Conditioning Regimen For Autologous Transplantation Research Articles

Busulfan/Cyclophosphamide Compared with Melphalan as a Conditioning Regimen for Autologous Transplantation of Multiple Myeloma: A Long-Term Assessment.

Melphalan was poorly available in mainland China. The aim of this study is to explore the dose-adjusted busulfan/cyclophosphamide (BU/CY) as an alternative regimen in auto stem cell transplantation (ASCT) for multiple myeloma (MM). A total of 105 newly diagnosed MM patients undergoing ASCT during May 2012 and August 2017 were retrospectively analyzed. The BU/CY regimen was applied to 64 patients. Busulfan (9.6 mg/kg or 8.0 mg/kg in total) and cyclophosphamide (3.6 g/m2 or 3.0 g/m2 in total) were administered according to the creatinine clearance rate (CCR). A high-dose melphalan (HDMEL) regimen (200 mg/m2) was given to the other 41 patients. At a median follow-up of 65 (1~119) months, estimated overall survival (OS) and progression-free survival (PFS) at 104 months in the BU/CY and HDMEL groups were 35.6% vs. 20.5% (p = 0.263) and 20.2% vs. 2.4% (p = 0.035), respectively. The median overall survival (OS) and PFS of the HDMEL and BU/CY groups were 55 vs. 70.5 months and 26 vs. 46.5 months, respectively. In multivariate analysis, the BU/CY regimen was found to be the only protective factor for PFS. No lethal toxicity was found in the BU/CY group, and treatment-related mortality (TRM) in 100 days was similar to the HDMEL group. MM patients may also benefit from the dose-adjusted BU/CY regimen.

Tecam (Thiotepa, Etoposide, cyclophosphamide, Cytarabine and Melphalan) Is an Effective and Safe Conditioning Regimen for Autologous Transplant in Lymphoma

Background: Autologous stem cell transplant (ASCT) is still a cornerstone in the treatment armamentarium of both Hodgkin's lymphoma (HL) and various non-Hodgkin lymphoma (NHL) subtypes. BEAM (carmustine, cytarabine, etoposide and melphalan) is the most commonly used conditioning regimen; however, due to limited availability and toxicity of carmustine, thiotepa-containing regimens have been suggested. We previously reported encouraging results with TECAM conditioning regimen (thiotepa, etoposide, cyclophosphamide, cytarabine and melphalan). Objectives: We aimed to update our experience with TECAM as the conditioning regimen for ASCT in all lymphomas, by adding our experience from Oct 2013 to 2020 to the previously reported cohort of Jan 2000 - Sep 2013 (Grisariu et al 2018). Moreover, we aimed to utilize the detailed data on the two transplant cohorts, from different eras, to appreciate possible improvement in ASCT outcome in the recent era. Furthermore, we aimed to evaluate our ASCT results in different NHL subgroups. Methods: We retrospectively analyzed all lymphoma patients who underwent ASCT in our center between 2000 and 2020. Results: Three hundred and fifty-three patients were included (141 in the newer cohort added to the 212 in the cohort of 2000-2013 previously reported), all of whom were treated with TECAM, which is our standard conditioning regimen for lymphoma patients undergoing ASCT. The cohort included 126 HL patients, 108 diffuse large B-cell lymphoma (DLBCL) patients and 119 patients of other subtypes (among them 14 diagnosed with primary central nervous system lymphoma (PCNSL)). The median number of treatment lines before ASCT was 2 (range 1-7). Compared to the older cohort, the newer cohort was characterized by significantly poorer Eastern Cooperative Oncology Group performance status (ECOG-PS) prior to ASCT (45.6% vs 19.3% with ECOG-PS ≥1, p<0.001), while A Higher proportion of patients in the newer cohort were in complete remission (CR) status at transplantation (71.9% vs. 47.8%, p<0.001). The median follow-up from ASCT was 38.8 months (range: 0.03-251.6). The 3-years progression-free survival (PFS) and overall survival (OS) rates post-ASCT were 59.8% and 79.3% respectively. For HL, the 3-years PFS and OS rates were 61.1% and 89% respectively; for DLBCL 59.4% and 67.9% respectively and for PCNSL 64.3% and 78.6% respectively. Outcomes of the newer cohort were significantly favorable (3-years OS of 87.3% vs. 73.8%, p=0.015, 5-year OS of 86.6% vs 69%, p=0.008, Figure 1). Poor disease status and poor ECOG-PS at ASCT entry were associated with worse outcomes across all lymphoma subtypes. Dose reduction was associated with a shorter PFS but did not affect OS. Similar to our previous report, patients entering transplantation for DLBCL with a partial response (PR) achieved similar outcomes as those with CR. Eighteen patients died within the first 100 days, eight due to disease progression, and 10 due to transplant related causes (2.8%). There were no cases of interstitial pneumonitis syndrome (IPS). Twenty cases (5.7%) of secondary malignancies were documented. Discussion: Our results confirms that TECAM is an effective and safe conditioning regimen for ASCT in patients with HL and various NHL's, including favorable results in PCNSL. Though outcomes were compared to published experience with BEAM, we have shown similar efficacy with a favorable toxicity profile. Despite a higher proportion of frail patients, the newer cohort's outcomes were favorable, probably due to better lymphoma control at transplant entry, which can be explained by more efficacious therapies pre- and post-transplant. In the DLBCL cohort, ECOG performance status was more prognostic than achieving a CR before ASCT, a finding that is relevant to the optimal selection of patients to different second-line options in the era of chimeric antigen receptor (CAR-T) availability. Conclusion: TECAM is a safe, effective, CNS-penetrating conditioning regimen for ASCT, in HL and various NHL's. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P-009: Busulfan and cyclophosphamide as a conditioning regimen for autologous transplantation in patients with multiple myeloma after treatment with proteasome inhibitors and/or immunomodulatory drugs

