A new conditioning regimen involving total marrow irradiation,busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma

The overall survival of patients with advanced multiple myeloma (MM) undergoing high-dose chemotherapy and autologous stem cell transplantation (SCT) depends mainly on the quality of response. Thus, to improve the response rate, a new intensified high-dose chemoradiotherapy was evaluated in a phase I/II study. After induction chemotherapy, 89 patients (median age 51 years, range 32-60 years) with MM stage II/III received a conditioning regimen with total marrow irradiation (9 Gy), busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) followed by SCT. Regimen-related toxicity according to WHO criteria and response rates defined by EBMT/IBMTR were analyzed. The main toxicity was mucositis grade III/IV in 76%, and fever grade >I in 75% of patients. Three patients developed reversible veno-occlusive disease. Transplant-related mortality was 2%. Among patients with de novo and pretreated MM, a CR rate of 48 and 41%, respectively, was documented. With a median follow-up of 45 months, the actuarial median durations of event-free survival (EFS) and overall survival (OS) after transplant were 29 and 61 months for the whole group, 36 and 85 months for patients with de novo MM, respectively. Thus, administration of this intensified conditioning regimen was associated with tolerable toxicity, a high response rate and long EFS and OS.     

Dose-reduced conditioning regimen followed by allogeneic stem cell transplantation in patients with myelofibrosis with myeloid metaplasia

Three patients with myelofibrosis received allogeneic stem cell transplantation after a dose-reduced conditioning regimen of busulphan (8 mg/kg), fludarabine (180 mg/m2) and antithymocyte globulin (4 x 10 mg/kg). The median age at transplantation was 51 years (range 44-58). All patients engrafted with a leucocyte count > 1.0 x 10(9)/l after a median of 18 d (range 16-20). Grade II acute skin graft-versus-host disease (GvHD) occurred in one patient. One limited and one extensive chronic GvHD was observed. All patients achieved complete haematological remission. In one patient the fibrosis resolved completely 180 d post transplant. All patients are alive 126, 466 and 764 d after transplantation.     

Clinical trial of rubidazone in solid tumors and malignant lymphomas.

Rubidazone, a semisynthetic daunorubicin derivative, was administered to 33 patients with advanced solid tumors or malignant lymphomas. The doses used were 200, 150, or 100 mg/m2 repeated at 3-week intervals. The antitumor effect was very modest. Partial remission was obtained in only one patient and stable disease was observed for periods of 4--18 weeks in seven additional patients. The major toxic effects were gastrointestinal and myelosuppressive. In two patients, cardiac toxic effects were noted and one patient had an anaphylactic-like reaction. No clinical cross-resistance seemed to exist between rubidazone and adriamycin.     

Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases

Allogeneic hematopoietic SCT is well established as a potentially curative therapy for children and adults with both malignant and nonmalignant diseases. However, myeloablative SCT is associated with significant short- and long-term complications. The goals of a reduced intensity-conditioning (RIC) regimen are to prevent graft rejection and establish stable donor-derived hematopoiesis at a level sufficient for cure of the underlying disease and, in patients with hematologic malignancy, to provide a GVL effect, while decreasing the short- and long-term complications associated with myeloablative conditioning therapy. RIC regimens have enabled SCT to be performed in children with preexisting comorbidities that preclude conventional conditioning. RIC-SCT has been most extensively studied in patients with nonmalignant disorders and for some of these, including primary immunodeficiencies and hemophagocytic lymphohistiocytosis, sufficient data now exist to support its routine use even in patients without comorbidity. Less data exist on RIC-SCT for children with hematologic malignancies and at present this should be restricted to children who are not candidates for, or have relapsed after, myeloablative SCT. Here we review available data on the use of RIC-SCT in pediatric patients, highlighting important clinical lessons and areas that require further study.     

