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Recent therapy advances for haematological cancers including new drugs and targeted and immune therapies raise the question whether there is a future for haematopoietic cell transplants. Although encouraging, the survival improvements achieved with these new modalities in persons who might otherwise receive a transplant are modest. Furthermore, these modalities are likely to be complementary, not competitive. For example, randomised trials in multiple myeloma, the most common transplants, indicate an ongoing role for transplant despite new anti-myeloma drugs. Targeted therapies in myeloid cancers are estimated to be effective in only about 10 percent of persons with these cancers. The potential impact of current immune therapies on transplant activity is also limited because: (1) they predominately target B-cell rather than myeloid cancers; (2) many successfulimmune therapy recipients subsequently receive a transplant; (3) considerable data indicate much of the efficacy of allotransplants results from allogeneic rather than cancer-specific immunity not expected to operate with current immune therapies; and (4) they are at an early development stage with unknown long-term safety and efficacy. These data suggest an ongoing role for haematopoietic cell transplants in diverse haematological and genetic disorders.

Therapy-related myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML) have a poor prognosis with conventional therapy. Encouraging results are reported after allogeneic transplantation. We analyzed outcomes in 868 persons with t-AML (n = 545) or t-MDS (n = 323) receiving allogeneic transplants from 1990 to 2004. A myeloablative regimen was used for conditioning in 77%. Treatment-related mortality (TRM) and relapse were 41% (95% confidence interval [CI], 38-44) and 27% (24-30) at 1 year and 48% (44-51) and 31% (28-34) at 5 years, respectively. Disease-free (DFS) and overall survival (OS) were 32% (95% CI, 29-36) and 37% (34-41) at 1 year and 21% (18-24) and 22% (19-26) at 5 years, respectively. In multivariate analysis, 4 risk factors had adverse impacts on DFS and OS: (1) age older than 35 years; (2) poor-risk cytogenetics; (3) t-AML not in remission or advanced t-MDS; and (4) donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50% (95% CI, 38-61), 26% (20-31), 21% (16-26), 10% (5-15), and 4% (0-16), respectively (P < .001). These data permit a more precise prediction of outcome and identify subjects most likely to benefit from allogeneic transplantation.

Therapy-related myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML) have a poor prognosis with conventional therapy. Encouraging results are reported after allogeneic transplantation. We analyzed outcomes in 868 persons with t-AML (n = 545) or t-MDS (n = 323) receiving allogeneic transplants from 1990 to 2004. A myeloablative regimen was used for conditioning in 77%. Treatment-related mortality (TRM) and relapse were 41% (95% confidence interval [CI], 38-44) and 27% (24-30) at 1 year and 48% (44-51) and 31% (28-34) at 5 years, respectively. Disease-free (DFS) and overall survival (OS) were 32% (95% CI, 29-36) and 37% (34-41) at 1 year and 21% (18-24) and 22% (19-26) at 5 years, respectively. In multivariate analysis, 4 risk factors had adverse impacts on DFS and OS: (1) age older than 35 years; (2) poor-risk cytogenetics; (3) t-AML not in remission or advanced t-MDS; and (4) donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50% (95% CI, 38-61), 26% (20-31), 21% (16-26), 10% (5-15), and 4% (0-16), respectively (P< .001). These data permit a more precise prediction of outcome and identify subjects most likely to benefit from allogeneic transplantation.

Beginning in 1985, patients in British Columbia with Hodgkin lymphoma (HL) that was not controlled by conventional chemotherapy routinely underwent high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). Long-term complications of HD-ASCT have become apparent as more patients survive without recurrence of HL. Data were obtained retrospectively on the first 100 patients that underwent HD-ASCT for HL in Vancouver, focusing on relapse, treatment-related complications, and the occurrence of late events. Fifty-three patients remain alive (median follow-up, 11.4 years [range, 10.0-17.4 years]) with an overall survival (OAS) of 54% at 15 years. OAS was significantly better in patients in first relapse (67%) than in patients with primary refractory-induction failure (39%) and advanced disease (29%) (P = .002). The major cause of death was progression of HL (32% at 15 years). Treatment-related mortality, including death from second malignancy, was 17% at 15 years. Cumulative risk of a second malignancy was 9% at 15 years. Karnofsky performance status was at least 90% in 47 patients although hypogonadism (20 patients), hypothyroidism (12 patients), unusual infections (10 patients), anxiety or depression (7 patients), and cardiac disease (5 patients) were not uncommon in survivors. HD-ASCT can lead to durable remissions in relapsed or refractory HL with acceptable but definite late toxicity. The occurrence of late events necessitates lifelong medical surveillance. (Blood. 2005;106:1473-1478)

Beginning in 1985, patients in British Columbia with Hodgkin lymphoma (HL) that was not controlled by conventional chemotherapy routinely underwent high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). Long-term complications of HD-ASCT have become apparent as more patients survive without recurrence of HL. Data were obtained retrospectively on the first 100 patients that underwent HD-ASCT for HL in Vancouver, focusing on relapse, treatment-related complications, and the occurrence of late events. Fifty-three patients remain alive (median follow-up, 11.4 years [range, 10.0-17.4 years]) with an overall survival (OAS) of 54% at 15 years. OAS was significantly better in patients in first relapse (67%) than in patients with primary refractory-induction failure (39%) and advanced disease (29%) (P= .002). The major cause of death was progression of HL (32% at 15 years). Treatment-related mortality, including death from second malignancy, was 17% at 15 years. Cumulative risk of a second malignancy was 9% at 15 years. Karnofsky performance status was at least 90% in 47 patients although hypogonadism (20 patients), hypothyroidism (12 patients), unusual infections (10 patients), anxiety or depression (7 patients), and cardiac disease (5 patients) were not uncommon in survivors. HD-ASCT can lead to durable remissions in relapsed or refractory HL with acceptable but definite late toxicity. The occurrence of late events necessitates lifelong medical surveillance. (Blood. 2005;106:1473-1478)

