48) months, overall survival and disease-free survival were 63% (95% CI, 33–83) and 57% (95%CI, 28–78), respectively.Our results indicate that a pronounced graft-versus-lymphoma occurs after BEAM/Rituximab and allogeneic transplantation for patients with refractory lymphoma or in kinetic failure. This treatment has been associated with a lower than expected treatment-related mortality and a higher chance of durable remission.

A long-term follow-up of 33 patients with non-Hodgkin's lymphoma who received the BEAM high-dose intensification regimen with cytokine support only and no transplant.

High-dose intensification and autologous stem-cell transplantation (ASCT) is widely used to consolidate patients with non-Hodgkin's lymphoma (NHL), who have reached a stage of minimal residual disease. However, patients with persisting marrow and/or blood involvement and those who fail peripheral blood hemopoietic progenitor mobilization are excluded from ASCT. For such patients with no available graft to infuse, we developed 15 years ago, before the anti-CD20 monoclonal antibody therapeutic era, the use of the BEAM pretransplant regimen followed only by the administration of three cytokines (erythropoietin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor). We report here on the long-term follow-up of 33 patients treated with this approach. In all, 33 NHL patients underwent the BEAM (carmustine, VP-16, cytosine-arabinoside, melphalan) followed by the administration of the three cytokines from January 1994-2000. A backup marrow, albeit infiltrated by tumor cells, had been collected earlier and stored in all. A total of 30 patients (91%) recovered normal hematopoiesis. In total, 32 patients (97%) recovered neutrophils (>500/microl) at a median of 19 days and 30 patients (91%) recovered platelets (>20,000/microl) at a median of 26 days. Age, richness of backup graft and blood-hemoglobin level at intensification had an impact on the time for hematopoietic recovery (P=0.014, P=0.014, P=0.048). The median follow-up was 62 months. Five patients died from toxicity related to the procedure. Eight patients relapsed and died. A total of 20 patients (61%) are alive, 16 (49%) in complete remission. A 5-year disease-free survival was 52+/-9%, relapse incidence 35+/-16%, mortality due to the procedure 12+/-12% and overall survival 61+/-10%. The BEAM regimen is not myeloablative. The BEAM+3CK procedure is a feasible therapeutic option that has shown efficacy in poor risk NHL patients who were not eligible for autografting because of persisting marrow/blood tumor contamination, or poor hemopoietic progenitor harvesting. It is unclear today whether some of these patients would have cleared their marrow/peripheral blood with the additional use of anti-CD20 treatment, thereby making the classical approach (BEAM followed by the infusion of a clean autograft) feasible.

Front-line high-dose chemotherapy (HDT) combined with rituximab for adults with aggressive large B cell lymphoma (DLBCL). A pilot study by the GOELAMS

6662 Background: The beneficial effect of adding rituximab to CHOP has been shown for elderly patients with DLBCL (Coiffier et al NEJM 2002). We have shown that HDT with autologous stem cell transplantation is superior to CHOP in young adults with DLCL (Milpied et al NEJM in press). The feasibility of adding rituximab to front-line HDT remains to be established. Methods: A prospective pilot trial was proposed to patients with DLBCL, with intermediate-high or high age-adjusted IPI, up to the age of 60 y.o. This program consisted of 2 courses of high-dose CHOP-like regimen, 15 days apart, with rituximab (375 mg/ m2) on d1 of each course, followed by rituximab on d 22, harvest of peripheral blood stem cells (G-CSF mobilized) on days 28,29, then rituximab on d 36 followed by a course of high-dose methotrexate with cytarabine and by a BEAM regimen starting on d 66 to 80, followed by the infusion of stem cells. Results: Between 04/2002 and 05/2003, 41 consecutive patients gave their informed consent and were included in that trial. Their median age was 50y.o.( 18–60 yo); 23 had WHO PS >/= 2, the LDH level was > N in 37 patients and 38 had Ann Arbor stage III or IV. The age-adjusted IPI was intermediate-high in 21 and high in 19 patients.At the time of this abstract, the program has been completed in 75% of the patients. Three patients died of toxicity of the treatment before the BEAM regimen and autologous transplantation. On an intent-to-treat basis, the response rate at the end of the treatment was CR/CRu= 64%, PR=8%, failure to achieve a response or progression= 20% and toxic death=8%. No toxic death was directly attributable to the addition of rituximab. Conclusions: The addition of 4 doses of rituximab to this HDT program is feasible with no unexpected toxicity, allows the harvesting of sufficient numbers of stem cells to allow an autologous transplantation following a BEAM regimen in responding patients . Follow-up and comparison with historical control will be performed and presented Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pharmaceutical Roche France

