Long-Term Follow-up of CALGB (Alliance) 100001: Autologous Followed by Nonmyeloablative Allogeneic Transplant for Multiple Myeloma.

CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by nonmyeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than 1 prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m2). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m2/d i.v. on days -7 through -3) and cyclophosphamide (1 g/m2/d i.v. on days -4 through -3). The primary objective was to determine the 6-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host disease (GVHD), disease-free survival, and overall survival (OS). Sixty patients were enrolled, of whom 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49; 90% confidence interval, 0.10% to 9.3%). Moderate to severe (grades 2 to 3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of nonprotocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate.

Lenalidomide after stem-cell transplantation for multiple myeloma.

BACKGROUND: Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. METHODS: Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15). RESULTS: The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P=0.03). More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic adverse events occurred in patients who received lenalidomide (P<0.001 for both comparisons). Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%). CONCLUSIONS: Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00114101.).

Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance).

Allogeneic stem cell transplantation is the standard approach to Philadelphia chromosome positive acute lymphoblastic leukemia. We hypothesized that imatinib plus sequential chemotherapy will result in significant leukemia cell cytoreduction in patients with Philadelphia chromosome positive acute lymphoblastic leukemia, allowing collection of normal hematopoietic stem cells uncontaminated by residual BCR/ABL1(+) lymphoblasts and thus reduce the likelihood of relapse after autologous stem cell transplantation for patients under 60 years of age without sibling donors. We enrolled 58 patients; 19 underwent autologous and 15 underwent allogeneic stem cell transplantation on study. Imatinib plus sequential chemotherapy resulted in reverse-transcriptase polymerase chain reaction-negative stem cells in 9 patients and remained minimally positive in 4 (6 were not evaluable). Overall survival (median 6.0 years vs. not reached) and disease-free survival (median 3.5 vs. 4.1 years) were similar between those who underwent autologous and those who underwent allogeneic stem cell transplantation. We conclude that autologous stem cell transplantation represents a safe and effective alternative for allogeneic stem cell transplantation in Philadelphia chromosome positive acute lymphoblastic leukemia patients without sibling donors (clinicaltrials.gov identifier:00039377).

Characteristics of CliniMACS® System CD34-enriched T cell-depleted grafts in a multicenter trial for acute myeloid leukemia-Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0303.

Eight centers participated in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0303 to determine the effect of extensive T cell depletion (TCD) on the outcome of HLA matched sibling donor transplantation for acute myeloid leukemia. One goal of the study was to determine if TCD could be performed uniformly among study sites. TCD was achieved using the CliniMACS(®) CD34 Reagent System for CD34 enrichment. Processed grafts needed to contain ≥ 2.0 × 10(6) CD34(+)cells/kg with a target of 5.0 × 10(6) CD34(+) cells/kg and <10(5) CD3(+) T cells/kg. Up to 3 collections were allowed to achieve the minimum CD34(+) cell dose. In total, 86 products were processed for 44 patients. Differences in the starting cell products between centers were seen in regard to total nucleated cells, CD34(+) cells, and CD3(+) T cells, which could in part be ascribed to a higher dose of granulocyte-colony stimulating factor used for mobilization early in the trial. Differences between centers in processing outcomes were minimal and could be ascribed to starting cell parameters or to differences in graft analysis methods. Multivariate analysis showed that CD34(+) cell recovery (66.1% ± 20.3%) was inversely associated with the starting number of CD34(+) cells (P = .02). Median purity of the CD34 enriched fraction was 96.7% (61.5%-99.8%) with monocytes and B cells the most common impurity. All patients received the minimum CD34(+) cell dose, and 39 patients (89%) came within 10% or exceeded the target CD34(+) cell dose without exceeding the maximum T cell dose. All patients proceeded to transplantation and all achieved initial engraftment. Products processed at multiple centers using the CliniMACS System for CD34 enrichment were comparably and uniformly highly enriched for CD34(+) cells, with good CD34(+) cell recovery and very low CD3(+) T cell content.

Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909.

BACKGROUND: In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial. DESIGN AND METHODS: Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression. RESULTS: Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis. CONCLUSIONS: Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma.

Reduced-intensity conditioning allogeneic hematopoietic cell transplantation for patients with hematologic malignancies who relapse following autologous transplantation: a multi-institutional prospective study from the Cancer and Leukemia Group B (CALGB trial 100002).