Amifostine treatment may allow chemotherapy dose increases beyond those permitted by autologous hematopoietic stem cell transplantation. In a recent study in patients with solid tumors receiving a high-dose regimen of etoposide, ifosfamide, and carboplatin plus autologous stem cell transplantation, amifostine pretreatment was associated with significant reductions in time to neutrophil and thrombocyte engraftment, fewer days of neutropenic fever, less need for salvage antibiotic therapy. Also, there were significant reductions in grade 3 or 4 stomatitis/diarrhea, and delayed nausea/vomiting. A phase I/II study in patients with refractory/high-risk malignancies indicated that a 140% increase of high-dose melphalan (up to 280 mg/m2) can be safely used with amifostine and autologous stem cell transplantation with manageable mucosal toxicity and a reduced incidence of regimen-related toxicity. Preliminary findings in another phase II study indicate that melphalan 280 mg/m2can also be safely used with amifostine/stem cell transplantation in the treatment of patients with myeloma. Additional studies are ongoing or planned to examine the potential hematoprotective and hematostimulating effects of amifostine in the setting of high-dose chemotherapy and autologous stem cell transplantation. Semin Oncol 29 (suppl 19):53-56. Copyright 2002, Elsevier Science (USA). All rights reserved.

The results of cytotoxic therapy, including dose-intensive therapy requiring autologous stem cell transplantation (ASCT), have been disappointing in patients with metastatic breast cancer, as almost all patients eventually experience disease progression. There has been a renewed interest in immunotherapeutic strategies in this disease, including evaluation of several breast cancer vaccines. In the current study, we describe the results of a program in which the anti-idiotype breast cancer vaccine 11D10 (TriAb®) was administered before and after ASCT in patients with metastatic breast cancer chemosensitive to previous conventional therapy. The toxicity of this approach was acceptable, and idiotype-specific humoral and T-cell proliferative responses were observed in the majority of patients within a few weeks post-ASCT. The actuarial 3-year overall survival rate was 48% (95% CI, 32%-64%), while the progression-free survival rate was 32% (95% CI, 19%–45%). Multivariate analysis identified achievement of a strong antibody and cellular immune response to the vaccine as the only significant prognostic factors for outcome. The ability to reliably produce robust immune responses after ASCT is encouraging. Further studies are required to determine if the immune response mediates an antitumor benefit in these patients.

The anti-idiotype monoclonal antibody breast cancer vaccine 11D10 (TriAb®) was administered before and after autologous stem cell transplantation (ASCT) in 45 patients with metastatic breast cancer whose disease was responsive to conventional chemotherapy. Evidence of a positive anti-anti-idiotype antibody (Ab3) humoral response was noted at a median of 1.75 months post-ASCT (range, before ASCT–6 months) with this strategy. Maximal Ab3 levels and idiotype-specific T-cell proliferative responses were observed at a median of 3 and 4 months, respectively, after ASCT. The achievement of rapid immune responses after ASCT, during a known period of decreased immunoresponsiveness, opens the possibility of an additional antitumor effect at a time when the tumor burden is relatively small. Moreover, in this interim analysis, patients with the most vigorous humoral and cellular immune responses had a significant improvement in progression-free survival. Further follow-up and evaluation of this approach is warranted.

BTI-322, a rat monoclonal IgG2b directed against the CD2 antigen on T cells and natural killer (NK) cells, blocks primary and memory alloantigen proliferative responses in vitro. We have evaluated the pharmacokinetics and safety of BTI-322 during treatment of 20 transplant recipients with steroid-refractory acute graft-versus-host disease (GVHD). Treatment consisted of BTI-322 by intravenous (IV) bolus or 30-minute infusion at approximately 0.1 mg/kg/d for 10 days in addition to continuing high-dose steroids and tacrolimus or cyclosporine. Pharmacokinetic sampling was performed in 10 patients; the t1/2 ± SE was 9.1 ± 1.3 hours, the Cmaxwas 2,549 ± 291 ng/mL, the Vd was 3.97 ± 0.95 L, and the Vd/kg was 0.05 ± 0.01 L/kg. Ten patients experienced transient dyspnea sometimes accompanied by nausea, vomiting, diarrhea, and tachycardia shortly after the initial bolus dose of drug, but serious drug-related adverse events were not seen during the remainder of the infusions. At the end of treatment (day 11), there were six patients with complete responses and five with a reduction in grade of GVHD for a total response rate of 55% (95% confidence interval [CI], 32% to 77%). Antibodies targeting CD2 may be active in the treatment of acute GVHD, and evaluation of a humanized form of BTI-322 is warranted.

