Autologous Hematopoietic Stem Cell Support Research Articles

Steady-State Versus Chemotherapy-Based Stem Cell Mobilization in Multiple Myeloma: A Single-Center Study to Analyze Efficacy and Safety.

High-dose chemotherapy followed by autologous hematopoietic stem cell support is recommended in the treatment of eligible multiple myeloma (MM) patients. The aim of this study was to compare the efficacy and safety of steady-state versus chemotherapy-based stem cell mobilization in our Hungarian patient population. The subjects were 210 MM patients who underwent stem cell mobilization procedure between 2018 and 2022. Solo granulocyte colony-stimulating factor (G-CSF) was administered in 104 cases, while 106 patients received chemotherapy which was followed by G-CSF administration. We evaluated the ratio of successful mobilizations, the amount of collected stem cells, the incidence of infections and cost-effectivity in the two groups. In the steady-state group, there was a significantly higher need for plerixafor (45% vs. 13%, P < 0.001), unsuccessful stem cell mobilization was more frequent (11% vs. 3%, P = 0.024) and the mean amount of collected stem cells was lower (6.9 vs. 9.8 × 106, P < 0.001) than in the chemotherapy group. However, infections were less frequent (4% vs. 27%, P < 0.001) and the number of days spent in hospital was significantly lower (6 vs. 14 days, P < 0.001). Plerixafor was more frequently administered in those who had received lenalidomide or daratumumab than in those who had been treated with other regimens (41% vs. 23%, P = 0.007 and 78% vs. 23%, P < 0.001, respectively). Steady-state mobilization is a safe method; however, the higher rate of plerixafor administration and unsuccessful attempts may question its superiority to chemomobilization.

Salvage treatment for children with relapsed/refractory germ cell tumors: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience.

Malignant germ cell tumors (GCTs) are a heterogeneous group of rare neoplasms in children. Optimal outcome is achieved with multimodal therapies for patients with both localized and advanced disease, especially after the introduction of platinum-based chemotherapy regimens. In this respect, data on salvage treatment for children with relapsed or platinum-refractory disease are still limited. Retrospective analysis of data regarding patients affected by malignant GCTs with platinum-refractory or relapsed disease after first-line treatment according to AIEOP TCGM 2004 protocol was conducted. Twenty-one patients, 15 females and 6 males, were considered for the analysis. All 21 patients received second-line conventional chemotherapy (SLCT), two of these immediately after surgery for local relapse removal. Two patients showed a progression of disease during SLCT and died of disease shortly thereafter, whereas 19 patients were in partial remission (PR) or complete remission (CR) after SLCT. Treatment after SLCT consisted in surgery on residual tumor mass (9/19) followed by high dose of chemotherapy (HDCT) with autologous hematopoietic stem cell support (16/19). The overall survival (OS) and event-free survival of the whole populations are 71% and 66.6%, respectively. Platinum-refractory patients OS is 54.5% compared with 91.5% of the relapsed group. There were no treatment-related deaths. SLCT followed or not by HDCT is an effective salvage treatment for children with relapsed/refractory GCTs. However, the role of HDCT following SLCT needs to be further investigated, especially regarding the identification of specific patient subgroups, which can benefit from this more intensive treatment.

High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group

High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group

High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Support for Relapsed or Refractory Primary CNS Lymphoma - a Prospective Multicentre Trial By the German Cooperative PCNSL Study Group

