Poor-risk non-Hodgkin's Lymphoma Research Articles

The impact of allogeneic hematopoietic cell transplantation on the mortality of poor-risk non-Hodgkin lymphoma: an intent-to-transplant analysis.

Purpose of this single-centre retrospective study was to assess the outcome of allogeneic hematopoietic cell transplantation (alloHCT) for relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) by intent-to-transplant (ITT). Included were all consecutive patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and peripheral T-cell lymphoma (PTCL) for whom a donor search was performed between 2004 and 2018. Primary endpoint was overall survival (OS) measured from search initiation. A donor search was initiated for 189 patients (DLBCL 61, FL 32, MCL 43, and PTCL 53), with 76% of the patients having active disease. OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 26%, 44%, 52%, and 50%, respectively. AlloHCT was performed in 137 patients (72%; DLBCL 64%). Main reason for not undergoing alloHCT was disease progression, whereas donor unavailability accounted for only 4% of pretransplantation failures. These results suggest that survival of patients with r/r NHL entering the alloHCT route may be overestimated by a factor of 1.2-1.4 if based on actually transplanted patients only. This effect should be taken into account when using alloHCT as benchmark for new therapeutic approaches for the treatment of poor-risk NHL.

The Impact of Allogeneic Hematopoietic Cell Transplantation (alloHCT) on the Outcome of Poor-Risk Non-Hodgkin Lymphoma (NHL): A Retrospective Intent-to-Transplant (ITT) Analysis

Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

Phase I Studies of Cellular Immunotherapy Using Central Memory Derived-CD19-Specific T Cells Following Autologous Stem Cell Transplantation for Patients with High-Risk Intermediate Grade B-Lineage Non-Hodgkin Lymphoma

IntroductionEfforts to improve the survival of non-Hodgkin lymphoma (NHL) patients with recurrent disease have focused primarily on the use of consolidative myeloablative autologous hematopoietic stem cell transplantation (HSCT). However, the major limitation of HSCT for NHL is the high incidence of relapse, even at maximally tolerated preparative regimen intensities. In a series of phase I studies designed to improve HSCT longterm remission rates, we have assessed the safety and feasibility of cellular immunotherapy utilizing ex vivo expanded autologous central memory (Tcm)-enrichedT cells that are genetically modified to express CD19-specific chimeric antigen receptors (CD19CAR), given in conjunction with standard of care myeloablative HSCT.MethodsHere we present results from the first two studies investigating different starting cell populations and CAR constructs. The NHL1 trial utilized a starting population of CD8+ Tcm and transduced with a lentiviral vector encoding the 1st-generation CD19CAR (CD19R:zeta), consisting of a CD19-specific scFv linked to a CD3-zeta (CD19R:zeta) signaling domain. The NHL2 trial used a bulk Tcm population including both CD4+ and CD8+cells, which were transduced with lentiviral vectors encoding a 2nd-generation CD19CAR that added a CD28 costimulatory domain (CD19R:CD28:zeta) and a selectable marker for cell tracking (EGFRt). Engineered Tcm-derived CD19CAR T cells were infused 2 days after HSCT at dose levels of 25-200 x10^6 CAR T cells (dose levels in table), and all participants were followed for dose limiting toxicity (DLT) for 28 days. Both phase I studies utilized the target equivalence range design, which defines the dose escalation and de-escalation rules for determining maximum tolerated dose based on a target range of acceptable toxicity.ResultsNHL1 protocol (NCT01318317): Eight participants were consented and received CD8+ Tcm -derived CD19R:zeta T cell therapy. Seven patients had a diagnosis of diffuse large B cell lymphoma (DLBCL) and 1 had mantle cell lymphoma (MCL). Four of the 8 were female, and 3/8 were ≥ age 65 years. The mean age was 62 years (50-75). The median number of prior chemo/immunotherapy regimens was 3 (2-4). Two of the 8 (25%) participants had prior radiation. Five of 8 (63%) participants on NHL1 achieved a best response of CR or continuing CR. Four of 8 (50% 95% CI [16%, 84%]) participants have progressed. The progression free survival (PFS) at both 1 and 2 years is 50%, 95% CI[16%,84%] with a median follow-up of 24.7 (min=24.0, max=26.7) months. There were 2 deaths, both from disease progression.NHL2 protocol (NCT 01815749): Eight participants were consented and received Tcm-derived CD19R:CD28:zeta/EGFRt T cell therapy. Four patients had MCL, 4 had DLBCL, 3/8 were female, 2/8 were ≥ age 65 years. The mean age was 58 years (23-71). The median number of prior chemo/immunotherapy regimens was 2 (1-3). All eight NHL2 participants achieved a best response of CR or continuing CR. The PFS at 6 months is 100%, 95% CI[63%, 100%] with a median follow-up of 12.2 (min=10.0, max=14.1) months. To date 2 participants of the 8 (25%, 95% CI [3%, 65%]) have progressed (one at 6.4 months and one at 12.6 months). There was 1 death from disease progression.Both NHL1 and NHL2 trials demonstrated safety and feasibility. There were no DLTs, delayed hematopoietic reconstitution, or non-relapse mortality on either study. In NHL2, we employed bulk Tcm including both CD4+ and CD8+ cells in the CAR transduction and also added a CD28 co-stimulatory domain in the CAR design, to enhance persistence and antitumor activity. NHL2 exhibited better CAR T cell persistence compared to NHL1 T cell therapy based on area under the curve of log10copies/µg of genomic DNA from day 1 to 25 post infusion (mean difference = 14.8, 95% CI [7.4, 22.3], P<0.001) based on analysis of WPRE PCR data.ConclusionsWe conclude that Tcm-derived CD19CAR T cell therapy is very safe for treatment of poor-risk NHL patients undergoing autologous HSCT. We continue follow-up of these patients long-term to assess efficacy, and preliminary data are promising. Meanwhile we are exploring CAR vector design and T cell population modifications to improve the duration of anti-tumor immunity in the setting of immune reconstitution following engineered autograft.TableTrialCAR+ Cell Dose# of PatientsNHL125 x 10^6150 x 10^64100 x 10^63NHL 250 x 10^63200 x 10^65 DisclosuresKhaled:Sequenom: Research Funding. Siddiqi:Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting; Seattle Genetics: Speakers Bureau. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; Cell Medica: Membership on an entity's Board of Directors or advisory committees. Jensen***:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding. Forman***:Amgen: Consultancy; Mustang: Research Funding.