Fifty-seven patients with refractory acute leukemia were treated with high-dose cytosine arabinoside to establish the maximum tolerated dose and duration and to determine the antileukemic activity. The maximum tolerated regimen was found to be 3 g/sq m every 12 hr for 6 days. At this dose, nonhematologic toxicity was limited to conjunctivitis in approximately half of the patients, and liver toxicity (transient elevations in transaminase, alkaline phosphatase, or bilirubin) was frequently observed, but neither was dose-limiting. Extending the duration of treatment to 8 days resulted in excessive diarrhea and skin toxicity (painful erythema with bullae), while increasing the dose to 4.5 g/sq m q. 12 hr for 6 days resulted in severe cerebellar toxicity. Myelosuppression was severe, but was not related to the intensity of treatment; granulocyte recovery occurred a median of 28 days (range 22–40 days) after initiating therapy, and platelet recovery occurred after a median of 25 days (range 16–41 days). Antileukemic activity was evaluable in the 46 patients who survived at least 3 wk. Complete remissions were obtained in 1 of 6 patients with chronic myelogenous leukemia (CML) in accelerated phase and 1 of 3 acute lymphoblastic leukemia (ALL) patients. A more detailed analysis of response was possible for the 37 evaluable patients with acute nonlymphoblastic leukemia: 70% of these patients responded, with 51 % complete remissions. The median unmaintained response was 4 mo (range 2–26+ mo). The complete response rate was higher in patients who received at least 12 doses of high-dose cytosine arabinoside compared to shorter regimens [17/28 (61%) versus 2/9 (22%), p< 0.05]. Resistance to cytosine arabinoside in conventional doses was documented in 11 patients, 5 of whom responded (2 complete remissions) to high-dose regimens. We conclude that high-dose cytosine arabinoside in the maximally tolerated regimen of 3 g/sq m every 12 hr for 6 days has substantial antileukemic activity in patients refractory to standard therapy. Durable unmaintained remissions can be achieved, even in patients who fail to respond to cytosine arabinoside in conventional doses.

Advanced low-grade lymphomas are usually incurable with conventional-dose chemotherapy. It is uncertain whether cures are possible with high-dose therapy and bone marrow transplant from a human leukocyte antigen (HLA)-identical sibling. We sought to determine the outcome of HLA-identical sibling bone marrow transplants in advanced low-grade lymphoma in an observational study of 113 patients conducted at 50 centers participating in the International Bone Marrow Transplant Registry (IBMTR). The median patient age was 38 years (range, 15 to 61). Eighty percent had stage IV disease at the time of transplantation. The median number of prior chemotherapy regimens was two (range, 0 to 5). Thirty-eight percent had refractory disease and 29% a Karnofsky performance score (KPS) less than 80%. All patients underwent allogeneic bone marrow transplantation from a HLA-identical sibling donor. The conditioning regimen included total-body irradiation (TBI) in 82% of patients; cyclosporine was used for graft-versus-host disease prophylaxis in 74%. Survival, disease-free survival, recurrence rate, treatment-related mortality, and causes of death were determined. Three-year probabilities of recurrence, survival, and disease-free survival were 16% (95% confidence interval [CI], 9% to 27%), 49% (95% CI, 39% to 60%), and 49% (95% CI, 39% to 59%), respectively. Higher survival was associated with pretransplant KPS =90%, chemotherapy-sensitive disease, use of a TBI-containing conditioning regimen, and age less than 40 years. We conclude that high-dose therapy followed by transplantation from a HLA-identical sibling leads to prolonged survival in some patients with advanced low-grade lymphoma. Most mortality is treatment-related, and recurrences are rare. © 1998 by The American Society of Hematology.

The outcome of treatment for a first relapse of Hodgkin’s disease after primary chemotherapy was analyzed in 80 patients. They were divided into four groups: group 1 (n = 24) had initially been treated with three cycles of (mechlorethamine, vincristine, prednisone, and procarbazine [MOPP]) and wide-field irradiation therapy; group 2 (n = 25) had six cycles of MOPP; group 3 (n = 15) and group 4 (n = 16) both initially received MOPP/ABVD (MOPP plus doxorubicin, bleomycin, vinblastine, and dacarbazine) or MOPP/ABV hybrid, but group 3 received conventional salvage regimens whereas group 4 was treated with high-dose chemotherapy and autologous bone marrow transplantation as salvage therapy (n = 16). Freedom from second failure (FF2F) was used as the major endpoint. Actuarial FF2F for all patients was 38% after a median follow-up of 75 months for patients who were alive. Risk factor analysis was performed on the 71 patients who had been treated with curative intent. The presence or absence of any one of three risk factors had a strong negative impact on outcome: stage IV disease at primary diagnosis, B symptoms at relapse, or a time from primary treatment to relapse of less than 1 year. Actuarial FF2F at 5 years was 17% in the group of patients with one or more of these three factors present (n = 49). If none of these factors was present, FF2F was 82% (n = 22) (P <.001). Even high-dose chemotherapy and autologous bone marrow transplantation were not able to overcome the negative impact of one or more risk factors (FF2F = 19%, n = 12). The outcome of salvage treatments depends most on the presence or absence of these three risk factors and less on the type of salvage treatment. Patients with none of these risk factors present have an excellent outcome if they are treated with non–cross-resistant chemotherapy, or radiotherapy, or both. Novel approaches are needed for patients with one or more of these factors present. Reports on salvage treatments for Hodgkin’s disease in first relapse after primary chemotherapy should include data on the proportion of patients having stage IV disease at diagnosis, B symptoms at relapse, and a time from primary treatment to relapse of less than 1 year.

Acute steroid-resistant graft-versus-host disease (AGVHD) after allogeneic bone marrow transplantation is frequently fatal. A new treatment for this T-lymphocyte-mediated condition uses an immunotoxin, H65-RTA, comprised of a monoclonal antibody that recognizes the CD5 lymphocyte differentiation antigen coupled to ricin A chain, a cytotoxic enzyme that inhibits protein synthesis. The safety and efficacy of this lymphocyte-targeted immunotoxin was evaluated in patients with severe AGVHD in a phase I-II dose escalation study with group expansion at the two middle doses. Thirty-four patients received up to 14 daily intravenous infusions of the immunotoxin. The principal side effects were constitutional symptoms such as fatigue and myalgias, and hypoalbuminemia with weight gain was seen at all doses. Thirty-two patients were evaluated for improvement or resolution of disease. Durable complete or partial responses were not dose-related and were seen in 16 patients. Skin GVHD had the highest incidence of response (73%), although improvement or resolution in gastrointestinal tract (45%) and liver (28%) GVHD was also noted. Survival in responding patients was significantly prolonged at all times as compared with those with no response (P= .03). Treatment was associated with a rapid decrease in peripheral blood T lymphocytes, which persisted for greater than 1 month after therapy. Anti-immunotoxin antibodies were seen in 6 of the 23 patients tested; these were of low titer and did not block immunotoxin binding to T cells. Results of this study indicate that anti-T-lymphocyte immunotoxins may form a new class of immunosuppressive agents useful in T-lymphocyte-mediated diseases.