▪PurposeTo investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in patients with relapsed or refractory primary CNS lymphoma (PCNSL).Patients and methodsWe conducted a single-arm multicentre phase 2 study for immunocompetent patients (<66 years of age) with PCNSL failing prior HD-MTX based chemotherapy. Induction treatment consisted of 2 courses of rituximab (rituximab 375mg/m2), high-dose cytarabine (2 x 3g/m2) and thiotepa (40mg/m2) with collection of autologous stem cells in between. Conditioning treatment for HCT-ASCT consisted of rituximab 375mg/m2, carmustine 400mg/m2 and thiotepa (4 x 5mg/kg). Patients commenced HCT-ASCT irrespective of response status after induction. Only patients not achieving complete remission (CR) after HCT-ASCT received whole brain radiotherapy (WBRT). The primary endpoint was CR after HCT-ASCT by intention-to-treat (ITT). Secondary endpoints included safety, progression free survival (PFS, time to progression or death) and overall survival (OS, time to death due to any cause).ResultsBetween May 2007 and July 2012, we enrolled 39 patients from 12 German centres. The median age and Karnofsky performance score was 57 years (range 37 to 65) and 90% (range 60% to 100%), respectively. 28 (71.8%) patients had relapsed and 8 (28.2%) refractory disease. 22 (56.4%) patients responded to induction (4 CR, 18 partial remissions [PR]) and 32 (82.1%) patients commenced HCT-ASCT. 22 patients (56.4%, 95% CI 39.6% to 72.2%) achieved CR after HCT-ASCT, 6 (15.4%) achieved PR, and 1 (2.6%) had stable disease. In 9 (17.8%) patients the final scan was not done, because 7 (18.0%) did not undergo HCT-ASCT and 2 died (5.1%) during HCT-ASCT procedure. After a median follow-up of 45.2 months, the respective 2-year PFS and OS rates were 46.0% (95% CI 30.3% to 61.7%, median PFS 12.4 months, Figure 1) and 56.4% (95% CI 40.8% to 72.0%); median OS not reached (Figure 2). The non-relapse mortality rate was 10.3% (95% CI 4.1% to 26.0%) at 1 year without any further increase afterwards. In the subset of 32 patients who received HCT-ASCT, 14 (56.3%) experienced progression or died translating into 1 and 2-year PFS rates (calculated from date of HCT-ASCT) of 62.5% (95% CI 45.7% to 79.3%) and 56.1% (95% CI 38.8% to 73.3%) with no further decrease afterwards. Main grade 3 or higher toxicities were hematological as expected. We recorded four (10.3%) treatment-related deaths, 2 during induction and 2 during HCT-ASCT.ConclusionsIn eligible PCNSL patients failing HD-MTX based chemotherapy, a short induction with high-dose cytarabine and thiotepa followed by HCT-ASCT is an effective treatment option. Our data provide a reliable benchmark for future comparative studies needed to further scrutinize the role of HCT-ASCT in the salvage setting for PCNSL. [Display omitted] [Display omitted] DisclosuresKasenda:Riemser: Other: Travel Support. Schmidt-Wolf:Janssen: Research Funding; Novartis: Research Funding. Röth:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Stilgenbauer:Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding. Illerhaus:Riemser: Honoraria; Amgen: Honoraria.

Myeloblative therapy with autologous haematopoietic stem cell support as consolidation of first remission in acute myeloid leukaemia - very long follow-up.

Myeloblative therapy with autologous haematopoietic stem cell support as consolidation of first remission in acute myeloid leukaemia - very long follow-up.

Where we were, where we are, where we are going: progress in multiple myeloma.

The celebration of the 50th anniversary of the founding of the American Society of Clinical Oncology provides the occasion to review the progress that has been made in the biology and treatment of multiple myeloma. With the advent of melphalan and cyclophosphamide in the early 1960s the median survival of patients with multiple myeloma more than doubled from 10 months to approximately 24 months. Throughout multiple clinical trials in the 1970s and 1980s, melphalan and prednisone remained the gold standard, with a 3-year survival of 42%. The use of high-dose melphalan with autologous hematopoietic stem cell support provided an incremental advance in the 1990s. The outlook for patients was dramatically improved in the 2000s with the introduction of thalidomide analogs and proteasome inhibitors, so that the 3-year survival of patients treated in 2008 with melphalan and prednisone had increased to 66%. The 2010s are dominated by studying the optimal combination, sequence, and duration of therapies. These clinical advances have occurred along with our evolving understanding of the molecular pathogenesis of myeloma. Myeloma can be divided into two main groups: hyperdiploid, with multiple trisomies of odd-numbered chromosomes, and nonhyperdiploid, with recurrent immunoglobulin heavy chain gene translocations. Disease progression is associated with rearrangements of MYC, the most common mutation in myeloma, present in nearly half of patients. Genomic studies have highlighted marked subclonal heterogeneity that poses one of the main challenges to successful control of the disease. This problem will be addressed in future studies in the 2020s, which will include a focus on immunologic approaches such as monoclonal antibodies, checkpoint inhibitors, engineered T-cells, and novel immunomodulators.

