Single-agent High-dose Melphalan Research Articles

High-Dose Bendamustine, Etoposide, Cytarabine, and Melphalan (BeEAM) Conditioning Before Autologous Transplantation for Patients With Multiple Myeloma

Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM), and efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed. Bendamustine combines both alkylating and antimetabolite properties, can induce responses in MM resistant to other alkylators and represents a promising agent to combine with Mel prior to ASCT. We performed a phase II study to test the safety and efficacy of the high-dose chemotherapy combination of bendamustine, etoposide, cytarabine, and melphalan (BeEAM) in newly diagnosed MM patients up to 70 years of age. The primary study endpoint was the day 100 complete response rate. Sixty-five patients with a median (range) age of 59 (40-69) years underwent transplantation from 2015 to 2020. Other characteristics included Karnofsky performance status <80%, hematopoietic cell transplantation-comorbidity index ≥3, International Staging System III, and high-risk fluorescein in situ hybridization (FISH) in 35%, 46%, 26%, and 44%, respectively. ASCT after BeEAM was well tolerated, and there were no non-relapse deaths through 1 year after transplantation. Although at least 1 nonhematologic grade 3 toxicity was reported in 58 (89%) patients (including grade 3 febrile neutropenia in 48% and stomatitis/esophagitis in 28%), there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. The day 100 response rate was ≥CR1 and ≥ very good partial response (VGPR1) in 40% and 89%, respectively. With a median follow-up of 44 (13-70) months, the 3-year overall survival was 92%, 96%, and 90% for all patients and those with standard- and high-risk FISH, respectively. The corresponding values for 3-year progression-free survival was 57%, 72%, and 40%, respectively. When BeEAM-conditioned patients were compared to historical Mel-conditioned cohort, no significant differences were noted in relapse or survival outcomes in univariate or multivariable analysis. In summary, BeEAM was shown to be a safe and effective conditioning regimen before up-front autologous transplant for MM. Although the BeEAM regimen does not appear to offer a significant advantage over single-agent Mel, further studies combining bendamustine and melphalan in the front-line setting may be warranted.

Salvage High-dose Melphalan With Autologous Stem cell Transplantation as Bridge to Consolidation Therapy for Chemoresistant Aggressive B-cell Lymphoma

BackgroundPatients suffering from refractory aggressive B-cell lymphoma not responding to salvage chemotherapy have a dismal prognosis. CAR T-cells or allogeneic stem cell transplantation (SCT) are potentially curative approaches. However, obtaining a remission, and lowering tumor burden before consolidation seems crucial for long-term efficacy of both treatment modalities. Materials and MethodsIn this retrospective analysis, we reviewed patients with chemoresistant aggressive B-cell lymphoma, defined as being refractory or progressive to at least second line salvage chemotherapy including the regimen immediately preceding autologous stem cell transplantation (ASCT), treated at 2 tertiary centers, who were eligible for intensive treatment using single agent high-dose (HD) melphalan to obtain a remission before consolidating therapy. ResultsWe identified 36 patients that received single agent HD melphalan and ASCT as remission induction followed by CAR T-cells or allogeneic stem cell transplantation (SCT). Thirteen of the evaluable patients (39.4%) achieved a partial remission and 9 patients (27.73%) a complete remission, resulting in an overall response rate (ORR) of 66.7%. High remission rates were seen across all subgroups including patients with primary refractory lymphoma (ORR 58.3%), uncontrolled disease and high tumor burden as indicated by increased LDH levels (ORR 66.7% for patients with elevated LDH above 2 times upper limit of norm). 22 patients proceeded to allogeneic SCT and 5 to CAR T-cell therapy. Treatment related mortality of ASCT was 5.5% (2 patients, both due to infections). Two-year overall survival of all patients was 15.8%, primarily due to a high non–relapse mortality (45.5%) of allogeneic SCT patients treated with myeloablative conditioning chemotherapy. ConclusionSingle agent HD melphalan produces high remission rates in patients with chemoresistant, uncontrolled aggressive B-cell lymphoma and provides a window of opportunity for consolidation therapy. MicroabstractPatient with refractory/relapsed aggressive B-cell lymphoma after salvage therapy are an unmet medical need because of their very poor prognosis. In our retrospective analysis of 36 patients we showed that single agent high-dose melphalan can achieve high response rates (ORR 66.7%) even in uncontrolled disease enabling consolidation therapy e.g. with allogeneic stem cell transplantation or CAR T-cell therapy.