The development and validation of a gas chromatographic assay method for determination of total and free busulfan concentrations in human plasma for pharmacokinetic studies is reported. 1,6-Bis(methanesulfonyloxy)hexane, the internal standard, and a potential metabolite, 3-hydroxysulfolane, were synthesized. Plasma and plasma ultrafiltrate samples containing busulfan and internal standard were extracted with ethyl acetate and derivatized with 2,3,5,6-tetrafluorothiophenol prior to gas chromatographic determination. The63Ni electron-capture detector provided a limit of detection of 0.0600 µg/ml with a limit of quantitation of 0.100 µg/ml busulfan in biological samples. Calibration curves were linear from 0.100 to 3.00 µg/ml in plasma (500 µl) and 0.100 to 2.00 µg/ml in plasma ultrafiltrate (100 µl). Extraction and derivatization yields ranged from 78.4% to 89.6% and 56.0% to 71.3%, respectively. Specificity of this assay for busulfan in the presence of its potential metabolites was demonstrated. Also, plasma samples containing co-administered drugs gave no response under these conditions. Clinical samples obtained following administration of a 1 mg/kg oral busulfan dose demonstrate the applicability of this method to analysis of total and free plasma concentrations.

High-dose (HD) cytosine arabinoside (ARA-C) is more effective treatment than conventional-dose ARA-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). We report here that HD ARA-C given during the first remission of ANLL has resulted in long remission durations and a high proportion of patients who survive more than three years free of disease. From August 1979 to September 1983, 36 adult patients with ANLL in first remission received one to three courses of HD ARA-C (3 g/m2by one-hour infusion every 12 hours for 12 doses on days 1 through 6) alone or with daunorubicin (30 mg/m2for two or three doses on days 7 through 9). Three patients died of sepsis or hemorrhage during consolidation, and 14 patients have relapsed from five to 48 months after diagnosis. The remaining 19 patients are in continued complete remission (CCR) from 11 to 62 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 42% at 62 months, with an apparent plateau in the survival curve. Of the first 22 patients treated, ten remain in CCR from 37 to 62 months with no therapy for at least three years. Due to its heightened anti-leukemic activity, HD ARA-C allows brief but effective consolidation of ANLL in first remission, with long-term disease-free survival comparable to other approaches. © 1985 by Grune & Stratton, Inc.

The storage of platelet concentrates (PC) at 22°C in Polyvinylchloride containers has been limited to 3 days. Even within this time interval, fall in pH to 6.0 or less with associated loss of viability occurs in a substantial number of PC. Previous work demonstrated that the fall in pH resulted from increased production of lactic acid due to hypoxic conditions within the container and could be prevented by storage in a container constructed from material that was more permeable to oxygen than conventional Polyvinylchloride plastic, PL-146. We have now studied PC storage in a new polyolefin plastic, PL-732. This material has increased permeability to oxygen, and pH fall to less than 6.0 does not occur during 5 days of storage. In autologous studies using chromium-51 labeling, mean in vivo recovery and survival T1/2were 51% and 3.1 days, respectively, after 5 days of storage. After the same storage interval, mean corrected platelet increments in thrombocytopenic patients were 15.7, 11.1, and 6.9 × 103/cu mm/sq m/1011platelets infused at 1-3,4-6, and 24 hr after infusion. In paired studies in the same patient, PC stored for 5 days in PL-732 were consistently superior to PC stored for 3 days in PL-146. At 4-6 and 24 hr after infusion, bleeding times were shortened appropriately for the elevation of the platelet count achieved. These good results were achieved by agitating PC (50 ml) on a flat-bed agitator at 70 cycles per minute. Inconsistent results were observed in autologous studies with two other forms of agitation. We conclude that the use of PL-732 will permit the satisfactory storage of PC for 5 days at 22°C. Storage of PC at 4°C has not been evaluated in this container.

Chemotherapy-resistant cells cause disease recurrence in a significant proportion of patients with acute leukemia treated with autologous stem cell transplantation due to the lack of immune-mediated effects which contribute significantly to the prevention of post-treatment disease recurrence. This conclusion is based on the observation that relapse after high dose chemotherapy supported by a stem cell transplant from a twin donor is 3-4 times higher than after transplant from an allogeneic donor. This anti-leukemic mechanism of transplanted donor cells has been termed graft-versus-leukemia (GVL) effect, and efforts are being directed toward utilizing such an immune-mechanism after autologous transplantation. Since interleukin-2 (IL-2) can induce remissions in selected patients with advanced leukemia, it has become a candidate cytokine to be used in attempts to introduce GVL after autologous stem cell transplantation. Here we review the available clinical data with IL-2 and critically evaluate whether IL-2 has a place as adjunct treatment to prevent relapse after autologous transplantation for acute leukemia.