Adjuvant High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Support for High-Risk Primary Breast Cancer: Results from the Italian National Registry

The efficacy of high-dose chemotherapy (HDC) and autologous hemopoietic progenitor cell transplantation (AHPCT) for breast cancer (BC) patients has been an area of intense controversy among the medical oncology community. The aim of this study was to assess toxicity and efficacy of this procedure in a large cohort of high-risk primary BC patients who underwent AHPCT in Italy. A total of 1183 patients receiving HDC for high-risk BC (HRBC) (>3 positive nodes) were identified in the Italian registry. The median age was 46 years, 62% of patients were premenopausal at treatment, 60.1% had endocrine-responsive tumors, and 20.7% had a human epidermal growth factor receptor 2 (HER2)–positive tumor. The median number of positive lymph nodes (LN) at surgery was 15, with 71.5% of patients having ≥ 10 positive nodes. Seventy-three percent received an alkylating agent-based HDC as a single procedure, whereas 27% received epirubicin or mitoxantrone-containing HDC, usually within a multitransplantation program. The source of stem cells was peripheral blood in the vast majority of patients. Transplantation-related mortality was .8%, whereas late cardiac and secondary tumor-related mortality were around 1%, overall. With a median follow-up of 79 months, median disease-free and overall survival (OS) in the entire population were 101 and 134 months, respectively. Subgroup analysis demonstrated that OS was significantly better in patients with endocrine-responsive tumors and in patients receiving multiple transplantation procedures. HER2 status did not affect survival probability. The size of the primary tumor and number of involved LN negatively affected OS. Adjuvant HDC with AHPCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk primary BC. Our results suggest that this treatment modality should be proposed in selected HRBC patients and further investigated in clinical trials.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Efficacy of repeat myeloablative chemotherapy with autologous stem-cell support in multiple myeloma.

Induction high-dose chemotherapy followed by myeloablative melphalan (HD-Mel) treatment and autologous hematopoietic stem-cell support (autoSCT) is a standard treatment for multiple myeloma (MM) either upfront or in relapse after conventional treatment. We performed a retrospective analysis of consecutive patients undergoing a late repeat HD-Mel/autoSCT treatment for MM. Data from 24 consecutive patients with MM who underwent a myeloablative treatment with HD-Mel late after completion of upfront first high-dose therapy were assessed for toxicity, response, progression-free survival (PFS) and time to next treatment (TTNT). These data were correlated with the results obtained after the initial high dose therapy and autoSCT. A total of 23 patients were treated with novel drugs (lenalidomide, thalidomide, bortezomib) after relapse to initial autoSCT. The median overall survival (OS) of all patients was 90 months. 19 patients (79%) achieved a very good partial remission (VGPR) or complete remission (CR) after initial autoSCT, compared with 42% after late autoSCT. PFS and TTNT were 19 and 24 months after initial compared with 13 and 21 months after late autoSCT. Univariate analysis identified initial response duration and the achievement of a CR/VGPR after the initial transplantation to be associated with prolonged response after repeat autoSCT. Our data indicate that late high-dose treatment followed by autoSCT is safe and effective after upfront intensive treatment, can bridge to allogeneic SCT, and encourage collection of an additional graft.

Dosimetry, toxicity, and response in a phase IIa trial of no-carrier added iobenguane I-131 (nca-MIBG): A New Approach to Neuroblastoma Therapy (NANT) study.