High-Dose Bendamustine, Etoposide, Cytarabine and Melphalan (BeEAM) Conditioning Prior to Autologous Transplantation for Patients with Multiple Myeloma: Results of a Prospective Phase II Trial

Single-agent high-dose melphalan followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM). Efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed, with the exception of a sole phase III study showing improved progression-free survival (PFS) with the addition of busulfan to melphalan (Lancet Haematology 2019, 6:266-75). Bendamustine is a synthetic agent that combines the alkylating properties of a mustard-group with the antimetabolic activity of a purine analog. It can induce responses in MM resistant to other alkylators and is therefore a promising agent to test synergy in conditioning regimens. The high-dose chemotherapy combination of bendamustine, etoposide, cytarabine and melphalan (BeEAM) has been shown to be a safe and effective transplant regimen for lymphoma patients (Blood 2011, 118:3419-25). We performed a phase II study to test the safety and efficacy of BeEAM in MM patients, 18-70 years of age, with adequate organ function (EF≥40% predicted, CrCl ≥40ml/min) and within 9 months of starting induction therapy. Results were compared to a contemporaneously treated control group receiving a single high-dose melphalan 200mg/m2 transplant (Mel200) but otherwise meeting study eligibility criteria. Study patients (n=65) had a median (range) age of 59 (40, 69) years and were transplanted from 2015-2020. Other characteristics included KPS<80%, HCT-CI≥3, ISS III, and high-risk FISH in 35%, 46%, 26% and 44% respectively. Pre-BMT status was (s)CR1, VGPR1, PR1 and <PR1 in 26%, 43%, 26% and 5% respectively. ASCT following BeEAM was well tolerated with no non-relapse deaths through one-year post-transplant. Although at least one non-hematologic grade 3 toxicity was reported in 32 (49%) patients, there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. With a median f/u of 44 (13, 70) months, three-year OS and PFS was 92% and 57% respectively. When BeEAM patients were compared to contemporaneously treated Mel200 patients, there were no significant differences in baseline characteristics, induction regimen or use of post-transplant maintenance therapy. Neutrophil and platelet engraftment was faster following BeEAM (11 vs. 12 days, 17 vs 18 days, p<0.001 and p=0.007 respectively), when compared to Mel200 patients. One-year non-relapse mortality was 0% with both BeEAM and Mel200. No significant differences were seen in quality of response, PFS or OS between BeEAM and Mel200, when analyzing either the whole cohort (see figure) or by genetic risk stratification. In multivariate analysis, controlled for genetic risk and year of transplantation, the use of BeEAM conditioning offered no benefit to Mel200 in terms of OS, PFS or risk of relapse/progression. In summary, BeEAM was shown to be a safe and effective conditioning regimen prior to up-front autologous transplant for MM. However, BeEAM conditioning appears to offer no significant advantage when compared to conventional Mel200 conditioning. [Display omitted] DisclosuresSolh: Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding; ADCT Therapeutics: Consultancy, Research Funding. OffLabel Disclosure:Bendamustine for Multiple Myeloma

Phase I/II Study of Infusional Gemcitabine and High-Dose Melphalan Conditioning Prior to Autologous Stem Cell Transplantation for Patients with Relapsed/Refractory Lymphoma: Interim Safety Analysis