About 30% of adults with acute lymphoblastic leukemia (ALL) and 20% to 40% of children and adults with acute myelogenous leukemia (AML) never achieve remission, even with intensive chemotherapy. Most die of resistant leukemia, often within 6 months or less. In this study of 126 patients with resistant ALL or AML, allogeneic bone marrow transplants from HLA-identical siblings produced remissions in 113 of 115 (98%) evaluable patients. The 3-year probability of leukemia-free survival was 21% (95% confidence interval, 15% to 29%). Leukemia-free survival was similar in ALL (23%, 12% to 40%) and AML (21%, 14% to 31%). Only 3 of 27 patients at risk relapsed more than 2 years posttransplant. © 1992 by The American Society of Hematology.

Obstructive lung disease (OLD) has been described as a significant complication after allogeneic bone marrow transplantation (BMT). The incidence of OLD in adults appears to be low (~3%), but there is little data for children. We analyzed 89 consecutive pediatric allogeneic BMTs, ≥1.5 years post-BMT, performed at British Columbia's Children's Hospital from 1980 to 1992 for evidence of OLD. Diagnosis of OLD was based on clinical findings (nonproductive cough, wheezing, and dyspnea with no evidence of infection), pulmonary function tests (FEV1< 80% and FEF25-75% < 60% predicted), lung biopsy, and computed tomography scan. Sixty-seven of the 89 children evaluated survived 2:90 days and were classified as at risk for OLD. Thirteen of 67 (19.4%), developed OLD, 3 of which were transient. The development of OLD was strongly associated with the following high-risk groups: chronic graft-versus-host disease (GVHD) (37.1% OLD), increased donor age, acute GVHD, and either mismatched related or matched unrelated donor transplants. No correlation was found with methotrexate prophylaxis for GVHD, total body irradiation, or cytomegalovirus reactivity in either donor or recipient and the development of OLD. Further analysis of only children with chronic GVHD showed that liver involvement by GVHD before the onset of OLD (57.9%) was the only other significant predictive factor. We observed an overall increased prevalence of OLD in children compared with that previously reported in adults. Further studies are required to confirm whether age is a risk factor for development of OLD after allogeneic BMT.

Macrophage inflammatory protein‐1α (MIP‐1α) is a chemokine that can inhibit the cell cycle progression of both primitive haemopoietic and epidermal progenitor cells. This property could potentially be exploited to attenuate both the myelosuppressive effects of chemotherapy as well as mucositis. We evaluated both the biological and clinical effects of BB‐10010, a genetically engineered variant of MIP‐1α, in patients with malignant lymphoma or breast cancer receiving high‐dose etoposide (VP 3.6 g/m2) and cyclophosphamide (Cy 200 mg/kg). 52 patients were randomized to one of three cohorts. Cohort A received no BB‐10010; cohorts B and C received 10 μg/kg and 100 μg/kg of BB‐10010, respectively. All patients received post‐chemotherapy G‐CSF. BB‐10010 was well tolerated. There were no significant differences between groups in recovery to an ANC > 0.5 × 109/l, 1 × 109/l or 1.5 × 109/l, the number of days with an ANC < 0.5 × 109/l, days to a platelet count >50 × 109/l or 100 × 109/l, or the incidence and severity of mucositis. There was no evidence of any effect of BB‐10010 on colony‐forming cell (CFC) or long‐term culture‐initiating cell (LTC‐IC) mobilization, cycling activity in the marrow or on chemotherapy‐induced changes in CFC or LTC‐IC number both of which were in the normal range by 22 d after completion of the chemotherapy. To our knowledge this is the first report of a myelointensive regimen having no apparent long‐term effect on the LTC‐IC compartment. In summary, BB‐10010 is safe when used in patients receiving high‐dose therapy but has no effect on reducing the toxicity of such therapy.

Previous studies indicate that human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells. Cells of this nature can initiate and maintain leukemic cell growth in both long-term cultures and nonobese diabetic/severe combined immune-deficient mice. To characterize the biology of primitive AML cells, gene expression screens were performed with 7 primary AML and 3 normal specimens. For each sample, stem cell populations (CD34+/CD38−) were isolated and used to synthesize radiolabeled complementary DNA (cDNA). AML vs normal probes were then hybridized to cDNA arrays containing genes related to cancer and apoptosis. Of approximately 1400 genes analyzed, 2 tumor-suppressor genes were identified that were overexpressed in all 7 of the AML CD34+/CD38−cell populations: death-associated protein kinase and interferon regulatory factor 1. Expression of each gene was confirmed by reverse-transcription polymerase chain reaction and immunoblot analysis. It is proposed that tumor-suppressor proteins play a role in the biology of primitive AML cells.

Previous studies indicate that human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells. Cells of this nature can initiate and maintain leukemic cell growth in both long-term cultures and nonobese diabetic/severe combined immune-deficient mice. To characterize the biology of primitive AML cells, gene expression screens were performed with 7 primary AML and 3 normal specimens. For each sample, stem cell populations (CD34+/CD38−) were isolated and used to synthesize radiolabeled complementary DNA (cDNA). AML vs normal probes were then hybridized to cDNA arrays containing genes related to cancer and apoptosis. Of approximately 1400 genes analyzed, 2 tumor-suppressor genes were identified that were overexpressed in all 7 of the AML CD34+/CD38−cell populations: death-associated protein kinase and interferon regulatory factor 1. Expression of each gene was confirmed by reverse-transcription polymerase chain reaction and immunoblot analysis. It is proposed that tumor-suppressor proteins play a role in the biology of primitive AML cells.

No relevant conflicts of interest to declare.

High dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is standard consolidative treatment for patients with Hodgkin’s or non-Hodgkin’s lymphoma that persists or recurs following standard chemotherapy and/or radiation (Philip, T et al,1995; Linch, D.C et al, 1993). The BEAM regimen (Carmustine (BCNU), Etoposide (ETP), Cytarabine (Ara-C), and Melphalan (Mel)) is often utilized as the conditioning regimen for AHSCT (Mills, W et al, 1995). Traditionally, patients are admitted for conditioning and remain hospitalized until hematologic recovery. We implemented a protocol for outpatient administration of BEAM followed by admission for stem cell infusion and post-transplant supportive care. To evaluate safety and consequences of outpatient conditioning, we compared outcomes of lymphoma patients receiving outpatient BEAM (OP BEAM) to a previous cohort receiving inpatient BEAM (IP BEAM) chemotherapy prior to AHSCT.

Prolonged intervals of thrombocytopenia are common after stem cell transplantation, and platelet transfusions are the only temporary therapy before engraftment. Risk of thrombocytopenia is greater in patients receiving total body irradiation (TBI) in their conditioning regimen. Eltrombopag is a small-molecule, nonpeptide oral agent that functions as an agonist of the thrombopoietin receptor. It is approved by the FDA for the treatment of chronic idiopathic thrombocytopenic purpura and is being developed as a treatment for thrombocytopenia of other various etiologies. We report updated results of a Phase I clinical trial assessing the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of once daily oral eltrombopag in patients undergoing stem cell transplantation with a conditioning regimen containing TBI ≥ 400 cGy.A Phase I dose-escalation clinical trial was conducted to evaluate the safety and PK of eltrombopag at 4 different dose levels: 75, 150, 225, and 300 mg given once daily for 27 days, starting 24–48 hours post stem cell transplantation to eligible patients ≥18 years old. Patients with various indications for stem cell transplantation, KPS ≥70%, and TBI ≥ 400 cGy were eligible. Patients receiving either an autologous (Auto) or allogeneic (Allo) stem cell transplantation from a sibling, related donor, or matched unrelated donor (MUD) were eligible. Stem cells from peripheral blood (PBSC) or bone marrow were permitted; however, cord blood stem cell transplantation was not permitted. Patients at risk of thromboembolism or with a history of thromboembolic disease in the preceding 6 months were excluded. PK sampling was obtained over a 24 hour period after the first dose of eltrombopag as well as during the second week of treatment (steady-state).As of August 1 2012, a total of 19 subjects (7 AML, 4 lymphoma, 1 CML, 1 MDS, 1 myelofibrosis, 2 ALL, 1 APML, 1 Biphenotypic Leukemia and 1 CLL/SLL) were enrolled, and 15 completed protocol treatments. All 19 were PBSC transplants with 12 MUD, 6 Allo and 1 Auto. Three subjects were completed at each dose level up to 225 mg with six completing treatment at the highest dose of 300mg. Four subjects were replaced because drug compliance was less than 75%. To date, 11/19 are alive while 8/19 have died (3 related to graft vs. host disease (GVHD), 3 Infection-related and 2 related to disease progression (f/u interval: 5.7 – 30 months). No dose limiting toxicities (DLTs) have been observed. The most common adverse events (AEs) up to the 300 mg dose level were related to standard stem cell transplantation, which included low blood counts, fatigue, headache, diarrhea, nausea, peripheral edema, hypoalbuminemia, hyperglycemia, hypocalcemia, and hypomagnesemia. Possibly drug-related AEs were dry skin, rash, elevated creatinine, and hypokalemia; these were all grade 3 or less. There were 12 severe AEs observed in 8 subjects, which included infection (3/19), pulmonary embolism (PE) (1/19), acute renal failure (3/19), gastrointestinal (2/19), acute respiratory distress syndrome (1/19), pericarditis (1/19) and GvHD skin rash (1/19). Most SAEs were considered related to stem cell transplant, except one subject at 75 mg with PE possibly related to eltrombopag, but also possibly related to stem cell transplant and cancer diagnosis. The PE occurred 9 days after stopping eltrombopag at which time platelet count was 252K. Time to platelet engraftment and number of platelet transfusions were also documented for each enrolled patient. Median time to platelet engraftment for all subjects on this study was 16 days. PK data are summarized in Table 1 and Figure 1. A dose-dependent increase in plasma exposure of eltrombopag was observed; although some saturation of absorption is evident at the 300 mg dose level. (Figure 1).27-day once daily dosing of eltrombopag to enhance platelet recovery for post-transplant thrombocytopenia is well tolerated, with no DLTs observed up to the 300 mg dose level. Most AEs were transplant related. PK showed proportional plasma concentration up to 225 mg daily dosing, with some saturation of drug absorption above 225 mg.Liesveld: Eisai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Ariad: Honoraria. Off Label Use: Eltrombopag not approved post-transplant. Dawson:GlaxoSmithKline: Employment.