Case-matched comparison with standard versus reduced intensity conditioning regimen in chronic myeloid leukemia patients

This retrospective case-matched study evaluated the efficacy of reduced intensity conditioning (RIC) regimen on early and late allogeneic transplant outcome in chronic myeloid leukemia (CML) patients. Twenty-eight patients conditioned with RIC regimen were matched to 56 patients who received a myeloablative conditioning (MAC) regimen. The main criteria for case matching among our CML allotransplant cohort were the Gratwohl scoring system. The median score was 2 (1–4) in each group. The pretransplant disease status was first chronic phase (CP1, n = 20), CP2 (n = 2), and advanced phase (n = 6) in RIC, and CP1 (n = 46), CP2 (n = 3), and advanced phase (n = 7) in MAC. The duration of neutropenia and thrombocytopenia was shorter in RIC than MAC. The grade and duration of mucositis were less in RIC. The need for total parenteral nutrition (21% vs. 77%, p < 0.0001) and febrile neutropenic episodes (50% vs. 95%, p < 0.0001) were observed less frequently in RIC compared with MAC-given patients. Acute or chronic graft versus host diseases (GvHD) were not affected by the intensity of conditioning regimen. The incidence of transplant-related mortality was higher in MAC (7% vs. 14%, p = 0.01). Although more relapse/progression was observed in the RIC group, the probability of 5- and 10-year leukemia-free- and overall survival were similar regardless of conditioning regimen intensity (p > 0.05). In early first CP, the pair of female donor–male recipient and the development of chronic GvHD prolonged both leukemia-free survival and overall survival in multivariate analysis. According to our single-center matched-pair analysis, the use of RIC regimens in patients with low-risk CML results with toxicities less, responses later, and relapses more frequent than the MAC regimens.     

Reduced intensity conditioning (RIC) haematopoietic cell transplants in elderly patients with AML

Reduced intensity conditioning (RIC) transplants were first developed almost a decade ago to reduce the transplant-related mortality (TRM) of allogeneic haematopoietic cell transplantation (HCT) and to make the graft-versus-leukaemia effect accessible to patients otherwise ineligible for HCT. Acute myelogenous leukaemia (AML) in elderly patients is now a frequent indication for RIC-HCT. The major reasons for these rapid developments have been on the one hand the high median age of patients with AML coupled with the unsatisfactory results with conventional chemotherapy, and on the other hand with the promising results already reported for RIC-HCT. Using RIC-HCT, overall survival rates at 2 years of 45-50% have been observed in patients with AML. This compares favourably with overall survival rates of 10-15% under chemotherapy in AML CR1, or no long-term survivors in patients >CR2. From the available data we conclude that RIC-HCT is a promising treatment for elderly patients with AML. However, phase-III studies with unrelated donors will have to be done in order to formally prove its superiority in comparison to conventional chemotherapy.     

Busulfan, cyclophosphamide, and etoposide as high-dose conditioning regimen in patients with malignant lymphoma

We investigated the efficacy and toxicity of the combination of busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP-16) as a preparative regimen prior to autologous hematopoietic stem cell transplantation (ASCT) in patients with Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL). Fifty-three patients with recurrent ( n=30), refractory ( n=20), or high-risk ( n=3) lymphoma were enrolled. The 10 patients with HD and 43 with NHL (median age: 46 years, range: 18-64) received busulfan (16 mg/kg), cyclophosphamide (120 mg/kg), and etoposide (30 or 45 mg/kg) followed by ASCT. A total of 50 patients (94%) were consolidated in complete ( n=25) or partial ( n=25) remission, whereas 3 patients had chemoresistant disease before Bu/Cy/VP-16. Thirty-five patients (66%) had received prior radiotherapy (RT) excluding total body irradiation (TBI) as part of the conditioning regimen. The main nonhematological toxicities (grade II-IV according to the Bearman score) in 52 evaluable patients were mucositis (79%) and hepatic toxicity (15%). Severe veno-occlusive disease (VOD) occurred in three patients (5.8%) including one treatment-related death caused by VOD. Overall, treatment-related mortality was 3.8%. After a median follow-up for surviving patients of 21 months (range: 6-118), 20 patients (38%) are in continuous complete remission, 8 patients (15%) are alive in relapse, and 25 patients (47%) died. Probabilities of relapse, event-free survival, and overall survival at 3 years were 63% [95% confidence interval (CI): 48-79%], 31% (95% CI: 17-46%), and 43% (95% CI: 27-59%), respectively. In conclusion, Bu/Cy/VP-16 is an effective and well-tolerated conditioning regimen in patients with HD and NHL. Both toxicity and outcome were not significantly different in patients treated with 30 mg/kg and 45 mg/kg etoposide, respectively. The observed long-term results are even comparable to those published for other established high-dose protocols, including TBI-based regimens. However, further investigations are necessary to evaluate the value of Bu/Cy/VP-16 as a high-dose protocol for malignant lymphoma, especially in patients who have already received extensive RT.     