IntroductionThe optimal re-induction and high dose chemotherapy regimens for transplant-eligible patients with relapsed lymphoma are not known. Our centre has previously established the efficacy and tolerability of single-agent high-dose melphalan and ASCT in patients with relapsed/refractory Hodgkin's lymphoma (HL), and others have similarly demonstrated this with non-Hodgkin's lymphoma (NHL). The activity of alkylating agents such as melphalan is dependent on the extent of DNA damage, and combining melphalan with drugs known to inhibit DNA damage repair would be predicted to produce synergistic effects. Gemcitabine is a nucleoside analogue that has been shown to inhibit DNA damage repair caused by prior exposure to alkylating agents, and has clinical anti-tumour activity against lymphoma, and therefore presents a promising combination with alkylators in high-dose chemotherapy studies for lymphoma.ObjectiveTo evaluate the safety and efficacy of infusional gemcitabine prior to high-dose melphalan followed by autologous stem cell transplantation in patients with relapsed/refractory lymphoma. The data reported currently reflects a planned interim safety analysis after the first 40 patients enrolled on the study.MethodsThis is an investigator-initiated single centre study currently enrolling patients as of April 2015. Adult patients with relapsed or refractory HL, aggressive NHL, or indolent NHL after at least one prior systemic therapy are eligible for this study. Inclusion/exclusion criteria included ECOG performance status ≤2, no significant end-organ dysfunction, no prior history of stem cell transplantation, no CNS involvement, and chemo-sensitive disease (at least partial remission to salvage chemotherapy) at the time of transplantation. High dose therapy regimen was as follows: On Day -1, IV gemcitabine was administered as a loading bolus of 75 mg/m2, followed by a continuous infusion rate of 10 mg/m2/min, followed immediately by IV melphalan 200 mg/m2. In the phase I portion of the study, the starting dose of gemcitabine was 1.5 g/m2 in the first cohort, with dose escalation based on standard “3+3” design, increasing by 0.5 g/m2 increments at each dose level to maximum of 2.5 g/m2. Dose-limiting toxicity was defined as grade 3 mucositis >5 days, grade 3 skin toxicity >3 days, grade 3 diarrhea >7 days, or any grade 4 non-hematological toxicity.ResultsThe mean age of the study population was 52 (SD +/-14) with equal numbers of male and female patients. 12 (30%) patients had aggressive NHL (6 DLBCL, 1 PMBCL, 3 ALCL, 2 PTCL), 17 (42.5%) had indolent NHL (15 follicular, 1 lymphoplasmacytic, 1 marginal zone lymphoma), and 11 (27.5%) had HL. At time of relapse, 30% (12/40) of patients had refractory disease after first line therapy, 70% (28/40) had stage III/IV disease, and 6 patients (16%) had >1 prior line of systemic chemotherapy. The median time from relapse to transplant was 90 days (range 12 to 189 days). There were no dose limiting toxicities at 1.5 g/m2 dose of gemcitabine. 8 patients received 2.0 g/m2 and dose-limiting toxicity (grade 3 diarrhea >7 days) was noted in 2 patients, thus the remaining patients received 1.5 g/m2 gemcitabine. 18 patients experienced 24 grade 3-4 adverse non-hematological events: mucositis (7), infectious enterocolitis (5), pneumonia (4), sepsis (2), non-infectious diarrhea (1), esophagitis (1), emesis (1), transaminitis (1), pulmonary edema (1), and stroke (1). There were no treatment-related deaths associated with this regimen. Post-transplant complete remission and partial remission was attained in 25/40 and 9/40 patients, respectively. 6/40 (15%) patients have progressed after transplant, and 2 have died of lymphoma. At a median follow-up of 10 months (range 2-26 months), the progression-free survival is 59.3% and overall survival is 93.8% (Figure 1).ConclusionInfusional gemcitabine at a maximum tolerated dose of 1.5 g/m2 in combination with high dose melphalan as a conditioning regimen for autologous stem cell transplantation is tolerable and appears to be efficacious in patients with relapsed/refractory lymphoma. [Display omitted] DisclosuresStewart:BMS: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Seattle Genetics: Honoraria; Servier: Honoraria; Gilead: Honoraria; Merck: Honoraria; Lundbeck: Honoraria; Roche: Honoraria.

BEAM Versus Single Agent High Dose Melphalan (HDM) Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplant (ASCT): A Retrospective Matched Analysis in Relapse/Refractory Hodgkin Lymphoma

Background The ideal conditioning regimen still remains a challenge in the autologous stem cell transplantation (ASCT) setting for relapsed/refractory Hodgkin Lymphoma (RR-HL). BEAM is the most popular preparative regimen but single agent high dose Melphalan (HDM) has also been used. However, the experience and data comparing BEAM vs. HDM are limited. Methods After the Institutional Review Board approval, we retrospectively evaluated the clinical course of 112 RR-HL patients, autografted from November 2008 till May 2017 in two different institutions. Twenty eight conditioned with HDM and compared in a matched paired analysis (1:3) with a cohort of 84 patients who received BEAM. The study groups had similar median age (30ys) and sex (M:F 1.7:1 vs. 1.8:1) and were matched for disease status before salvage (late relapse: 36 vs. 12, early relapse/primary refractory: 48 vs. 16 and disease status pre ASCT [complete remission (CR): 39 vs. 13 and partial remission (PR): 45 vs. 15]. BEAM regimen was given in the standard doses over 6 days, while HDM (200mg/m2) was given in a single day infusion. All patients received prophylaxis against microbial, fungal and viral infections; GCSF was routinely administered at the dose of 5mcg/kg at +1 day (BEAM group) and at +5 day (HDM group). The T-test and Kaplan-Meier method were used for the statistical analyses. Results The engraftment was successful; the median day for neutrophils >1000/mm3 was +11 for both groups while for platelets >20000/mm3 a faster recovery was noticed for HDM group: +13 vs. +22 days (p The 100 days non relapse mortality was acceptable for both groups: 2/84 (2.3%) in the BEAM group vs. 1/28 (3.5%) in the HDM group. Conclusion In this study, though retrospective, demonstrated that for RR-HL patients, the conditioning regimen consisting of HDM, offered at least comparable efficacy to the BEAM regimen. The earlier platelets recovery, and the shorter duration of chemotherapy administration (6 days for BEAM vs. 1 day for HDM), resulted in less hospitalization days, which along with the shorter period of GCSF administration post ASCT, may contribute to a better cost effectiveness for the HDM regimen. Nevertheless, prospective studies with larger series of patients and longer follow-up, including also a meticulous cost analysis, are warranted to determine the accurate role of single agent HDM as preparative regimen for ASCT in HL patients.