Y90 Plus High Dose BEAM with Autologous Stem Cell Transplantation for Chemorefractory Non Hodgkin Lymphoma.

Abstract 3423Poster Board III-311Long term survival for patients with chemo-refractory non-Hodgkin lymphoma (NHL) is poor even with high dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Strategies such as novel transplant conditioning regimens and post transplant maintenance therapy are being evaluated to improve outcomes. Herein we report on the results of a phase II study designed to assess the impact of a novel radioimmunotherapy (RIT) based conditioning regimen of Y90 ibritumomab tiuxetan in conjunction with high dose BEAM (BCNU, Etoposide, Ara–C, Melphalan) in patients with poor risk NHL. Between May 2002 and Jan 2009, 31 patients who were either primary induction failure (n=18) or in partial remission (n=13) underwent HDC with Y90 plus BEAM. Patients received an imaging dose of Indium 111 on day -21 followed by a treatment dose of Y90 (0.4mCi/kg) on day-14. HDC with BEAM was started on day -7. The median age at ASCT was 57 (range: 19–70). The majority of patients were male (n=23, 74%) and had advanced stage disease (III or IV) at the time of diagnosis, (n=23, 74%). The histologies included Follicular n=6, Diffuse Large B-cell n=13, Mantle cell n=8, and Transformed n=4. The median number of prior regimens was 2 (range: 1-5). All patients engrafted at a median of 11 days. At the time of analysis, 23 (74%) patients were alive, and eight had expired (seven due to relapse/progressive disease, one due to COPD). The non-relapse mortality was 3.2%. The median length of follow-up for surviving patients is 46.9 months (range: 3.3-75.0). The two-year overall survival and disease-free survival was 77.9% (95%CI: 62.7-87.6%) and 50.9% (95%CI: 40.5-60.3%) respectively for the entire cohort. However, the relapse rate in the subset of MCL pts was strikingly high and approached 80% at 4 yrs. The other subgroups had a stable DFS (figure 1). In conclusion in this poor risk group of patients Y90 plus high dose BEAM can induce responses and long term remissions, however, for patients with chemorefractory MCL other treatment approaches may be warranted. [Display omitted] DisclosuresOff Label Use: yttrium 90 in combination with high dose BEAM chemotherapy.