Front-line high-dose chemotherapy (HDT) combined with rituximab for adults with aggressive large B cell lymphoma (DLBCL). A pilot study by the GOELAMS

6662 Background: The beneficial effect of adding rituximab to CHOP has been shown for elderly patients with DLBCL (Coiffier et al NEJM 2002). We have shown that HDT with autologous stem cell transplantation is superior to CHOP in young adults with DLCL (Milpied et al NEJM in press). The feasibility of adding rituximab to front-line HDT remains to be established. Methods: A prospective pilot trial was proposed to patients with DLBCL, with intermediate-high or high age-adjusted IPI, up to the age of 60 y.o. This program consisted of 2 courses of high-dose CHOP-like regimen, 15 days apart, with rituximab (375 mg/ m2) on d1 of each course, followed by rituximab on d 22, harvest of peripheral blood stem cells (G-CSF mobilized) on days 28,29, then rituximab on d 36 followed by a course of high-dose methotrexate with cytarabine and by a BEAM regimen starting on d 66 to 80, followed by the infusion of stem cells. Results: Between 04/2002 and 05/2003, 41 consecutive patients gave their informed consent and were included in that trial. Their median age was 50y.o.( 18–60 yo); 23 had WHO PS >/= 2, the LDH level was > N in 37 patients and 38 had Ann Arbor stage III or IV. The age-adjusted IPI was intermediate-high in 21 and high in 19 patients.At the time of this abstract, the program has been completed in 75% of the patients. Three patients died of toxicity of the treatment before the BEAM regimen and autologous transplantation. On an intent-to-treat basis, the response rate at the end of the treatment was CR/CRu= 64%, PR=8%, failure to achieve a response or progression= 20% and toxic death=8%. No toxic death was directly attributable to the addition of rituximab. Conclusions: The addition of 4 doses of rituximab to this HDT program is feasible with no unexpected toxicity, allows the harvesting of sufficient numbers of stem cells to allow an autologous transplantation following a BEAM regimen in responding patients . Follow-up and comparison with historical control will be performed and presented Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pharmaceutical Roche France

CHOP and DHAP plus rituximab followed by autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL): A pilot study from the GELA

6529 Background: Sequential chemotherapy by CHOP and DHAP regimens followed by ASCT improves complete response (CR) rate and EFS in younger patients with MCL (Lefrère et al, Leukemia, 2002). Since Rituximab (R) may induce significant response in relapsing MCL, we conduct a pilot, multicentric study to determine the impact of the CHOP/DHAP protocol plus R followed by ASCT as a first line therapy in the treatment of MCL at advanced stage. Methods: Patients under 66 years with histologically proven, stage III-IV MCL were included. Treatment consisted of two courses of CHOP, one R-CHOP (Rituximab : 375 mg/m2) and three R-DHAP. Peripheral blood stem cells harvest was performed at the end of the third R-DHAP. Responding pts were eligible for an ASCT after high dose therapy with TBI (10 Gy), Aracytine (6g/m2) and Melphalan (140 mg/m2) (TAM 6) or BEAM if TBI could not be performed. Results: From May 2000 to November 2003, 56 pts were included in this study. Median age is 57 years. Fourty-eight pts are evaluable for treatment response. Characteristics of patients are as follow : bone marrow involvement (42/48), leukemic disease (23/48), PS>1 (3/48), extramedullary involvement (20/48) included gastrointestinal (10/22 tested), LDH > 1N (15/48). Fourty-four pts are evaluable after the three courses of (R)-CHOP. Response rates were as follow : CR (4/44), PR > 50% (37/44) and stable disease (3/44). Fourty patients have completed the three courses of R-DHAP. After the R-DHAP, response rates were : PR (14/40), CR (23/40) and SD (3/40). PBSC harvest was successful in 39/40 patients. Thirty patients were autografted with a TAM 6 (28 pts) or a BEAM regimen (2 pts). After ASCT, all patients but one were in CR. Currently, with a median follow up of 25 months, 28/30 pts were in CR 1 and only one relapse was observed. One patient died from unrelated cause. Conclusions: Chemotherapy with DHAP followed by a Aracytine containing regimen provide a high response rate in untreated MCL. However, longer follow-up is needed to assess impact of Rituximab on EFS and survival. Multicentric European study is currently ongoing to test this approach against R-CHOP induction therapy. No significant financial relationships to disclose.