9512 Background: 131I-MIBG is specifically taken up in neuroblastoma, with a response rate >30% in relapsed disease. The presence of non-radioactive “carrier” MIBG molecules increases risk of cardiovascular side effects and can inhibit tumor uptake of 131I-MIBG, reducing tumor radiation. Our primary aim was to establish the maximum tolerated dose (MTD) of no-carrier-added MIBG with autologous hematopoietic stem cell (AHSC) support. Methods: Eligible patients were age 1-30 years with resistant neuroblastoma, MIBG avid tumors, and cryopreserved AHSC. The nca-MIBG therapeutic dose was escalated in 3 mCi/kg increments from 12-21 mCi/kg using a 3+3 design. The administered dose was limited by gamma image-derived pretreatment organ dosimetry and normal tissue tolerance estimates of Emami (1991). AHSC were infused 14 days post therapy. Response and toxicity were evaluated day 60. Dose limiting toxicity (DLT) was failure to engraft or grade 3 or 4 non-hematologic toxicity except grade 3 pre-defined exclusions. Results: Fifteen eligible patients were treated with 8.8 to 18.6 mCi/kg, including 3 patients each entered and evaluable at levels 12, 15, 18 mCi/kg (444-666 GBq/kg) without required dose adjustment or DLT. Of six additional patients entered, one was inevaluable for DLT due to early disease progression, and the other five assigned to 21 mCi/kg required dose reductions of 13 to 45% to meet organ dose limits. Median whole body radiation dose received was 3.3 Gy (2.0-4.0); median liver dose, 11.6 Gy (9.1-25.8); lung 11.5 Gy (5.9-15.3); kidney 15.5 Gy (8.3-23.4); adrenal 3.3 (2.0-3.9); thyroid 35.7 (2.1-108). In 7 patients there were 12 target lesions (mass 1.8-175 g) with received doses of 26-378 Gy. There was no related grade 3 or 4 non-hematologic toxicity; all patients engrafted promptly. No patients at 15 or 18 mCi/kg had ANC<500. The overall response rate (complete + partial) was 27%; by dose received responses were 0/6 at 12 mCi/kg, 1/3 at 15 mCi/kg, and 3/6 at 18 mCi/kg. Conclusions: No-carrier added iobenguane-131 with AHSC support is feasible at 18 mCi/kg with an apparent dose/response. The promising responses support a pivotal phase IIb study of 18 mCi/kg.

A Phase II study of 153Sm‐EDTMP and high‐dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma

Multiple myeloma (MM) remains an incurable illness affecting nearly 20,000 individuals in the United States per year. High-dose melphalan (HDM) with autologous hematopoietic stem cell support (ASCT) is one of the mainstays of therapy for younger patients, but little advancement has been made with regards to conditioning regimens. We opted to combine (153)Samarium ethylenediaminetetramethylenephosphonate ((153)Sm-EDTMP), a radiopharmaceutical approved for the palliation of pain caused by metastatic bone lesions, with HDM and ASCT in a Phase II study. Individualized doses of (153)Sm were based on dosimetry and were calculated to deliver 40 Gy to the bone marrow. The therapeutic dose of (153)Sm-EDTMP was followed by HDM and ASCT. Forty-six patients with newly diagnosed or relapsed disease were treated. Study patients were compared to 102 patients contemporaneously treated with HDM and ASCT. Fifty-nine percent of study patients achieved a very good partial response (VGPR) or better. With a median follow-up of 7.1 years, the median overall survival and progression free survival (PFS) from study registration was 6.2 years (95% CI 4.6-7.5 years) and 1.5 years (1.1-2.2 years), respectively, which compared favorably to contemporaneously treated non-study patients. Addition of high-dose (153)Sm-EDTMP to melphalan conditioning appears to be safe, well tolerated, and worthy of further study in the context of novel agents and in the Phase III setting.

Successful mobilization, harvest and transplant of peripheral blood stem cells using AMD3100 and G‐CSF following high dose craniospinal irradiation for medulloblastoma in a young child

Contemporary protocols for the treatment of malignant brain tumors such as medulloblastoma (MB) in children, often involve craniospinal irradiation (CSI) at diagnosis followed by serial courses of high dose chemotherapy and autologous hematopoietic stem cell support. Patients often require several pheresis procedures in order to collect sufficient stem cells for this type of treatment, particularly if they have already had CSI. We describe the successful mobilization, collection and subsequent transplant of a 7-year-old female with medulloblastoma after recent CSI using granulocyte colony stimulating factor (G-CSF) and the CXCR4 antagonist AMD3100 after a failed previous mobilization attempt using G-CSF alone.