We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic HCT (allo-HCT) using a reduced-intensity conditioning regimen of fludarabine 150 mg/m(2) plus intravenous busulfan 6.4 mg/kg. Both matched sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit antithymocyte globulin (ATG) 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9-5.8), treatment-related mortality (TRM) at 6 months and 2 years was 8% and 23%, respectively. Neither TRM nor the rates of acute GVHD (aGVHD) were different in those with sibling or MUD donors. Donor CD3 cell chimerism >90% at day +30 was achieved more often in patients with MUD than with matched sibling donors, 70% versus 23% (P < .0001). Median event-free suvival was higher in patients who achieved early full donor chimerism (14.2 versus 8 months, P = .0395). Allo-HCT using this reduced-intensity conditioning regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve event-free survival.

Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901.

Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.

Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303.

Graft-versus-host disease (GVHD) is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but its role in the treatment of patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in complete remission (CR) remains unclear. We performed a phase 2 single-arm multicenter study to evaluate the role of TCD in AML patients in CR1 or CR2 up to age 65 years. The primary objective was to achieve a disease-free survival (DFS) rate of >75% at 6 months posttransplantation. A total of 44 patients with AML in CR1 (n = 37) or CR2 (n = 7) with a median age of 48.5 years (range, 21-59 years) received myeloablative chemotherapy and fractionated total body irradiation (1375 cGy) followed by immunomagnetically selected CD34-enriched, T cell‒depleted allografts from HLA-identical siblings. No pharmacologic GVHD prophylaxis was given. All patients engrafted. The incidence of acute GVHD grade II-IV was 22.7%, and the incidence of extensive chronic GVHD was 6.8% at 24 months. The relapse rate for patients in CR1 was 17.4% at 36 months. With a median follow-up of 34 months, DFS for all patients was 82% at 6 months, and DFS for patients in CR1 was 72.8% at 12 months and 58% at 36 months. HCT after myeloablative chemoradiotherapy can be performed in a multicenter setting using a uniform method of TCD, resulting in a low risk of extensive chronic GVHD and relapse for patients with AML in CR1.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting cellular immunotherapy in combination with autologous stem cell transplantation (ASCT) as postremission therapy for acute myeloid leukemia (AML).

Preclinical models have demonstrated the efficacy of granulocyte-macrophage colony-stimulating factor-secreting cancer immunotherapies (GVAX platform) accompanied by immunotherapy-primed lymphocytes after autologous stem cell transplantation in hematologic malignancies. We conducted a phase 2 study of this combination in adult patients with acute myeloid leukemia. Immunotherapy consisted of autologous leukemia cells admixed with granulocyte-macrophage colony-stimulating factor-secreting K562 cells. "Primed" lymphocytes were collected after a single pretransplantation dose of immunotherapy and reinfused with the stem cell graft. Fifty-four subjects were enrolled; 46 (85%) achieved a complete remission, and 28 (52%) received the pretransplantation immunotherapy. For all patients who achieved complete remission, the 3-year relapse-free survival (RFS) rate was 47.4% and overall survival was 57.4%. For the 28 immunotherapy-treated patients, the RFS and overall survival rates were 61.8% and 73.4%, respectively. Posttreatment induction of delayed-type hypersensitivity reactions to autologous leukemia cells was associated with longer 3-year RFS rate (100% vs 48%). Minimal residual disease was monitored by quantitative analysis of Wilms tumor-1 (WT1), a leukemia-associated gene. A decrease in WT1 transcripts in blood was noted in 69% of patients after the first immunotherapy dose and was also associated with longer 3-year RFS (61% vs 0%). In conclusion, immunotherapy in combination with primed lymphocytes and autologous stem cell transplantation shows encouraging signals of potential activity in acute myeloid leukemia (ClinicalTrials.gov: NCT00116467).

The role of autologous transplantation for acute myeloid leukemia in first and second remission.