Outpatient Busulfan (BU)/Cytoxan (CY)/VP-16 and Autologous Stem Cell Transplant (ASCT) for Non-Hodgkin's Lymphoma (NHL) and Hodgkin's Disease (HD): Comprehensive Supportive Care Program Associated with Low Treatment Related Mortality and Hospital Utilization.

Busulfan based ASCT protocols are effective therapy for patients (pt.s) with poor risk NHL and HD. This therapy historically required pt.s to be hospitalized to manage treatment related toxicities until neutrophil engraftment with a median stay in most institutions of 21 days. We have developed a comprehensive outpatient approach for the management of pt.s undergoing ASCT. While potential benefits include decreased hospital utilization and increased patient satisfaction, there is paucity of data regarding its feasibility and safety. We report on treatment related mortality (TRM) and outcome results using a comprehensive outpatient care approach in 169 consecutive patients with NHL and HD transplanted at a single institution between February 1998 and December 2006. Excluding the planned admission for stem cell infusion on Day 0, all other aspects of their management (chemotherapy, supportive care) were to be performed in the outpatient facility. Exceptions to this model occurred for pt.s with circumstances that might compromise the safety of the outpatient management, otherwise this was standard practice. Pt.s were seen daily in the clinic during the first 30 days, unless they were hospitalized. The most common reasons for admission included the development of neutropenic fever or mucositis. One hundred sixty-nine consecutive pt.s with a median age of 54 yr.s (22–73) underwent ASCT for NHL (57 diffuse B-cell large cell (DLC), 53 HD, 17 Mantle Cell (MC), 24 Follicular NHL (FL), 6 ALCL, 3 Burkitts, and 9 other subtypes). The conditioning regimen consisted of dose targeted oral BU (1 mg/kg every 6 hours) on days -8 thru -5, CY 60 mg/kg on days -3 and -2 and VP-16 10 mg/kg days -4, -3 and -2. Autologous peripheral blood stem cells were used for 151 pt.s, bone marrow for 8 pt.s and 10 pt.s received both cell sources. The median CD34+ cell dose was 4.9 × 106/kg. Median time to neutrophil and platelet engraftment was 11 (range 9–34) and 17 (range 0–85) days, respectively. There were no (0%) treatment related deaths in the 169 pt.s during either the first 100 days or 1 year post-transplant. Eight high risk patients (3 DLC, 2 ALCL, 1 Burkitts NHL, 1 HD and 1 FL) died of progressive disease by day 100 (days 52 - 85). Stratifying for disease risk per the CIBMTR criteria, the 3-year Kaplan-Meier overall survival (OS) and progressive-free survival (PFS) for pt.s with DLC NHL in all pt.s (n=57), intermediate risk pt.s (n=24) and low risk pt.s (CR1, n= 9) is 67%, 86% and 100%; and 46%; 60% and 100%, respectively. The 3-year OS and PFS for pt.s with HD with low/intermediate risk (n=24) and high risk (n=29) is 78% and 72%; and 51% and 45%, respectively. The 3-year OS and PFS for patients with MC NHL (low risk n=9, intermediate risk n=6) is 68% and 65%, respectively. The 3-year OS for pt.s with FL is 75%. In summary, outpatient ASCT with expectant inpatient management for treatment related toxicities can be conducted safely in the setting of a comprehensive outpatient treatment program with treatment related mortality outcomes that is at least as comparable, if not superior, to those reported in the literature for conventional inpatient ASCT for similar patient cohorts.

Autologous Stem Cell Transplantation (ASCT) for Poor Prognosis Non Hodgkin Lymphomas (NHL).