P-009: Busulfan and cyclophosphamide as a conditioning regimen for autologous transplantation in patients with multiple myeloma after treatment with proteasome inhibitors and/or immunomodulatory drugs

Clinically significant delay in engraftment with day -1 melphalan prior to stem cell infusion in myeloma patients receiving stem cell transplant.

Although single agent melphalan is considered the standard conditioning regimen for autologous transplant in myeloma, the timing of melphalan administration is less standardized with limited evidence on optimal timing of infusion.

Continuous Infusion Cyclophosphamide and Low-Dose Total Body Irradiation Is a Safe and Effective Conditioning Regimen for Autologous Transplant in Multiple Myeloma

We present the results of a novel conditioning regimen in multiple myeloma (MM) patients undergoing tandem autologous stem cell transplant (ASCT). MM patients were enrolled in a prospective phase II clinical trial. After initial ASCT, disease response was assessed by day +100. Patients achieving very good partial remission (VGPR) were offered maintenance therapy. If patients achieved VGPR, they were offered a second ASCT using continuous intravenous cyclophosphamide (CICy) 6 g/m2 over 4 days and low-dose total body irradiation (ldTBI) 600 rads over 2 days. Total body irradiation was replaced by melphalan 140 mg/m2 if patients had received prior radiation. Twenty-one patients received tandem ASCT. Three patients received CICy and melphalan. Median duration of neutropenia with CICy/ldTBI was 11 days. Fifteen patients (71.4%) developed febrile neutropenia while grade 1 to 2 diarrhea was the next most common adverse event (42.9%). There was no treatment-related mortality. Four patients had entered complete remission (19%) and 6 achieved VGPR (28.6%). In conclusion, this conditioning regimen is safe and effective and may be useful in patients who do not benefit from first ASCT using more traditional conditioning regimen.