Since 1986, the University of California San Francisco has developed novel approaches to autologous transplantation for acute myeloid leukemia (AML). Strategies have included intensive preparative regimens using busulfan and etoposide, and evolving strategies for pre-transplant consolidation and stem cell collection. Treatment-related mortality has been low (<5%), and after problems with slow engraftment and extended mucosal and skin toxicity in initial studies using 4-hydroperoxycyclophosphamide (4-HC)-purged bone marrow, peripheral blood autologous stem cell transplantation (ASCT) has been well tolerated even in older patients. In particular, careful attention to avoiding neurotoxicity associated with the use of high-dose cytarabine has limited dropout rates. Long-term event-free survival (EFS) has been excellent in first remission (CR1) cytogenetically favorable groups, particularly with post-transplant treatment for acute promyelocytic leukemia (APL) patients with all-trans retinoic acid (ATRA; EFS 88%). ASCT in advanced disease showed overall long-term EFS of 44%; patients with APL in second remission achieved long-term EFS of 64%. Even among those failing primary induction, after remission induction with an alternative regimen, EFS was 61%. ASCT appears to be a treatment of choice for those in APL CR2, and offers some curative potential for AML CR2. The role of ASCT for those in CR1 is less clear, in part because high dropout rates in large randomized studies complicates interpretation of those studies. New directions for ASCT in the treatment of AML should focus on improving therapy, including calibrated intensification of induction regimens using plasma-kinetics targeting of dosages and the development and incorporation of immunotherapies into consolidation regimens.

The cancer and leukemia group B transplant committee.

The Transplant Committee of the Cancer and Leukemia Group B has a robust portfolio of studies and is poised to make significant contributions to the field. We are working in collaboration with the Cancer and Leukemia Group B Leukemia and Lymphoma Disease Committees and importantly in collaboration with other groups to define the role of both autologous and reduced-intensity allogeneic transplantation in the management of selected hematologic malignancies. Some of our studies have the potential to change the standard of care in areas such as the maintenance therapy for multiple myeloma after autologous transplantation and to generate the data that could lead to acceptance of new approaches to the initial post-remission therapy of older adults with acute myeloid leukemia. The cooperative group setting allows us to advance the transplant field by showing which approaches are successful outside of single institutions and are therefore feasible on a generalized basis.

Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial.

BACKGROUND: In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. METHODS: Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated ß2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. FINDINGS: Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6-103·1). The median time to progression was 57·3 months (95% CI 44·2-73·3) for the lenalidomide group and 28·9 months (23·0-36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46-0·71; p<0·0001). The most common grade 3-4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. INTERPRETATION: Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. FUNDING: The National Cancer Institute.

Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG).

Thirty patients with malignant pheochromocytoma (PHEO) or paraganglioma (PGL) were treated with high-dose 131I-MIBG. Patients were 11-62 (mean 39) years old: 19 patients males and 11 females. Nineteen patients had PGL, three of which were multifocal. Six PGLs were nonsecretory. Eleven patients had PHEO. All 30 patients had prior surgery. Fourteen patients were refractory to prior radiation or chemotherapy before 131I-MIBG. Peripheral blood stem cells (PBSCs) were collected and cryopreserved. 131I-MIBG was synthesized on-site, by exchange-labeling 131I with 127I-MIBG in a solid-phase Cu2+-catalyzed exchange reaction. 131I-MIBG was infused over 2 h via a peripheral IV. Doses ranged from 557 mCi to 1185 mCi (7.4 mCi/kg to 18.75 mCi/kg). Median dose was 833 mCi (12.55 mCi/kg). Marrow hypoplasia commenced 3 weeks after 131I-MIBG therapy. After the first 131I-MIBG therapy, 19 patients required platelet transfusions; 19 received GCSF; 12 received epoeitin or RBCs. Four patients received a PBSC infusion. High-dose 131I-MIBG resulted in the following overall tumor responses in 30 patients: 4 sustained complete remissions (CRs); 15 sustained partial remissions (PRs); 1 sustained stable disease (SD); 5 progressive disease (PD); 5 initial PRs or SD but relapsed to PD. Twenty-three of the 30 patients remain alive; deaths were from PD (5), myelodysplasia (1), and unrelated cause (1). Overall predicted survival at 5 years is 75% (Kaplan Meier estimate). For patients with metastatic PHEO or PGL, who have good *I-MIBG uptake on diagnostic scanning, high-dose 131I-MIBG therapy was effective in producing a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.

Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia.