Patterns of Outcome Following Recurrence in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Long Follow-up From a Single Centre.

Abstract 2921Poster Board II-897 Background:Despite improvements in outcome of patients (pts.) with DLBCL, the prognosis for those who relapse after first-line treatment remains very poor. This retrospective analysis reports outcome of pts. with DLBCL treated before the routine use of Rituximab, with a median (med.) follow-up of 12 years. Patients and Methods:Between 1985 and 2003, 461 pts. were diagnosed with DLBCL at SBH. 384/461 (83%, male: 208, med. age: 60 years, range 17-95) were treated with curative intent (CI) and form the basis of this analysis. Those with primary CNS or primary mediastinal B-cell lymphoma and HIV +ve pts. were excluded. Histology at diagnosis included 31 pts. with ‘composite' lymphoma (29 follicular [FL], 1 lymphoplasmacytic, 1 ‘MALT') and 17 with ‘discordant' lymphoma (all FL).The majority, 142 (37%), had Stage IV disease, 99 (26%) stage I, 88 (23%) stage II and 55 (14%) stage III. The IPI score (ascribed retrospectively) was low-risk in 189 (49%), low-intermediate (int.) in 110 (29%), high-int. in 64 (17%) and high-risk in 21 (5%). 354/384 (92%) received an anthracycline-containing regimen, according to protocols in use at the time. 30 pts. (8%) with localised disease received radiotherapy alone. Prior to 2001, all pts. received prophylactic intra-thecal methotrexate; subsequently, only those at high risk for CNS relapse did so. Results:CR/CRu was achieved in 240/384 pts. (63%) and PR in 67 (17%). 53 (14%) did not respond (NR) and 24 (6%) died of causes related to initial therapy. Overall survival (OS) correlated with outcome to therapy (CR/CRu vs PR vs NR, p<0.0001). The med. overall (OS) and cause-specific survival were 6 and 12 years respectively. The med. remission duration (RD) has not been reached, after a med. follow-up for living pts. of 12 years (range 2-24). On univariate analysis, age, stage and IPI score at diagnosis correlated with both survival (p=0.0006, <0.0001, <0.0001) and RD (p=0.02, 0.02, 0.008) respectively. 92 of the 240 pts. (38%) in whom CR/CRu was achieved relapsed at a med. of 10 months; none in the CNS. 82/92 pts. (89%) had a repeat biopsy at recurrence which in 6 revealed FL and in 1 ‘MALT' lymphoma. In 14 pts. recurrence of DLBCL occurred after 5 years. The med. age at relapse was 65 years. Stage and IPI score were assessable in 80/85 pts. with ‘pure' DLBCL at relapse, namely: Stage I:26 pts. (31%), II:10 (12%), III:19 (22%), IV:25 (29%). 46% of pts. who relapsed with Stage I disease had Stage I at presentation and 72% who relapsed with Stage IV had the same stage at diagnosis. IPI scores at recurrence were: low-risk:42 (49%), low-int:25 (29%), high-int:9 (11%), and high-risk:4 (5%). 66/85 pts. (78%) received further treatment with CI, 2nd CR/CRu being achieved in 36/66 (55%; 36/85 if all pts. with recurrent DLBCL are considered), and PR in 14 (21%). 16 pts. had NR (only 1 of them responded to subsequent alternative therapies). OS from recurrence (med. for all pts.= 22 months) correlated with outcome to ‘salvage' therapy (CR/CRu vs PR vs NR, p<0.0001). The med. 2nd RD was 3 years. Amongst the 45 pts. aged '60 years at relapse and thus eligible for high-dose treatment (HDT) with autologous haematopoietic stem cell support, 19 (16 in CR/CRu and 3 in PR; med. age, 46 years) went on to receive it but only 5 of the latter are alive at last follow-up, 13 (including the 3 pts. treated in PR) having died of lymphoma (9) or treatment-related causes (4). The reasons for not proceeding to HDT (in 21 pts. achieving a 2nd CR) were: age (8), comorbidity (4), early recurrence (2) failure to mobilise cells (2), toxicity of prior therapy (3) and pt. choice (2). On univariate analysis, survival from recurrence correlated only with the IPI score at recurrence (p=0.009). Overall, 65% of pts. who developed recurrent disease died of lymphoma (including 28/30 pts. in whom 2nd CR/CRu was not achieved with the first ‘salvage' therapy). Thus, only 12/85 pts. with recurrent disease are currently alive, 3 have been lost to follow-up. Conclusion:Despite the curative potential of HDT, these data confirm that recurrence of DLBCL, in an unselected patient population, carries an appalling prognosis. Improving initial therapy is therefore crucial. In pts. in whom conventional 2nd-line therapy has failed, it is entirely justifiable to evaluate experimental therapies. Disclosures:No relevant conflicts of interest to declare.