Reduced-intensity conditioning regimen with thiotepa and fludarabine followed by allogeneic blood stem cell transplantation in haematological malignancies

The aim of this study was to investigate thiotepa (TT) and fludarabine (Fluda) as a preparative regimen for allogeneic peripheral stem cell transplant in patients not eligible for a standard myeloablative regimen due to comorbidities and/or poor performance status. TT was given at a dose of 10 mg/kg over 2 days and Fluda at 125 mg/m(2) over 5 days. In all, 21 patients (14 male, seven female; 10 acute leukaemia, eight myelodysplastic syndrome, two non-Hodgkin's lymphoma, one Hodgkin's disease) were treated. The median age was 51 years (range 30-55 years). All patients achieved full donor-type chimaerism. Adverse events included mild nausea and vomiting in two patients and a slight increase of serum amylase in three. A total of 13 patients received RBC transfusions (median 6 U, range 1-23), and all received platelets (median 4 U, range 1-27). Four patients died of nonrelapse causes and five of relapse. The 1-year probabilities of transplant-related mortality and relapse were 19 and 29%, respectively. In total, 12 patients remain in complete remission (median follow-up: 786 days). The 3-year overall survival probability was 58%. We conclude that this regimen is feasible and well tolerated.     

DNA synthesis in unstimulated blood lymphocytes of patients with untreated malignant lymphomas or other malignant tumors.

Blood lymphocyte DNA synthesis, as expressed by 24-h uptake of 3H-thymidine in culture of mononuclear peripheral blood leucocytes has been reduced prior to treatment in 18 patients with Hodgkin's disease, 11 with non-leukaemic lymphosarcoma, 13 with reticulosarcoma and 20 with various solid tumors, and compared to 37 normal control subjects.The 3H-thymidine uptake was significantly increased in all the patient groups, but no significant difference existed between them. Increased uptake of 3H-thymidine did not appear to correlate with the degree of dissemination in any of the patient groups or with the presence or absence of general symptoms in malignant lymphoma. It is concluded that increased DNA synthesis in peripheral blood lymphocytes is a feature not limited to Hodgkin's disease, but found in non-Hodgkin's malignant lymphomas and other malignancies to about the same extent.     

A review of relative dose intensity and survival in patients with metastatic solid tumors

Studies have shown that in the curative setting patients with cancer receiving chemotherapy at higher relative dose intensity (RDI) had better clinical outcomes than those receiving treatment at lower RDI. However, the impact of RDI in advanced/metastatic disease remains unclear. A review of the literature was performed to evaluate the relationship between RDI and survival in patients with metastatic lung, breast, or ovarian cancer receiving chemotherapy. Few studies attempted to specifically associate RDI with survival in a systematic way. Findings from studies that analyzed overall survival with a prespecified RDI threshold support the emerging perception that maintaining an RDI ≥ 85% has a favorable impact on survival. Nonetheless, these studies were limited by their retrospective nature. More studies are needed to further evaluate the impact of maintaining planned chemotherapy dose intensity on outcomes in metastatic solid tumors.     

A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome.

We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.     

BU／CY预处理方案的异基因外周血干细胞移植治疗急性白血病

目的 :观察 BU / CY预处理方案的异基因外周血干细胞移植 (Allo- PBSCT)治疗急性白血病的疗效。方法 :用 BU / CY预处理方案行 Allo- PBSCT治疗急性白血病 5例 ,其中急性淋巴细胞白血病 (AL L ) 4例 (CR13例 ,CR2 1例 ) ,急性非淋巴细胞白血病 (ANL L) 1例 (CR1 )。预处理方案 BU/ CY:BU4m g/ (kg· d)× 4,CTX6 0m g/ (kg· d)× 2。其中 2例 AL L 分别加米托蒽醌 40～ 5 0 m g。用 G- CSF10 μg/ (kg· d)× 5 d进行造血干细胞动员 ,分离单个核细胞 (MNC)中位数 6 .48× 10 8/ kg〔(3.5～ 7.0 )× 10 8/ kg〕。 CD34+细胞中位数 6 .6× 10 6 / kg〔(4.0～9.6 6 )× 10 6 / kg〕。结果 :全部患者移植后均重建造血 ,粒细胞 >0 .5× 10 9/ L,中位数 13d;血小板 >30× 10 9/ L,中位数为 13d;血小板 >5 0× 10 9/ L,中位数为 15 d。发生迟发性出血性膀胱炎 1例 ,白血病复发死亡 1例 ,CMV肺炎死亡 1例。其余 3例分别无病生存 11、9、7个月。结论 :Allo- PBSCT具有造血重建快 ,采集干细胞方便 ,供者易接受等优点     