Melphalan 200 mg/m2 has remained the standard of care as a preparative regimen for patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Higher doses of melphalan are associated with unacceptable gastrointestinal toxicity. Preliminary studies suggested that administration of the cytoprotective agent amifostine could protect patients with MM undergoing ASCT from excessive toxicity from doses of melphalan as high as 280 mg/m2. We conducted a prospective, multicenter, randomized trial comparing melphalan 200 mg/m2 (mel200) v. 280 mg/m2 (mel280) using amifostine pretreatment in patients with MM undergoing ASCT.The primary endpoints of the trial were grades 3–4 toxicity and near complete response (nCR) or better 60–120 days after ASCT. Eligibility included age ≤70, no prior ASCT, acceptable organ function, measurable monoclonal protein in serum or urine by protein electrophoresis and adequate stem cells for ASCT. Patients were stratified by ß2 microglobulin >5 at study entry, del 13 by FISH and response (<≥PR) to the last cytoreductive regimen prior to ASCT. Amifostine 710 mg/m2, with appropriate hydration and pre-medications, was given by intravenous push the day prior to and again 15 minutes prior to mel200 or mel280 given as a single infusion over 30 minutes.Of 134 patients consented, consent was withdrawn for 4 patients, 1 patient who had abnormal renal function, one after a hypotensive episode following the first amifostine infusion, and 2 for other reasons. Manageable toxicities associated with amifostine infusion were hypotension (18), hypertension (3), dizziness (4), and nausea (33). Of 130 patients, 64 randomized to 200 mg/m2 and 66 280 mg/m2; 26 had del 13, and 55 had 5. Their median age was 60 years (range 42–70), they had received a median of 2 regimens (range 1–8) prior to stem cell collection, and 28 (22%) had received local radiation prior to ASCT. A total of 21 patients had grade 3–4 toxicity, 11% who received mel200 and 21% who received mel280 (p=0.11). Four of the seven in the mel200 group had a single grade 3–4 toxicity, while 3 had 2 grade 3–4 toxicities. Eight of the 14 in the mel280 group had a single toxicity, and 6 patients had two toxicities. By organ systems respectively, for mel200 v. mel 280, they were cardiac 1 v. 0, gastrointestinal 6 v. 11, mucositis 3 v. 7, CNS 0 v. 1 and pulmonary 0 v. 1. Hospitalization occurred in 94 patients 106 times; among the group receiving mel200 40 (62%) patients were hospitalized compared to 54 (82%) in the mel280 group, p=0.01. The mean total days of hospitalization were 7.3 and 10.2 days for mel200 and mel280, respectively (p=0.06); 3 patients in the mel200 group required 2 hospitalizations, 2 were admitted 3 times, while 5 patients in the mel280 group were admitted twice. The primary reasons for hospitalization for patients in receiving mel200 v mel280, respectively were, conditioning and transplant 9 v. 12, mucositis 2 v. 12, nausea and vomiting 8 v. 12, fever and infection 21 v. 18 and other 6 v. 6. No treatment related deaths occurred in this study. Responses following ASCT by EBMT criteria were for mel200 v. mel 280, respectively, ≥nCR 22% v. 39%, p=0.04, ≥PR 56% v. 70%, p= 0.09. The estimated progression-free survival at 1 and 3 years was 86% and 48%, respectively, for mel200 and 77% and 53%, respectively, for mel280. The risk of failure (death or progression) was similar (hazard ratio (mel280 vs. mel200) 1.12; 95% CI 0.64–1.95, p=0.69). The median follow-up among patients alive without progression was 524 and 555 days for mel200 and mel280, respectively. The estimated overall survival at 1 and 3 years was 96% and 83%, respectively, for mel200 and 89% and 73% for mel280, respectively. The risk of death was similar in the mel280 group relative to mel200 (HR=0.86; 95% CI 0.40–1.84; p=0.70).In summary the combination of amifostine and mel280 was generally well tolerated although there were more grade 3–4 regimen-related toxicities, primarily mucositis and gastrointestinal. This resulted in slightly more frequent and longer hospitalizations (by 3 days) compared to amifostine + mel200. Mel280 resulted in a higher major response rate (CR + nCR) and warrants further study.Off Label Use: amifostine.

Decitabine (5-aza-2'-deoxyctiidine) has demonstrated single agent activity in newly diagnosed acute myelogenous leukemia (AML). Complete response rates are low, however, and this agent has not been extensively studied in settings of relapsed or refractory disease where treatment responses are generally short in the absence of allogeneic stem cell transplantation. Most AML cases have activation of the mTOR pathway as evidenced by expression of phosphorylated p70S6 kinase or phopho-4EBP1. Since inhibitors of the mTOR pathway such as the tuberous sclerosis genes (TSC1 and TSC2) are hypermethylated in some cases of AML and there is evidence that decitabine may inhibit the PI3K/Akt pathway often activated after mTOR inhibition, we conducted a phase I study utilizing decitabine (DAC) followed by the mTOR inhibitor rapamycin in patients with relapsed/refractory AML to assess safety and feasibility.Patients ≥ 18 years of age with non-M3 AML with relapsed or refractory disease were eligible for this protocol. Patients who had relapsed after allogeneic stem cell transplant were eligible if they did not have active graft vs. host disease >grade 1 of skin. Patients received DAC 20 mg/m2 intravenously daily for 5 days followed by rapamycin from day 6 to 25 at doses of 2mg, 4mg, and 6 mg/day in a 3+3 dose escalation design. Cycles were 28 days in duration, and in the absence of overt progression of disease, patients could receive up to 6 cycles of therapy. A marrow aspirate was performed at day 5 to assess effects of single agent decitabine on mTOR and Akt pathway mediators. Bone marrow responses were assessed after cycles 1 and 3.Thirteen patients were treated, and 12 are available for safety evaluation. The median age of patients is 64 years (range 46–78). Median marrow blast percentage at enrollment was 35% (range 6–83%). In the 2 mg dose cohort, 1 patient had disease progression before completion of cycle 1 and another patient in the first cohort had a history of prolonged neutropenia at the time of enrollment and experienced reversible grade 3 mucositis, which was deemed a DLT. Three more patients enrolled at this dose, and no further DLTs were observed, allowing dose escalation to the 4 mg and 6 mg cohorts. The MTD has not yet been reached. Reversible grade 2–3 mucositis occurred in 7 patients, but no other recurrent non-hematologic toxicities were seen. On the 2 mg cohort, all patients achieved therapeutic rapamycin levels (5–15 ng/ml) during the first cycle, and in 5/7 patients, the therapeutic level was achieved within 4 days of beginning rapamycin. In the 2 mg cohort, no cumulative increase in rapamycin levels occurred over subsequent cycles (4/7 completed >1 cycle). In the 4 mg cohort, one patient had an elevated level at day 9, and one patient on concomitant voriconazole had supra-therapeutic levels at day 16 and day 23. At the end of one cycle, 4 patients demonstrated disease progression, 5 had stable marrow blasts, and 4 demonstrated a decline in marrow blast percentage. Median survival to date is 6 months (range 1 to 15+ months). Two patients proceeded to allogeneic stem cell transplant, and one patient who relapsed shortly after stem cell transplant survived 4 months and demonstrated stable donor chimerism during that time. As assessed by Western blotting in 9 patients with evaluable samples at baseline, 87% of these cases expressed phospho (p)-4EBP1 at diagnosis, 56% p70S6K, 67% peIF4E, and 44% pAKT. In the 7 patients with Western blot samples evaluable at the end of cycle 1, 3 had decreases in p4EBP1 after the first cycle, and 4 had increased expression. Of the 7 evaluable patients, only 3 expressed baseline p70S6K, and this decreased in 2 and was unchanged in 1 patient.The combination of decitabine and rapamycin can be safely administered to patients with relapsed/refractory AML. Based on this phase I data, a phase II cohort to define efficacy can be conducted at the 2 mg rapamycin dosing given the therapeutic rapamycin levels demonstrated at this dose. Effects on mTOR mediators and on AKT can be serially assessed and are variable. Correlation with clinical response will require a phase II study. This trial is registered at clinical trials.gov as NCT00861874.Liesveld: Eisai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Ariad: Honoraria. Off Label Use: This is a phase 1 study to see if rapamycin is safe in AML.