Combination Melphalan and Bortezomib Conditioning with Autologous Hematopoietic Stem Cell Support in Patients with Advanced Multiple Myeloma. A Phase I/II Study.

Abstract 1214Poster Board I-236Bortezomib is an active agent in the treatment of multiple myeloma (MM) and shows additive or synergistic effects when combined with various chemotherapeutics in pre-clinical and clinical models. We are conducting a phase I/II clinical study of bortezomib with dose-intense melphalan with autologous peripheral blood stem cell transplantation (PBSCT) in patients (pts) with disease progression or less than partial response after a prior PBSCT (tandem transplant). Primary exclusion criteria are active infection at time of PBSCT, cardiac amyloid deposition, and creatinine clearance of <20 ml/min. Peripheral neuropathy of less than grade 4 is not an exclusion. Bortezomib is given on days -4 and -1 with melphalan 200 mg/m2 (actual weight) given on day -2 before PBSCT. All pts are given oral ice during the melphalan infusion to prevent oral mucositis. For the phase I study, bortezomib was given at rising doses of 1.0, 1.3, and 1.6 mg/m2. Three pts were to be enrolled at each dose level, with an additional 3 pts enrolled in case of a serious toxicity event at any level. An additional 20 pts are being enrolled in the phase II portion of the study.Twelve pts (median age, 59 yrs) were treated in the phase I study with 6 pts treated at the 1.0 mg/m2 level after 1 pt experienced an SAE of prolonged diarrhea, and 3 pts treated at each of the subsequent levels. Eleven pts had 1 prior and 1 pt tandem prior cycles of dose-intense melphalan with PBSCT. All pts experienced the expected pancytopenia requiring red cell and/or platelet support. Ten pts had febrile neutropenia with bacteremia identified in 3 pts. One pt had mild tumor lysis. Mucositis was minimal and comparable to PBSCT with melphalan alone. All pts engrafted at a median time to ANC>500/uL of 11 days (range, 9-19) and plt>20,000/uL of 14 days (range, 11-27). No other SAEs occurred in the phase I study beyond the usual events of high-dose therapy. No neurological SAEs, including severe peripheral neuropathies, were observed. A bortezomib dose of 1.6 mg/m2 was chosen for the phase II study.Eleven pts (median age, 57 yrs) are now treated in the phase II study. Three pts had disease progression and 8 pts had less than PR after a prior PBSCT. All pts experienced pancytopenia and 10 engrafted with median time to ANC>500/uL of 10 days (range, 8-13) and plt>20,000 11 days (range, 9-65). Seven pts had febrile neutropenia with 3 pts with positive blood cultures and 1 pt with RSV bronchitis. Three SAEs are reported in the phase II portion: 1 pt expired of complications of Candida krusei infection and 1 of MRSA sepsis (before ANC recovery). A third pt developed tumor lysis requiring dialysis. One pt had a dysphoric reaction to anti-emetics and did not receive the 2nd bortezomib dose. No neurological SAEs attributable to this regimen were observed in this population.Pts underwent restaging studies at monthly intervals after transplantation with marrow examination at 3 and 12 months (mos). Response classification is in accordance to standard definitions. Three pts underwent subsequent allogeneic PBSC and 2 pts died of transplant-related complications and are not evaluable for response. Two pts succumbed to progressive disease. The remaining 16 pts are in ongoing follow-up. Eight pts including 6 of 11 pts with stable disease or minimal response after prior dose-intense melphalan achieved a CR. Six pts remain in continuous CR at 11+ to 23+ mos (median, 15+ mos) after PBSCT with 2 pts having disease progression at 12 and 26 mo after PBSCT.These data indicate that bortezomib can be added to dose-intense melphalan in this schedule with acceptable toxicities. Strikingly, 8 of 20 pts achieved CR after minimal response to dose-intense melphalan alone or disease progression after a prior PBSCT, and 2 pts showed tumor lysis, indicating a synergistic effect of adding bortezomib to dose-intense melphalan. This regimen will now be studied in a larger cross-over study of tandem PBSCT to assess relative response to the two regimens. Disclosures:Off Label Use: Bortezomib is indicated in the treatment of multiple myeloma. This study involved the use of bortezomib in combination with dose-intense melphalan with stem cell transplantation.. Siegel:Millenium: Consultancy, Research Funding, Speakers Bureau. Goy:Millenium: Speakers Bureau.