PURPOSE: To assess the efficacy and toxicity of a new treatment program of intensified and shortened cyclical chemotherapy (protocol 8707) in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Previously untreated adults < or = 60 years old with ALL were treated with a four-agent induction chemotherapy regimen. This was followed by cyclical postremission therapy with high-dose cytarabine/etoposide; high-dose methotrexate/6-mercaptopurine; and daunorubicin, vincristine, prednisone, and asparaginase. Maintenance chemotherapy with oral methotrexate and 6-mercaptopurine was continued for 30 months. CNS prophylaxis was given with intrathecal methotrexate in addition to the systemic chemotherapy indicated above. RESULTS: Seventy-eight of 84 patients (93%) achieved complete remission. With a median follow-up of 5.6 years, 5-year event-free survival (EFS) of all remission patients is 52%. Patients with high-risk features including adverse cytogenetics, failure to achieve remission with the first cycle of chemotherapy, and B-precursor disease with WBC counts more than 100,000/microL all relapsed unless taken off study for transplantation. For patients without these high-risk features, 5-year EFS was 60%. Compared with our previous treatment regimen, results appear to be improved for patients with standard-risk B-precursor disease (5-year EFS, 66% v 34%; P =.01). CONCLUSION: Intensified and shortened chemotherapy may improve the outcome for patients with ALL with B-precursor disease lacking high-risk features. Further trials of this regimen are warranted.

Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502.

PURPOSE: Long-term survival rates for older patients with newly diagnosed acute myeloid leukemia (AML) are extremely low. Previous observational studies suggest that allogeneic hematopoietic stem-cell transplantation (HSCT) may improve overall survival (OS) because of lower rates of relapse. We sought to prospectively determine the value of HSCT for older patients with AML in first complete remission. PATIENTS AND METHODS: We conducted a prospective multicenter phase II study to assess the efficacy of reduced-intensity conditioning HSCT for patients between the ages of 60 and 74 years with AML in first complete remission. The primary end point was disease-free survival at 2 years after HSCT. Secondary end points included nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, and OS. RESULTS: In all, 114 patients with a median age of 65 years received transplantations. The majority (52%) received transplantations from unrelated donors and were given antithymocyte globulin for GVHD prophylaxis. Disease-free survival and OS at 2 years after transplantation were 42% (95% CI, 33% to 52%) and 48% (95% CI, 39% to 58%), respectively, for the entire group and 40% (95% CI, 29% to 55%) and 50% (95% CI, 38% to 64%) for the unrelated donor group. NRM at 2 years was 15% (95% CI, 8% to 21%). Grade 2 to 4 acute GVHD occurred in 9.6% (95% CI, 4% to 15%) of patients, and chronic GVHD occurred in 28% (95% CI, 19% to 36%) of patients. The cumulative incidence of relapse at 2 years was 44% (95% CI, 35% to 53%). CONCLUSION: Reduced-intensity conditioning HSCT to maintain remission in selected older patients with AML is relatively well tolerated and appears to provide superior outcomes when compared with historical patients treated without HSCT. GVHD and NRM rates were lower than expected. Future transplantation studies in these patients should focus on further reducing the risk of relapse.

A phase I study of targeted, dose-escalated intravenous busulfan in combination with etoposide as myeloablative therapy for autologous stem cell transplantation in acute myeloid leukemia.

BACKGROUND: Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML. PATIENTS AND METHODS: In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) µmol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion. RESULTS: Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade ≥ 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 (P = .08). CONCLUSION: Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 µmol/min.

Treatment of acute leukemia with idarubicin, etoposide and cytarabine (IDEA). A randomized study of etoposide schedule.

BACKGROUND: The differences in toxicity of etoposide following continuous or bolus infusion are unknown. METHODS: We studied the schedule-dependent toxicity of high-dose etoposide when combined with high-dose cytarabine and idarubicin (IDEA) in 138 patients with acute leukemia. Four groups of patients were studied: group I, relapse; group II, secondary acute myeloid leukemia (AML); group III, de novo AML, age >60 years; and group IV, induction failure or blast crisis of myeloproliferative syndrome. Treatment for groups I-III was idarubicin 8 mg/m(2) per day days 1-3, cytarabine 2000 mg/m(2) once a day days 1-6, and etoposide 1600 mg/m(2) total dose. Group IV treatment differed by cytarabine given twice daily days 1-6. Patients were randomized to etoposide as a continuous infusion days 1-6 or as a bolus infusion over 10 h on day 7. RESULTS: Continuous infusion etoposide produced significantly more oral mucositis than bolus etoposide. In groups I-III, comparing continuous and bolus etoposide, there was a median of 3 vs 0 days of grade 2 or more oral mucositis (P<0.0001) and 13.5 vs 0 days of total parenteral nutrition (TPN) (P=0.0003). Group IV patients had a median 7 vs 0 days of grade 2 or more oral mucositis (P<0.01) and 21 vs 7 days of TPN (P<0.003), respectively. There were no differences in hematologic recovery, length of hospital stay, complete remission rate or overall survival between the two etoposide schedules. Of groups I-III patients, 51% achieved complete remission, and 11% died from treatment-related complications. CONCLUSION: The toxicity profile of high-dose etoposide is schedule-dependent with prolonged exposure producing significantly more non-hematologic toxicity.

Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103).

PURPOSE: Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (>60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability. METHODS: AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test. RESULTS: One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients ≥ 60 years old (median 66; range 60-74) had a significantly higher BuCL versus those <60 years old (median 50; range 18-60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p > 0.34). CONCLUSIONS: Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients.

Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma.

PURPOSE: To evaluate the safety and efficacy of high-dose [(131)I]metaiodobenzylguanidine ([(131)I]MIBG) in the treatment of malignant pheochromocytoma (PHEO) and paraganglioma (PGL). METHODS: Fifty patients with metastatic PHEO or PGL, age 10 to 64 years, were treated with [(131)I]MIBG doses ranging from 492 to 1,160 mCi (median, 12 mCi/kg). Cumulative [(131)I]MIBG administered ranged from 492 to 3,191 mCi. Autologous hematopoietic stem cells were collected and cryopreserved before treatment with [(131)I]MIBG greater than 12 mCi/kg or with a total dose greater than 500 mCi. Sixty-nine [(131)I]MIBG infusions were given, which included infusions to 35 patients treated once and infusions to 15 patients who received two or three treatments. Response was evaluated by [(123)I]MIBG scans, computed tomography/magnetic resonance imaging, urinary catecholamines/metanephrines, and chromogranin A. RESULTS: The overall complete response (CR) plus partial response (PR) rate in 49 evaluable patients was 22%. Additionally, 35% of patients achieved a CR or PR in at least one measure of response without progressive disease, and 8% of patients maintained stable disease for greater than 12 months. Thirty-five percent of patients experienced progressive disease within 1 year after therapy. The estimated 5-year overall survival rate was 64%. Toxicities included grades 3 to 4 neutropenia (87%) and thrombocytopenia (83%). Grades 3 to 4 nonhematologic toxicity included acute respiratory distress syndrome (n = 2), bronchiolitis obliterans organizing pneumonia (n = 2), pulmonary embolism (n = 1), fever with neutropenia (n = 7), acute hypertension (n = 10), infection (n = 2), myelodysplastic syndrome (n = 2), and hypogonadism (n = 4). CONCLUSION: Although serious toxicity may occur, the survival and response rates achieved with high-dose [(131)I]MIBG suggest its utility in the management of selected patients with metastatic PHEO and PGL.

A phase II study of continuous infusion homoharringtonine and cytarabine in newly diagnosed patients with chronic myeloid leukemia: CALGB study 19804.

BACKGROUND: Both homoharringtonine (HHT), an alkaloid derivative from the Chinese yew tree that inhibits protein synthesis, and low-dose cytarabine have independent activity in CML and have been used in combination after failure of interferon therapy. PATIENTS AND METHODS: The CALGB performed a phase II trial of HHT (2.5 mg/m(2) per day) plus cytarabine (7.5 mg/m(2) per day), given together via continuous intravenous infusion for 7 days in previously untreated patients with Ph chromosome positive chronic phase CML. HHT/cytarabine cycles were repeated every 28 days if the blood counts were adequate. The primary endpoint was the major cytogenetic response rate after 9 months. RESULTS: Forty of the 44 enrolled patients required reduction in the infusion duration during at least one cycle. Myelosuppression was common; 66% developed neutrophil count <500/microl, but grade 3 infections occurred in only 7%. Thirty-six of 44 patients (82%) achieved a complete hematologic remission; the median duration has not been reached. Only 4 of the 23 patients (17%) having adequate cytogenetic response assessment achieved a major response within nine cycles. CONCLUSIONS: Although HHT/cytarabine was generally well tolerated, the cytogenetic response rate did not exceed the level previously seen in patients with interferon-refractory CML and was not nearly as high as associated with imatinib in newly diagnosed patients.