Between 1995 and 2005, we performed 329 hematopoietic stem cell transplantation (HSCT), 286 autoulogous and 43 allogeneic.Long term results of treatment and outcome of ASCT in 100 Non Hodgkin Lymphoma (NHL) were analyzed. Median age was 47 years (range18 – 64) and the histology was: Follicular Lymphoma 15%, diffuse large B cell lymphoma (DLBCL) 47%, T lymphoma 27% and 11% others. At diagnosis 66% had advanced stage (III/IV), 40% had B symptoms, and 34% had extranodal involvement. Disease status at HSCT was: 5 % primary induction failure, 41% CR1, 20% CR2 +, 7% CRU, 12% relapsed. Number of prior chemotherapy regimens was 47% 2 lines, 20% 3 lines and 3% 4 lines; 27% had received prior induction or consolidation radiotherapy. Condition regimens consisted of BEAC (81%), BEAM (15%), others (4%). Stem cell source: 39% received BM + PBSC and 61% PBSC.Sixty nine are alive with a median survival of 3448 days (9.5 years). Median overall survival was similar in DLBCL (59%) and peripheral T lymphoma (60%). The best overall survival was observed in CR1 (77%) versus 52% in CR2 and 66% in PR1. Primary cause of death was relapsed or progression (24/31).We concluded that high dose therapy and autologous HSCT is an effective therapy for patients with poor risk NHL however relapse continues to be the most common cause of treatment failure. Newer strategies such as monoclonal antibody, require further investigation but early reports appear promising in reducing relapses in autologous HSCT.

In Vivo Chemotherapy Protection and Efficacy of Multidrug Resistance (MDR-1) Gene Transfer in a Patient with Refractory Non-Hodgkin's Lymphoma (NHL).

We report clinical and molecular data for the first subject enrolled in our gene therapy clinical trial. This patient had follicular transformed large cell lymphoma that relapsed with a large mediastinal mass >2 years after CHOP, and despite 3 cycles of ICE, had persistent residual disease. After mobilization with rituximab, cyclophosphamide (Cy), and G-CSF, 3X106 CD34+ cells/kg were cryopreserved directly. CD34+ cells from a 2nd apheresis product were transduced with retroviral vector, SF1m (SFFV LTRs, MESV leader and MDR-1 cDNA), in fibronectin CH-296 peptide (Retronectin) coated bags, serum-free, in cytokines. The final product was 95% CD34+, 96% viable, and represented 5.5X106 CD34+ cells/kg. Post transduction, 11% of the cells effluxed rhodamine (a function of the MDR-1 encoded p-glycoprotein), corresponding to 20–30% transduction efficiency due to production of alternatively spliced mRNAs, as compared to 1% of the non-transduced cells. The patient received low dose (100 cGy) total body irradiation (TBI) followed by infusion of the transduced (Tr) cells, then 4 cycles of vincristine, dose escalating VP-16, and prednisone. The platelet count nadir improved with each cycle (18, 65, 98, and 131 K after cycles 1, 2, 3, 4) as did the ANC nadir, 100 for cycle 1 v. 640 for cycle 4, likely due to selection and expansion of MDR-1 expressing cells. The patient was in CR prior to a 2nd myeloablative transplant of the original unmanipulated cells after high dose Cy/TBI (1200cGy). For 21 months (m) after infusion of Tr cells, the patient remained well, until he suffered a fatal myocardial infarction. The post mortem showed no evidence of lymphoma or other malignancy. PB and bone marrow (BM) samples collected every 1–3m were examined by RTQ-PCR and nested PCR for presence of the transgene. Tr cells were detected by RTQ-PCR as early as 2 weeks post-transplant. CFU assays of BM samples collected 1, 3, and 6m after transplant demonstrated increasing resistance to doxorubicin with increased time after Tr cell infusion. The transgene was not detected by nested PCR in colonies 1m after initial transplant, however, after 3m, the MDR-1 transgene was present in 3.1% of the colonies and in 10.2% of colonies after 6m. The more sensitive RTQ-PCR showed 16.3%, 25.5%, and 23.9% colonies positive at 1,3, and 6m after transplant. Thus far, insertion site analysis by inverse PCR revealed 13 products representing insertions in non-coding sequence of chromosomes 4, 12, 16, and 20; more sensitive analysis is in progress. Nested and RTQ-PCR of PB and BM samples from 6 weeks and on CFU from BM 14m after the 2nd transplant were negative. RCR safety testing was negative by RTQ-PCR for retroviral 4070A and VSVG envelopes. Thus, autologous engraftment of genetically modified cells with MDR-1 was achieved with 100 cGy TBI in a patient with poor risk NHL who subsequently achieved ‘myeloprotection' with debulking chemotherapy. Definitive treatment with Cy/TBI and autologous infusion of unmodified cells provided a unique safety feature to eliminate in vivo residual transduced cells, protecting against the risk of insertional mutagenesis.