Who should receive myeloablative therapy for diffuse large B-cell lymphoma?

Over half of all newly-diagnosed diffuse large B-cell lymphoma patients can be cured with first line treatment based on the combination of rituximab with anthracycline-based chemotherapy regimens. The authors of this Viewpoint discuss the use of high-dose therapy and autologous hematopoietic stem cell support in patients with DLBCL who have relapsed or are refractory to first line treatment.

Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up

Investigation of high-dose chemotherapy (HD-CT) compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and ≥10 axillary lymph nodes. From November 1993 to September 2000, 307 patients were randomized to receive after four cycles of epirubicin (90 mg/m2), cyclophosphamide (600 mg/m2) i.v. (every 21 days) and either HD-CT of cyclophosphamide (1500 mg/m2), thiotepa (150 mg/m2) and mitoxantrone (10 mg/m2) i.v. for four consecutive days followed by stem cell transplantation or a SD-CT of three cycles CMF (cyclophosphamide 500 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2, i.v. on day 1 and 8, respectively, every 28 days). After a median follow-up of 6.1 years, 166 events with respect to event-free survival (EFS) (SD-CT: 91, HD-CT: 75) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0.80 [95% confidence interval (0.59, 1.08)], P = 0.15. The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients and in patients with tumor grade 3 as compared with patients with tumor grade 1/2. With a follow-up of 6 years, there was a trend in favor of HD-CT with respect to EFS not being significant. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients who might benefit from HD-CT.

Long-term follow-up after nonmyeloablative allogeneic hematopoietic stem cell transplantation for systemic sclerosis

Systemic sclerosis (SSc) characteristically consists of fibrotic changes in various organs, and immunological abnormality is the main cause of the disease. Although high-dose immunosuppressive therapies with autologous or allogeneic hematopoietic stem cell support can reverse the disease course, they have a high treatment-related mortality. We report the successful use of nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for SSc. A 40-year-old woman with diffuse scleroderma and interstitial pneumonia underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling after conditioning with low-dose total-body irradiation and fludarabine. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and mycophenolate mofetil. No infection or acute GVHD developed. One year after transplantation, the patient developed membranous glomerulopathy caused by chronic GVHD that was successfully treated with prednisolone. The patient's skin score decreased dramatically, and her pulmonary function is stable 4 years after transplantation. Nonmyeloablative allogeneic HSCT may be more effective than conventional therapies for SSc.

Treatment of high‐risk relapsed Wilms tumor with dose‐intensive chemotherapy, marrow‐ablative chemotherapy, and autologous hematopoietic stem cell support: Experience by the Italian association of pediatric hematology and oncology