157 - Single-Agent High-Dose Melphalan as Conditioning Regimen in Autologous Hematopoietic Stem Cell Transplantation for Hodgkin's Lymphoma: Safety, and Long-Term Efficacy

Autologous hematopoietic stem cell transplantation (AHSCT) has been proven as the best therapeutic approach for selected patients (pts) with refractory/relapsed Hodgkin lymphoma (HL) more than 25 years ago. Nevertheless, the optimal conditioning regimen still remains debatable.

High-dose BCNU/Melphalan conditioning regimen before autologous stem cell transplantation in newly diagnosed multiple myeloma

Single-agent high-dose melphalan (HDM, 200 mg/m2) has been the most commonly used conditioning regimen prior to autologous stem cell transplant, since its introduction in 1992. We used a more aggressive alkylator-based conditioning regimen in an attempt to overcome early relapse and combat drug resistance. We present a retrospective comparison and long-term follow-up of newly diagnosed patients with multiple myeloma (MM) treated with induction followed by either high-dose carmustine (BCNU) and HDM, or HDM alone, both followed by autologous stem cell transplant (ASCT). Between 1997 and 2002, 104 patients were treated with BCNU/HDM; from 2001 to 2008, 103 patients were treated with HDM alone. Median follow-up of survivors was 78 and 68 months for the BCNU/HDM and HDM groups, respectively. The median PFS was significantly increased with the BCNU/HDM regimen (40.4 vs 20.5 months, P<0.001). Median overall survival was increased with the BCNU/HDM regimen when compared with HDM alone (88.4 vs 67.2 months, P=0.07), but the difference was not statistically significant. Transplant-related mortality was similar in both groups (2.9% with BCNU and HDM vs 3.9% with HDM alone). Our findings suggest that the BCNU/HDM preparative regimen should be investigated further and potentially compared in a prospective randomized manner with HDM alone.

Phase I/II Study of Lenalidomide and High Dose Melphalan As Preparative Regimen in Autologous Transplant in Myeloma: Report of Phase II Efficacy and Safety Data