CHOP and DHAP plus rituximab followed by autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL): A pilot study from the GELA

6529 Background: Sequential chemotherapy by CHOP and DHAP regimens followed by ASCT improves complete response (CR) rate and EFS in younger patients with MCL (Lefrère et al, Leukemia, 2002). Since Rituximab (R) may induce significant response in relapsing MCL, we conduct a pilot, multicentric study to determine the impact of the CHOP/DHAP protocol plus R followed by ASCT as a first line therapy in the treatment of MCL at advanced stage. Methods: Patients under 66 years with histologically proven, stage III-IV MCL were included. Treatment consisted of two courses of CHOP, one R-CHOP (Rituximab : 375 mg/m2) and three R-DHAP. Peripheral blood stem cells harvest was performed at the end of the third R-DHAP. Responding pts were eligible for an ASCT after high dose therapy with TBI (10 Gy), Aracytine (6g/m2) and Melphalan (140 mg/m2) (TAM 6) or BEAM if TBI could not be performed. Results: From May 2000 to November 2003, 56 pts were included in this study. Median age is 57 years. Fourty-eight pts are evaluable for treatment response. Characteristics of patients are as follow : bone marrow involvement (42/48), leukemic disease (23/48), PS>1 (3/48), extramedullary involvement (20/48) included gastrointestinal (10/22 tested), LDH > 1N (15/48). Fourty-four pts are evaluable after the three courses of (R)-CHOP. Response rates were as follow : CR (4/44), PR > 50% (37/44) and stable disease (3/44). Fourty patients have completed the three courses of R-DHAP. After the R-DHAP, response rates were : PR (14/40), CR (23/40) and SD (3/40). PBSC harvest was successful in 39/40 patients. Thirty patients were autografted with a TAM 6 (28 pts) or a BEAM regimen (2 pts). After ASCT, all patients but one were in CR. Currently, with a median follow up of 25 months, 28/30 pts were in CR 1 and only one relapse was observed. One patient died from unrelated cause. Conclusions: Chemotherapy with DHAP followed by a Aracytine containing regimen provide a high response rate in untreated MCL. However, longer follow-up is needed to assess impact of Rituximab on EFS and survival. Multicentric European study is currently ongoing to test this approach against R-CHOP induction therapy. No significant financial relationships to disclose.

High dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for HIV-associated lymphoma

6506 Background: The introduction of highly active antiretroviral therapy (HAART), has allowed the evaluation of aggressive therapeutic approaches in HIV-associated lymphoma (HIV-Ly). Methods: We report the results of a multiinstitutional program of high dose therapy (HDT) and autologous peripheral blood stem cell (PBSC) transplantation in HAART responsive pts with HIV-Ly refractory or relapsed after standard dose chemotherapy (CT). Pts with active opportunistic infections (OI) or CNS lymphoma were excluded. Results: Twentyfive pts entered the study: 10 HD (five 1st relapse, two 2nd relapse, three refractory) and 15 NHL (eight 1st relapse, one 2nd relapse, two partial remission (PR), four refractory). Median age was 38 (28–56) and CD4 count 207/cmm (17–506). Pts received 2–4 courses of debulking standard dose second-line CT. Five were refractory and died. Adequate PBSC collection was obtained in 17/20 pts (85%) (median CD34+ cells 6.8 x 106/Kg), after cyclophosphamide + G-CSF or G-CSF-supported CT. Two had early disease progression; one is on treatment and 14 received the BEAM regimen and PBSC transplantation with prompt engraftment in all (neutrophils and plt engraftment: 10 (8–10) and 12 days (8–18)). Pts received HAART during the entire program. Treatment-related toxicities (WHO grade 3–4): 3 oral mucositis (3) and 2 hepatic toxicity (3). Infections: 1 Staph. Epidermidis and 1 E. Coli sepsis, 1 Clostridium colitis and 3 FUO. OI: 2 varicella zooster at 3 and 5 mo and 2 esophagus candidosis at 1 and 9 mo. CD4 count decreased after treatment, but a trend toward recovery is seen few mo after transplant. 12/13 evaluable (1 is too early) pts (92%) achieved CR and 1 PR. Relapse occurred in 2 (mo 5 and 12). 11 are alive and 10 disease-free at 9 mo (2–24) after transplant with a projected overall survival (OS) of 64% at 2 ys. The median survival of the entire series (25 pts) from the study entry was 17 mo with a projected OS of 46% at 2 ys (f-up 12 mo (3–42)). Conclusions: Our data confirm on a multiinstitutional basis that HDT and PBSC transplantation is feasible and active as salvage therapy in HIV-Ly in unselected HAART responding patients. No significant financial relationships to disclose.