We evaluated an intensified chemotherapy strategy in children with Wilms tumor who relapsed with high-risk features. From January 2001 to June 2006, we treated 20 consecutive children with reinduction chemotherapy (using ifosfamide/carboplatin/etoposide in 15/20 cases), with (n = 15) or without (n = 5) subsequent high-dose chemotherapy and hematopoietic stem cell support, surgery where feasible, and radiation therapy. The median time to relapse was 10 months after nephrectomy. All but two children initially received doxorubicin as first-line therapy. All patients were assessed for outcome: 13 are currently alive, 12 of them in remission a median 25 months since their relapse, one with progressing tumor. The treatment was unsuccessful in eight children: the disease progressed during reinduction in three, and relapsed in five. There was one toxic death. All transplanted patients engrafted to a neutrophil count >0.5 x 10(3)/microl after a median 11 days, and to an unsustained platelet count >25,000/microl after a median of 13 days. Three-year disease-free and overall survival rates were 56 +/- 12% and 55 +/- 13%, respectively. Neither recurrence within 12 months of nephrectomy nor extra-lung recurrence negatively affected outcome. A survival advantage was demonstrated in patients without disease evidence prior to transplant. A disease-free survival rate nearing 50% is a realistic target in children with high-risk recurrent Wilms tumor. The benefit of autologous hematopoietic stem cell transplantation for consolidation deserves to be investigated in a randomized, controlled study.

Serial Intense Chemotherapy Combining Topotecan, Etoposide, Carboplatin and Cyclophosphamide (TECC) Followed by Autologous Hematopoietic Stem Cell Support in Patients with High Risk Soft Tissue Sarcoma (STS)

In nine patients (pts) with soft tissue sarcoma refractory to conventional therapy (incomplete response or relapse) intensified chemotherapy was administered combining 0.75 mg/m (2) topotecan, 100 mg/m (2) etoposide, 100 mg/m (2) carboplatin and 200 mg/m (2) cyclophosphamide on day 1-5 (TECC). To avoid prolonged intervals between the serial TECC courses autologous hematopoietic stem cell supports (median 1.0 x 10(6) CD34+ cells per kg body weight (bw), range 0.5-2.8 x 10(6) CD34+ cells/kg bw, SD 0.6 x 10(6) CD34+ cells/kg bw) were given on day 7. All pts received granulocyte colony stimulating factor (GCSF) from day 8 in addition. All together 39 TECC courses (minimum 2 courses, maximum 6 courses per pt) were administered, with a median interval of 32 (range 21-52) days until recovery. Leukopenia (<1000/microl) occurred 9 days (range 3-13 days; SD 2.4 days) after end of chemotherapy and persisted for 9 (range 3-15 days; SD 3 days) days. In 31/39 TECC courses readmission to hospital was required for supportive therapy mainly due to neutropenic fever. In this period pts received 0.83 (range 0-1) red blood cell units and 2.35 (range 1-4) platelet units. C-reactive protein in neutropenic pts as an indicator for infection after TECC chemotherapy was detectable after 36 of 39 chemotherapy courses leading to further supportive therapy (median 10.4 mg/dl, range 1.1-28.3 mg/dl; SD 6.67 mg/dl). Duration of total inpatient treatment per TECC course including supportive therapy was in median 13.5 days (range 7-53 days; SD 4.3 days). Only two children had a prolonged infection (77 and 100 days). Clinical and objective tumor responses, defined as complete remission, very good partial response and partial response were observed in 9/9 pts at eight weeks after the last TECC course and were maintained at six months in 7/9 pts. Median time to progression and median overall survival time after TECC chemotherapy were 20.3 months and 25.2 months, respectively. These data provide evidence that in very high risk pts refractory to standard high risk therapy, a combination of TECC chemotherapy and stem cell support is feasible in pts with incomplete remission respectively relapsed STS pts and demonstrates promising antineoplastic activity. Therefore, this regimen warrants further investigation in prospective trials.

High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Support for Solid Tumors in Adults

Supported by experimental evidence and convincing results of early phase II studies, since the 1980s high-dose chemotherapy (HDC) with autologous hematopoietic stem cell support (AHSCT) has been uncritically adopted by many oncologists as a potentially curative option for several solid tumors. As a result, the number (and size) of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) in this setting was limited and the benefit of a greater escalation of dose of chemotherapy with stem cell transplantation in solid tumors remains, with the possible exception of breast carcinoma (BC) and germ cell tumors (GCT), largely unsettled. In this article, we review and comment on the data from studies to date of HDC for solid tumors in adults.