Background: High-dose melphalan and autologous hematopoietic stem cell transplantat (auto-HCT) is a standard consolidation therapy for eligible multiple myeloma (MM) patients due to superior survival outcome as compared to chemotherapy alone. However, patients remain at continuous risk of disease relapse following auto-HCT. Lenalidomide is active in newly diagnosed and relapsed MM and has synergistic activity with melphalan, but has not previously been incorporated into preparative regimen for auto-HCT. While high dose lenalidomide induces myelosuppression, the anti-tumor activity of lenalidomide is dose-dependent.Methods: We conducted a single center, phase I/II study of lenalidomide and melphalan in patients with MM undergoing auto-HCT. The phase I portion included MM patients at all disease stages, including patients undergoing auto-SCT as salvage therapy. The phase II portion enrolled patients undergoing a first auto-SCT after achieving at least stable disease following their induction regimen. Phase I objectives included determination of side effect profile and recommended phase II dose (RP2D). Phase II objectives were disease response at day +100 and toxicity.Treatment: All patients received a standard melphalan dose of 200 mg/m2 (100 mg/m2 IV days -1 and -2). Phase I lenalidomide dose was escalated from 50 mg, 75mg, 100 mg, and 150 mg and administered orally daily from days -7 to +2. Phase I data were previously reported (Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 3146). Thirteen patients were treated and no MTD was reached. The RP2D lenalidomide dose (150 mg orally daily days -7 to +2) was further explored in the phase II portion of this study. Post-transplant lenalidomide maintenance therapy was started between days +100 and +120 in all responders. We now report the planned interim analysis of the efficacy and safety profile of the phase II study.Results:From 5/1/12 to 7/9/15, forty seven subjects were enrolled to the phase II portion of the study. Study accrual is complete. We report below on the 37 patients with at least 100 days follow-up (median duration of follow-up of 12 months). 36 patients were assessable for response. Responses are as followed: stringent CR 8 (22%), CR 3 (8%), VGPR 20 (54%), PR 3 (8%), progressive disease 2 (5%).Among responders, 34 were able to start maintenance lenalidomide on days +100 to +110 (two withdrew from the study to pursue tandem stem cell transplant). To date, 21 patients remain on the treatment. Of 13 who discontinued the therapy; 4 was due to progression, 4 due to physician/patient preference, 2 due to toxicities and 3 from other reasons. Median progression free survival has not been reached.Toxicities were considered treatment related if they occur after the initiation of study drugs. DLTs are defined as any AEs occurring from days -7 to -2 that cause delay or prevent subjects from proceeding to auto-SCTs, grade 3 or more non-hematologic toxicities that do not resolve to a grade 2 or less by day 30 after auto-SCT, or engraftment failure. No DLTs were observed. The median time for ANC and platelet engraftment was 12 and 15 days and no delayed engraftment was observed. Toxicities and posttransplant hematopoietic recovery rates were similar to historical data observed with single agent high dose melphalan. Lenalidomide related toxicities occurred more commonly during the maintenance phase. Common toxicities occurring in more than 10% of patients were diarrhea (24%), peripheral neuropathy (21%) and fatigue (10%). Grade 3-4 toxicities occurred in 16% percent of patients: fatigue (5%), neutropenia (5%) neuropathy (3%), and thrombocytopenia (3%).ConclusionThe use of high dose lenalidomide in combination with high-dose melphalan as a preparative regiment for auto-SCT is well tolerated. High VGPR or better disease response rates, compared to historical control, suggest that the preparative combination regimen may improve the depth of response. Stem cell rescue likely overcome lenalidomide induced myelosuppression. The study is now closed to accrual. Updated data on primary endpoints from all subjects will be reported at the meeting. DisclosuresSuvannasankha:Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Farag:Bristol Myers: Speakers Bureau; Millennium: Speakers Bureau; Teva: Research Funding; Celgene: Speakers Bureau. Silbermann:Amgen: Consultancy; Celgene: Research Funding. Abonour:Celgene: Research Funding, Speakers Bureau.

Y90-ibritumomab tiuxetan (Y90-IT) and high-dose melphalan as conditioning regimen before autologous stem cell transplantation (ASCT) for elderly patients with lymphoma in relapse or resistant to chemotherapy: A feasibility trial (SAKK 37/05).

8560 Background: Standard conditioning regimens for ASCT are often not tolerated by elderly patients. Single agent high-dose melphalan has been shown to be safe and active in elderly patients with multiple myeloma. Y90-IT is a well-tolerated lymphoma treatment and feasible in the transplantation setting. We therefore investigated this combination of high-dose melphalan and Y90-IT as a conditioning regimen for elderly patients. Methods: Patients ≥65 years with relapsed or chemotherapy resistant CD20-positive lymphoma in PR or CR after salvage chemotherapy could be enrolled prior to stem cell mobilization. Myeloablation regimen consisted of standard dose Y90-IT followed by melphalan at escalating doses (100, 140, 170 and 200mg/m2, with a 3+3 phase I design) and by ASCT. The primary objective was to identify the MTD of melphalan in combination with standard dose Y90-IT (as defined &lt; 1 DLT in 3 patients); secondary endpoints were toxicity and CR rate 100 days after transplantation. Results: Between 2006-2012 twenty patients were included. Median age was 72 years (range 66-77). One patient was considered retrospectively ineligible and was evaluable for toxicity but not for DLT. Thirteen patients received the treatment and were transplanted. Eleven patients were evaluable for DLT. No DLT occurred. Non-hematological grade 3 or higher treatment related adverse events were: infection (n=6, including 2 cases of febrile neutropenia), diarrhea (n=3), mucositis, anorexia, viral hepatitis, hypokalemia, dehydration and multi-organ failure (n=1). Seven patients did not start treatment because of mobilization failure (n=3), progressive disease (n=2), worsening of cardiac failure (n=1) and grade 3 dyspnea (n=1). Seven patients achieved a CR/CRu and 2 patients were stable 100 days after transplantation. Conclusions: The combination ofstandard dose Y90-IT and high dose melphalan (200mg/m2) is a safe and feasible conditioning regimen before ASCT for patients ≥65 years. The results show promising activity. Clinical trial information: NCT00392691.