In vivo selection of autologous MGMT gene-modified cells following reduced-intensity conditioning with BCNU and temozolomide in the dog model

Chemotherapy with BCNU and temozolomide (TMZ) is commonly used for the treatment of glioblastoma multiforme (GBM) and other cancers. In preparation for a clinical gene therapy study in patients with glioblastoma, we wished to study whether these reagents could be used as a reduced-intensity conditioning regimen for autologous transplantation of gene-modified cells. We used an MGMT(P140K)-expressing lentivirus vector to modify dog CD34+ cells and tested in 4 dogs whether these autologous cells engraft and provide chemoprotection after transplantation. Treatment with O6-benzylguanine (O6BG)/TMZ after transplantation resulted in gene marking levels up to 75%, without significant hematopoietic cytopenia, which is consistent with hematopoietic chemoprotection. Retrovirus integration analysis showed that multiple clones contribute to hematopoiesis. These studies demonstrate the ability to achieve stable engraftment of MGMT(P140K)-modified autologous HSCs after a novel reduced-intensity conditioning protocol using a combination of BCNU and TMZ. Furthermore, we show that MGMT(P140K)-HSC engraftment provides chemoprotection during TMZ dose escalation. Clinically, chemoconditioning with BCNU and TMZ should facilitate engraftment of MGMT(P140K)-modified cells while providing anti-tumor activity for patients with poor prognosis glioblastoma or alkylating agent sensitive tumors, thereby supporting dose-intensified chemotherapy regimens.

Achievement of Sustained Molecular Remission Induces Long-Term Freedom From Disease After Autologous-Allogeneic Tandem Transplantation in Patients with Multiple Myeloma

Abstract 148Multiple Myeloma (MM) is considered to be an incurable disease, but in some patient long-term survival can be achieved after high dose chemotherapy followed by autologous or allogeneic stem cell transplantation. Those patients, who achieved molecular remission, have a high probability of long-term disease-freedom and of cure. More recently the introduction of dose-reduced conditioning and the use of auto-allo tandem approach has broaden the use of allogeneic stem cell transplantation in MM, but the results of prospective trials are controversial. We here investigated within a prospective protocol the incidence and impact of molecular remission on long-term outcome obtained after auto-allo tandem approach in MM. (study registration NCT 00781170).From 4/2000 to 10/2008, 73 patients with a median age of 50 years (r 29–64) and advanced stage II/III MM were included. The conditioning regimen for autologous transplantation consisted of melphalan 200 mg/m2 given divided over 2 days. After an interval of 2–3 months, the patients received a dose-reduced conditioning consisting of melphalan 140 mg/m2, fludarabine 180 mg/m2 and ATG Fresenius® (Fresenius, Bad Homburg, Germany) at a dose of 10 mg/kg for related and 20 mg/kg for unrelated donors on day -3, -2, and -1 followed by allogeneic stem cell transplantation.Remission was defined according to modified EBMT criteria. In 46 patients with CR or nCR minimal residual disease could be monitored by myeloma-specific primers (allele specific oligonucleotides, ASO) targeting IgH gene rearrangements (n=20) or by highly sensitive plasma cell chimerism using real-time PCR after magnet-activated cell sorting of CD138+ cells (n=26). The sensitivity of plasma cell chimerism was 10−4 using real-time PCR and donor/patient specific polymorphisms and 10−5 in case of Y-PCR. Sensitivity for nested PCR with myeloma-specific primers was 10−5. In 5 patients only 1 MRD measurement was available and those patients were excluded from MRD sub-analysis. Molecular complete remission was defined as by least two negative PCR results with ASO primers or achievement of at least two times ≥99.9 % donor chimerism of plasma cells by real-time PCR from bone marrow samples. Sustained MRD negativity was defined by at least 4 negative molecular results either by ASO primer or plasma-cell chimerism. Mixed MRD was defined by negative molecular markers for at least two times, but intermittent positivity was defined by myeloma-specific primers or plasma cell chimerism.Overall 44 patients (60 %) achieved a CR according to EBMT criteria with negative immunofixation. 8 % achieved a VGPR and 18 % a partial remission. 3 % had progressive disease and 11 % were not evaluable for determination of remission. Molecular remission was observed in 30 patients, in 15 patients the molecular markers were sustained negative while in 15 patients molecular markers were only intermittent negative, resulting in an overall complete molecular remission rate of 46 % and a stable sustained complete molecular remission rate of 23 %.After a median follow-up at 7 years the 5 year progressive-free survival was 29 % (95% CI: 17–41%). Patients without del(13q14) had a significantly better PFS than those with del(13q14) (5 y: 56% vs. 17%, p=0.02). Patients who achieved CR after transplantation had improved PFS in comparison to non-CR patients (5 y: 41% vs. 28%, p=0.008). Patients with sustained negative molecular remission had a 5 year PFS of 85 % vs. 31 % for mixed molecular remission (p= 0.003).The 5 year overall survival was 52 % (95% CI: 40–64%). Patients without del(13q14) had significantly improved 5 year survival (75% vs. 40%. p=0.02). Patients who achieved a sustained molecular remission had a 5 year OS of 91 % while those with mixed molecular remission resulted in a 5 year OS of 87 % (p=0.06).The study underlines the importance of the depth of remission and shows that achieving molecular remission as determined by myeloma-specific IgH gene rearrangements and plasma cell chimerism is associated with long-term freedom from disease and potential cure of MM in an auto-/allo SCT approach. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Melphalan 200 mg/m2 versus melphalan 100 mg/m2 in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study