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.

Dose-intensified CHOP (Double-CHOP) Followed by Consolidation with High-dose Chemotherapy for High and High-intermediate Risk Aggressive Non-Hodgkin's Lymphomas

Patients with aggressive non-Hodgkin's lymphoma (NHL) showing several risk factors have a poor prognosis. In such patients, conventional chemotherapy results in a low complete response rate and a high relapse rate. We performed a prospective trial of intensive induction chemotherapy followed by high-dose consolidation therapy to determine the feasibility of such an approach. We treated 39 patients with aggressive poor risk NHL with double-CHOP (D-CHOP) chemotherapy followed by high-dose therapy (HDT) with or without peripheral blood stem cell transfusion (PBSCT). The median age of the patients was 54 years (range 17-65). Twenty-seven were considered to be at high (H) and 12 were at high-intermediate (H-I) risk according to the age-adjusted International Prognostic Index. Thirty-four patients (87%) responded (complete response: 74%, partial response: 13%) to D-CHOP chemotherapy. Of the 34 responders, 24 received HDT followed by PBSCT, 7 received high-dose methotrexate, and 3 refused consolidation therapy. At a median follow-up period of 26 months, the estimated 3-year overall survival rate and event-free survival rate was 64 and 51%, respectively. Our data suggest that dose-intensified D-CHOP followed by consolidation HDT is safe and appears efficacious in aggressive NHL patients with H-I and H risk.

Intensive sequential chemotherapy with repeated blood stem-cell support for untreated poor-prognosis non-Hodgkin's lymphoma.

To demonstrate the feasibility and efficacy of six ambulatory high-dose sequential chemotherapy courses that include three intensified cycles supported by stem-cell infusion in high-risk and high-intermediate-risk untreated non-Hodgkin's lymphoma (NHL) patients. A pilot nonrandomized study included 20 untreated patients aged less than 60 years with aggressive histologically identified NHL and two or three adverse-prognosis criteria (International Index). Patients received an ambulatory regimen with high-dose chemotherapy supported by granulocyte colony-stimulating factor (G-CSF) and repeated peripheral-blood stem-cell (PBSC) infusion. The median age was 39 years (range, 20 to 59), with 13 men and seven women. Chemotherapy consisted of one cycle every 21 days for a total of six cycles. The first three cycles (A1, A2, and A3) consisted of cyclophosphamide (Cy) 3,000 mg/m2, doxorubicin (Doxo) 75 mg/m2, and vincristine 2 mg (plus corticosteroids). The last three cycles (B4, B5, and B6) consisted of the same drug combination plus etoposide 300 mg/m2 and cisplatin 100 mg/m2. For an expected duration of 18 weeks, the projected dose-intensity was 25 mg/m2/wk for Doxo and 1,000 mg/m2/wk for Cy. G-CSF 300 micrograms was administered from day 6 following each cycle until neutrophil reconstitution. Two aphereses were performed at approximately day 13 after each A cycle, and PBSCs were injected at day 4 of each B cycle. Radiotherapy on tumor masses > or = 5 cm was scheduled after completion of the last cycle. The median duration of grade 4 neutropenia was 1 day (range, 0 to 7) for each A cycle and 4 days (range, 1 to 10) for each B cycle (P = .02). The median duration of grade 4 thrombopenia was 0 days (range, 0 to 8) for each A cycle and 6 days (range, 1 to 21) for each B cycle (P < .001). Hospitalization for febrile neutropenia was required for 18% and 44% of patients during cycles A and B, respectively (P < .01). Only three patients did not complete the protocol: one due to emergency surgery after cycle B4, one who died after cycle B5 from interstitial pneumonia, and one with delayed hematologic reconstitution after cycle B4. Chemotherapy delivery was optimal (median actual relative dose-intensity, 97%; range, 66 to 100). The median total dose administered over 18 weeks was 18,000 mg Cy (range, 12,000 to 18,000), 450 mg Doxo (range, 300 to 450), 900 mg etoposide (range, 300 to 900), and 300 mg cisplatin (range, 100 to 300). Evaluation of response after six courses showed 13 complete remissions ([CRs] 65%), four partial remissions (PRs), two nonresponses (NRs), and one toxic death. With a median follow-up period of 25 months (range, 16 to 43), 15 patients are alive, with 12 in continuous first CR; five patients relapsed (four of four PRs and one of 13 CRs). Two-year survival and failure-free survival (FFS) rates are 73% and 56%, respectively. The disease-free survival (DFS) rate for the CRs is 86%. PBSC support contributes to the feasibility of first-line, very-high-dose, ambulatory chemotherapy delivery in poor-risk NHL and is associated with a high rate of remission and FFS.