A Phase I/II Trial Combining High-Dose Lenalidomide with Melphalan and Autologous Transplant for Multiple Myeloma: A Report of the Phase I Dose-Finding Study.

Abstract 3146▪▪This icon denotes a clinically relevant abstract Background:High dose chemotherapy and stem cell transplantation (HDSCT) has been a standard of care for younger patients with adequate organ function since the early 1980s, due to its superiority over standard chemotherapy in prolonging disease-free and overall survival. Immunomodulatory agents, including thalidomide and lenalidomide, have significant single-agent activity and an additive effect when combined with melphalan. Preclinical data suggest an increased DNA damage and an anti-angiogenic effect with the combination. Additive clinical benefits were also observed when the 2 agents were used in combination in non-transplant settings. The antimyeloma effects of both agents are dose-dependent with myelosuppression being the dose limiting toxicity (DLT). This toxicity can be attenuated with stem cell rescue. Purpose:We conducted a phase I/II trial designed to evaluate the safety and efficacy of combining lenalidomide with high-dose melphalan as conditioning for autologous transplant for myeloma. The phase I portion of the study is complete and the results are reported in this abstract. Experimental Design:The enrolled patients included any patients with myeloma, regardless of the status of the disease, undergoing high dose melphalan for autologous stem cell transplantation. The melphalan dose was fixed (200 mg/m2) while the doses of lenalidomode were escalated from 50, 75, 100, and 150 mg/m2 administered orally days -7 to +2 of the transplantation. Dose escalation was based upon a 3+3 phase I design. DLTs were defined as grade ≥4, both hematologic and non-hematologic, occurring between days -7 to -2 which prevents subjects from undergoing stem cell transplantation, or grade 3 or 4 non-hematologic toxicity occurring after day -2 that does not resolve to a grade 2 or less by day +30 after transplantation, or delayed engraftment. The response was assessed at day +100 post transplantation using the International Myeloma Working Group criteria. Results:13 patients participated in the phase I portion of the study from September 2010 to May 2012. Patients ages ranged from 42– 72 years (median 63 years). Seven patients were undergoing their first autologous transplant with 2 patients having had 2 lines of previous therapy and 5 having one line of therapy. Six patients were undergoing their second transplantationas salvage for control of progressive disease and all had more than 3 lines of prior therapy. At baseline, 5 patients had progressive disease, 1 had SD, 3 had PR, 3 had VGPR and 1 had CR as responses to their most recent lines of therapy. The median time for ANC and platelet engraftment was 10 days and no delayed engraftment was observed. Toxicities and posttransplant hematopoietic recovery rates were similar to historical data observed with single agent high dose melphalan. The most common grade ≥ 3 adverse events were myelosuppression, neutropenic fever and electrolyte abnormalities, all of which are commonly observed with single agent high dose melphalan. Adverse events related to the study drugs were electrolyte abnormalities (hypokalemia, hyperkalemia and hypocalcemia), gastrointestinal side effects and rash, all of which were grade 1 to 2 and manageable without a delay or discontinuation of the study drugs. One patient died from disease progression prior to scheduled disease evaluation. One patient has not yet reached day +100 post transplant. Therefore, responses were evaluable for 11 patients. Three patients achieved stringent CR (27%), 3 CR (27%), 2 VGPR (18%), 3 PR (27%) and one had progressive disease (9%). The overall response rate was 91%, with 72% achieving VGPR or better. All patients had adequate count recovery and were able to initiate lenalidomide maintenance treatment by day +100 to +110 post transplantation. Conclusions:The use of high dose lenalidomide in conjunction with high-dose melphalan is well tolerated, with preliminary data suggesting that the combination is highly efficacious. DLT was not observed; therefore the recommended phase II dose is 150 mg of lenalidomide orally on days -7 to +2 in combination with melphalan 200 mg/m2. The phase II portion of this trial is ongoing in patients undergoing first HDSCT. Complete response at 3 months post transplantation is the primary end point. Disclosures:Off Label Use: Lenalidomide in myeloma transplant. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Single-agent high-dose melphalan followed by auto-SCT for relapsed and refractory Hodgkin lymphoma in children and adolescents