AbstractHigh-dose (200 mg/m2, MEL200) and intermediate-dose melphalan (100 mg/m2, MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.

Mel-140 and TBI vs Mel-200 Prior to Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma - a Single Institution Experience.

Between 1991–98, twenty-nine patients with myeloma received Mel-140 and TBI (960 cGy) followed by Cytoxan mobilized autologous PBSCT. Between 1998 and April, 2004, 41 patients received Mel-200 alone followed by autologous PBSCT. The two groups were comparable regarding age, gender, stage, number of prior regimens and ß2 microglobulin at diagnosis. However, the Mel-200 group had greater proportion of patients with IgG myeloma (78% vs 38%) and shorter time from diagnosis to transplant (301 days vs 581 days). Results: Neutrophil engraftment was similar in the two groups. However, platelet engraftment, transfusion requirements, length of stay and number of days on antibiotics were worse in the Mel-TBI group. The complete and very good partial responses were high in both groups Mel TBI 58.6% vs Mel-200 56% (p=0.81). Median overall survival (OS) was 3.5 years and 3.8 years for Mel TBI and Mel-200 groups, respectively (p=0.75). Event-free survival (EFS) was 1.9 years and 2.3 years, respectively (p=0.88). Survival after relapse post-PBSCT was short, median 1.1 and 1.8 years, respectively. We present here the results of two groups of myeloma patients treated consecutively in a single institution. The Mel-200 patients had a higher proportion of IgG myeloma and were transplanted earlier in the phase of their disease. As expected, regimen-related toxicities were higher in the Mel-TBI group. The response rates, OS, and EFS were similar. These results are in keeping with published reports of prospective randomized studies. Mel-200 is now the standard conditioning regimen for autologous transplant for myeloma.

Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH conditioning: an effective regimen with low procedure-related toxicity.

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure-related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti-CD52 antibody CAMPATH-1G from day -5 to day -1. Twelve patients (median age 46 years) underwent allogeneic transplantation for lymphoma (n = 11) or chronic lymphocytic leukaemia (n = 1) from HLA-identical (n = 9) or mismatched (n = 3) sibling donors. Cyclosporin A and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. One patient died of progressive lymphoma at day +12, the remaining 11 patients engrafted rapidly, with eight demonstrating full donor chimerism. One patient had an episode of rejection and received a further stem cell infusion with sustained recovery. Only one patient developed GVHD (grade I). The low incidence of acute GVHD may be in part related to persisting levels of in vivo CAMPATH-IG at the time of transplantation. Of 11 evaluable patients, nine achieved complete remission (CR), and a further patient achieved CR after donor lymphocyte infusion at 5 months. Our preliminary experience is that this regimen was well tolerated with a low risk of GVHD and appears no more toxic than a BEAM autograft. Further follow-up is required to see whether the low incidence of GVHD impacts upon relapse risk.