High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin's lymphoma with partial response to front-line chemotherapy: a prospective randomized italian multicenter study.

To evaluate, in a prospective multicentric study, the efficacy of a conventional salvage chemotherapy (dexamethasone, cisplatin, and cytarabine [DHAP]) versus high-dose chemotherapy (carmustine, etoposide, cytarabine, and cyclophosphamide [BEAC]) followed by autologous bone marrow transplantation (ABMT) in patients with aggressive non-Hodgkin's lymphoma (NHL) in clinical partial response (PR) after two thirds of a conventional front-line therapy. From August 1988 to August 1991, 286 patients with aggressive NHL were randomized in seven Italian institutions to receive fluorouracil, methotrexate, cytarabine, cyclophosphamide, doxorubicin, vincristine, and prednisone (F-MACHOP) or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) as front-line therapy. Of the 286 patients enrolled onto the trial, 77 (27%) were considered in PR after two thirds of the front-line therapy, and 49 of 77 (64%) were randomized: 27 to receive DHAP chemotherapy and 22 to receive BEAC followed by ABMT. The response after second-line treatment was as follows: in the DHAP group, four patients (15%) achieved a complete remission (CR), 12 (44%) remained in stable PR, and 11 (41%) showed progressive disease; in the ABMT group, three patients (14%) obtained a CR, 18 (82%) obtained a stable PR, and one (4%) progressed, with an overall response (CR + stable PR) of 59% and 96% (P < .001) in the DHAP and ABMT groups, respectively. The overall survival was 59% versus 73% and the progression-free survival (PFS) was 52% versus 73% in the DHAP and ABMT groups, respectively (P, not significant). The toxicity was mild, particularly in the ABMT group, and no treatment-related deaths occurred in either group. Because of the small number of patients randomized, we were unable to determine whether ABMT or a standard salvage regimen (DHAP) is superior for PR patients. However, we confirmed that myeloablative treatment is a safe and well-tolerated procedure in this category of patients and this may enable us to evaluate its role as part of a front-line treatment in poor-risk NHL patients.

Autologous transplantation in non-Hodgkin's lymphomas using high-dose cyclophosphamide mobilized blood The International Journal of Cell Cloning: The adelaide experience.

Sixteen patients (11F 5M) with Intermediate or high-grade non-Hodgkin's lymphoma (NHL) were enrolled into a trial of high-dose chemotherapy followed by autologous blood stem cell transplantation (ASCT) between 10/88 and 10/90. Patient's blood The International Journal of Cell Cloning were harvested following mobilization using high dose (4 or 7 G/m2) Cyclophosphamide (Cy) administered as a single daily dose. The International Journal of Cell Cloning were collected by daily leukaphereses on COBE “Spectra” or Fenwal CS3000. Twenty three cycles delivering a mean (± SD) of 4.6 ± 1.2 G of Cy were given, resulting in the collection of a median of 33 × 104/kg CFU-GM (range 6.8–119) from a median of 6 leukaphereses (R 4–10). Autologous stem cell transplantation took place after a median of 143 days post-Cy (R 58–170) using BCNU, Etoposide, ara-C and Melphalan. 10 patients were transplanted in CR 3 in PR and 2 in relapse. A median of 38 × 104/kg CFU-GM (R17–77) and 3.4 × 108/kg MNC (R1.1–5.9) was given on Day 0. Seven pts are alive and In CR (R 77–734+), 3 have relapsed but remain alive post-ASCT (R 625–840+) and 6 have died (R 5–424). The median follow-up time is 528d (R77–840), time from ASCT to relapse is 330d (R 116–813) and time to death is 165d (5–424). Post-ASCT morbidity was moderate; one patient died as a consequence of ASCT (Interstitial pneumonitis). In conclusion, high-dose chemotherapy and ASCT can result in long-term disease-free survival in a substantial proportion of patients with poor risk NHL.