Hodgkin lymphoma (HL) is cured in the majority of children and adolescents. However, there remains a group of patients with primary refractory or relapsed disease for whom cure is more difficult to achieve. Most of these patients receive high-dose chemotherapy followed by auto-SCT, with expected cure rates ranging from 40 to 60%. Conditioning regimens often consist of multiple non-cross-resistant agents, with well-described risks of morbidity and mortality. The use of single-agent high-dose melphalan (HDM) as conditioning, before autologous rescue, has been described in adult patients at our center, with comparable efficacy and less morbidity. We present a series of eight pediatric patients conditioned with single-agent HDM before autologous stem cell rescue for relapsed and primary refractory HL. All patients engrafted with a median of 12 days to neutrophil engraftment. Two patients subsequently relapsed. Seven patients are currently alive, and seven of eight patients have no evidence of disease (one in CR3). Toxicities included grade 4 hematologic in 8/8, grade 3 mucositis in 3/8, grade 3 infectious in 2/8 and grade 4 infectious in 1/8. Our analysis suggests that this regimen is feasible in pediatric patients with acceptable engraftment and toxicity.

R‐CHOP followed by consolidative autologous stem cell transplant and low dose rituxan maintenance therapy for advanced mantle cell lymphoma

We have read with great interest the report by Evens et al (2008) on the result of a phase II study of intensive chemotherapy followed by consolidative autologous stem cell transplant (SCT) for newly diagnosed mantle cell lymphoma (MCL) patients. In this study, an intensive induction chemotherapeutic regimen consisted of alternating cycles of cyclophosphamide, teniposide, doxorubicin and prednisone with vincristine, high dose methotrexate and cytarabine was used. Thirteen patients ≤65 years then proceeded to consolidative high dose busulfan/cyclophosphamide followed by autologous SCT. With this approach, the 5-year event-free survival (EFS) and overall survival (OS) was 54% and 75%, respectively. These results are encouraging, especially taking into account the long follow-up of the study. Further analysis of the whole group of 25 patients treated with this induction regimen showed that the one single factor predicting for improved survival was consolidative autologous SCT. High dose chemotherapy followed by autologous SCT has been investigated previously, but the results have been conflicting (Andersen et al, 1997;Khouri et al, 2003; Dreger et al, 2000). Furthermore, except for the report by Evens et al (2008), the median follow-up of these patients have generally been short. The conflicting results are probably related to the use of different chemotherapeutic agents as conditioning regimens for the transplant and also to different post-transplant therapy. We have chosen to induce newly diagnosed advanced stage MCL with R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone, rituximab), followed by a consolidative autologous SCT after single agent high dose melphalan. This regimen has not been previously tested in MCL. Furthermore, we reasoned that, as most patients relapse within the first two years after transplant, maintenance rituximab therapy might also be useful during the first two years after autologous SCT. Because the tumor load following autologous SCT is low, the patients may only need intermittent low dose rituximab over a 2 year-period. Following consent, eight consecutive patients with newly diagnosed advanced Stage III or IV MCL were treated. The clinical characteristics of these patients are shown in Table I. There were five males and three females, with a median age of 61 years (range 47–72 years). One patient had Stage III and the other seven had Stage IV disease. All eight patients received remission + 2 cycles of R-CHOP as induction chemotherapy. Autologous stem cells were harvested upon recovery from the last cycle of R-CHOP and autologous SCT carried out within 6 weeks from the last cycle of R-CHOP. High dose intravenous melphalan (200 mg/m2) was administered, followed 24 h later by the infusion of a minimum of 2 × 106/kg of CD34+ autologous stem cells. Rituximab maintenance therapy was initiated at a dose of 375 mg/m2, given as a single infusion once every three months starting Day +100. This approach was well tolerated. Despite the higher median age of the patients, treatment-related mortality was 0%. Complete remission (CR), documented clinically and by a positron emission tomography scan, was achieved in all eight patients before autologous SCT. Median time to engraftment following autologous SCT was 13 d (range 9–30 d). Not surprisingly, due to the older age of the group, two patients died from non-lymphoma causes, without evidence of lymphoma. One patient died due to metastatic breast cancer at 34 months and another one to myocardial infarction at 40 months. Lymphoma relapse occurred in only one patient, 28 months from diagnosis and during the rituximab maintenance period. This patient is still alive and is being re-induced with velcade/dexamethasone. As of February 2008, with a median follow-up of 54 months (range 28–76 months), the EFS and OS for the group was 57% and 67%, respectively (Fig 1). Adverse effects were as expected from the high dose melphalan, except that delayed immunoglobulin reconstitution, as reported previously (Lim et al, 2005), was observed in all eight patients. The delayed immunoglobulin reconstitution persisted beyond the rituximab maintenance period (Lim et al, 2008). Four of these hypogammaglobulinemic patients had recurrent infections (three with recurrent respiratory tract infection and one with a chronic diarrhoea that was Vancomycin sensitive) and three required monthly intravenous immunoglobulin replacement. Kaplan–Meier estimate of event-free survival (EFS) and overall survival (OS) of patients. The results presented here are, therefore, extremely encouraging for a group of patients who normally have a very poor clinical outcome, and support the notion, as suggested by Evens et al (2008), of an early consolidative autologous SCT for these patients. This approach is well tolerated and could be applied to even older patients.