A phase I dose escalation study of high-dose thiotepa, melphalan and carboplatin (TMCb) followed by autologous peripheral blood stem cell transplantation (PBSCT) in patients with solid tumors and hematologic malignancies

The purpose of this study was to determine the maximum tolerated dose of carboplatin administered with 500 mg/m2 thiotepa and 100 mg/m2 melphalan followed by autologous peripheral blood stem cell (PBSC) infusion in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose thiotepa (500 mg/m2, melphalan (100 mg/m2) and escalating doses of carboplatin 900-1500 mg/m2) followed by infusion of cryopreserved autologous PBSCs. The maximum tolerated doses were determined to be 500 mg/m2 thiotepa, 100 mg/m2 melphalan and 1350 mg/m2 carboplatin. Two consecutive patients receiving 1500 mg/m2 carboplatin experienced grade 3 mucositis and colitis. Ten patients were enrolled at the maximum tolerated dose and none had grade 3-4 regimen-related toxicity and mortality. All patients at this level experienced grade 1-2 mucositis, 90% grade 1-2 gastrointestinal toxicity, 30% grade 1-2 cardiac and renal toxicity, and 10% experienced grade 1 hepatic toxicity. The median time to achieve a granulocyte count of 0.5x10(9)/l was 9 days (range 7-12 days) and platelet count of 20x10(9)/l was 10 days (range 7-15 days). Of eight patients with stage IV refractory breast cancer, even were evaluable for response, one patient on day 75 will be evaluated soon. Five of seven (71.5%) evaluable patients achieved a complete remission (CR) and two had no response. Of seven patients with non-Hodgkin's lymphoma (n = 4) or Hodgkin's disease (n = 3), five achieved a CR (71.5%). Thiotepa, melphalan and carboplatin can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy-sensitive malignancies are warranted.     

Clinical outcomes of multiple myeloma patients who undergo autologous hematopoietic stem cell transplant with G-CSF or G-CSF and plerixafor mobilized grafts

Impact of Plerixafor (P) mobilized stem cells on immune reconstitution, such as absolute lymphocyte count at day 30 (ALC30), and on long-term outcomes of Multiple Myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) has not been well established. We evaluated total of 469 patients mobilized with G-CSF (G) alone, and 141 patients mobilized with G-CSF plus plerixafor (G+ P). Patients only received plerixafor if they had peripheral blood CD34⁺ blood count <20/μL on first planned day of collection. Primary endpoint, ALC30, was 1.3 K/μL (range, 0.1-4.5) and 1.2 K/μL (range, 0.1-5.1) for G and G + P, respectively (P =. 61). The median PFS was 2.5 years (95% CI, 2.1-3.2) and 2.8 years (95% CI, 2.0-3.3) for G and G + P, respectively (HR: 1.13; 95% CI, 0.84-1.50; P = .42). The median OS was 6.1 years (95% CI, 4.6-NR) for G group compared to 3.7 years (95% CI, 3.2-NR) for the G + P group (HR: 1.64; 95% CI, 1.12-2.40; P = .01). The median follow-up time for OS was 2.53 years (95% CI, 2.13-2.99) and 1.59 years (95% CI, 1.17-2.02) for G and G+ P group, respectively. In this large retrospective analysis of MM patients mobilized with G-CSF vs G-CSF + P, there was no significant difference in lymphocyte recovery or PFS. There was an overall survival difference in patients who were poor mobilizers and could not be mobilized with G-CSF alone.     

Continuous complete clinical and molecular remission in two patients with refractory lymphoid malignancies after autografting followed by allogeneic stem cell transplantation with reduced intensity conditioning

We present a 60-year-old patient with primary refractory non-Hodgkin's lymphoma and a 58-year-old patient with multiple myeloma with relapse after first autologous stem cell transplantation (ASCT), who underwent ASCT followed by allogeneic stem cell transplantation (alloSCT) with reduced intensity conditioning consisting of fludarabine and a single dose of total body irradiation. For graft-versus-host disease prophylaxis cyclosporine and mycophenolate mofetyl were given. Complete donor chimaerism was observed on d 28 after SCT. Both patients achieved sustained complete haematological and molecular remission of the immunoglobulin kappa light chain (Igkappa) rearrangement and are alive and well 17 and 16 months after SCT respectively.