Double high-dose therapy for Hodgkin's disease with dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP) prior to high-dose melphalan and autologous stem cell transplantation.

We previously reported a 50% (95% CI = 33-76%) 5 year event-free survival (EFS) rate for 23 patients with Hodgkin's disease (HD) who received salvage therapy with single agent high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT). Predictors of poor outcome included bulky disease and initial remission <1 year. Since 1995, similar poor prognosis patients have been treated with double high-dose therapy consisting of dose-intensive cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2, cisplatin 105 mg/m2 (DICEP) for tumor cytoreduction and stem cell mobilization followed by HDM/ASCT. The purpose of the present study is to determine if the use of DICEP is associated with improved event-free (EFS) and overall survival (OAS) for patients treated with HDM/ASCT. From February 1981 to June 1999, 46 consecutive patients received HDM/ASCT for relapsed (n = 35) or refractory (n = 11) HD. DICEP re-induction and blood stem cell mobilization was used for 21 patients. Factors considered for univariate and multivariate analyses included age at transplant, number of failed chemotherapy regimens, prior radiotherapy, length of initial remission, relapsed or refractory disease status, extranodal relapse, B symptoms at relapse, bulk, post-ASCT radiotherapy, and DICEP re-induction therapy. Cox proportional hazards models were constructed for both event and death. DICEP and HDM were well tolerated with no early treatment-related mortality or toxicity requiring life-sustaining measures. For all 46 patients, the projected 5 year EFS was 52% (95% CI = 38-72%) and OAS was 57% (95% CI = 40-82). Factors independently associated with relapse in multivariate analysis included bulk >5 cm (RR = 6.38, P = 0.002), prior radiotherapy (RR = 3.59, P = 0.027), and not using DICEP (RR = 5.29, P = 0.005). Factors independently associated with death included bulk >5 cm (RR = 5.13, P = 0.009), > or =3 prior chemotherapy regimens (RR = 4.72, P = 0.019), and not using DICEP (RR = 7.49, P = 0.015). This study demonstrates that DICEP re-induction prior to HDM/ASCT is feasible. The preliminary data are sufficiently encouraging to warrant a multicenter phase II or a phase III trial evaluating DICEP followed by HDM/ASCT as salvage therapy for HD.

Single-agent high-dose melphalan salvage therapy for Hodgkin's disease: Cost, safety, and long-term efficacy

Few data are available on the cost, safety, and long-term efficacy of single-agent high-dose melphalan (HDM) followed by autologous bone marrow (ABMT) or blood stem cell (ABSCT) transplantation in the salvage therapy of Hodgkin's disease (HD). From February 1981 to September 1996, 23 patients with relapsed (n = 15) or refractory (n = 8) HD received salvage therapy with HDM 140-200 mg/m2 followed by non-cryopreserved ABMT (n = 18) or cryopreserved ABSCT (n = 5). The cost of HDM/ABSCT in 1996, from initial consultation until transfer back to referring physician, was determined and compared to the estimate costs of two multi-agent regimens commonly used for HD. HDM was well tolerated with no early transplant-related mortality. The five-year overall and progression-free survival rates were 52% and 50%, respectively. The average total cost in Canadian funds of HDM/ABSCT in 1996 was $34,400/patient. This cost was estimated to be $4,700-6,800 cheaper per patient than the multi-agent high-dose regimens. These data suggest that HDM is safe, feasible, active, and reasonably inexpensive salvage therapy for patients with relapsed/refractory HD.