Abstract 2009

Abstract 3549

Abstract 219

Prolonged intervals of thrombocytopenia are common after hematopoietic stem cell transplantation (HSCT), and platelet transfusions are the only effective therapy. Risk of thrombocytopenia is greater in patients (pts) receiving total body irradiation (TBI) in their conditioning regimen. Eltrombopag (ePag) is a small-molecule, nonpeptide oral agent that functions as an agonist of the thrombopoietin receptor. It is approved by FDA for the treatment of chronic ITP and is being developed as a treatment for thrombocytopenia of other various etiologies. We report results of an ongoing Phase I clinical trial assessing the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of once daily oral ePag in pts undergoing HSCT with a conditioning regimen containing TBI ≥ 400 cGy.A Phase I dose-escalation clinical trial was conducted to evaluate the safety and PK of ePag at 4 different dose levels: 75, 150, 225, and 300 mg, once daily for 27 days, starting 24–48 hours post HSCT to eligible pts ≥18 yrs old. Pts with various indications for stem cell transplantation, KPS ≥70%, and TBI ≥ 400 cGy were eligible. Pts receiving either an autologous (Auto) or allogeneic (Allo) HSCT from a sibling, related donor, or matched unrelated donor (MUD) were eligible. Stem cells from peripheral blood (PBSC) or bone marrow were permitted; however, cord blood transplant was not permitted. Pts at risk of thromboembolism, or with a history of thromboembolic disease in the preceding 6 months, were excluded. PK sampling was obtained over a 24 h period after the first dose of ePag, as well as during the second week of treatment (steady-state).As of July 1 2011, a total of 10 subjects (4 AML, 2 lymphoma, 1 CML, 1 MDS, 1 myelofibrosis, and 1 CLL/SLL) were enrolled, and 9 completed protocol treatments. All 9 were PBSC transplants with 6 MUD, 2 Allo and 1 Auto. Three subjects were completed at each dose level up to 225 mg. Enrollment is continuing at the 300 mg dose level. To date, 6/9 are alive while 3/9 died of non-relapse related causes (CMV pneumonitis and respiratory failure in 1, and steroid refractory GI GvHD in 2, f/u interval: 4.4 – 6.9 mo). No dose limiting toxicities (DLTs) have been observed. Most common adverse events up to 225 mg dose level were related to standard stem cell transplantation, which included low blood counts, fatigue, headache, diarrhea, nausea, peripheral edema, hypoalbuminemia, hyperglycemia, hypocalcemia, and hypomagnesemia. There were 9 SAEs observed in 5 pts, which included infection (3/9), pulmonary embolism (PE) (1/9), acute renal failure (2/9), gastrointestinal (2/9), and ARDS (1/9). Most SAEs were considered unrelated or unlikely related to ePag treatment except for the PE, which was considered possibly related to ePag but not considered a DLT. This subject had other risk factors for PE and the PE occurred 9 days after ePag had stopped at a platelet count of 252K. Time to platelet engraftment and number of platelet transfusions were documented for each enrolled pt. PK sampling demonstrated a dose dependent increase in plasma concentration of ePag (Figure 1). PK parameters for the 75, 150, and 225 mg dose levels are summarized in Table 1.27-day once daily dosing of ePag to enhance platelet recovery for post-transplant thrombocytopenia is well tolerated, with no DLTs observed up to the 225 mg dose level to date. Most AEs were transplant related. PK and the plasma exposure of ePag appears dose proportional over the studied dose range after single-dose and steady-state administration. Once-daily administration of up to 225 mg ePag for the transplant population receiving TBI ≥ 400 cGy as part of the conditioning regimen appears to be safe and well tolerated.The study is supported by Biomedical Advanced Research and Development Agency (BARDA), and by GlaxoSmithKline who also provided the study drug.Off Label Use: Promacta (eltrombopag) is an oral TPO Receptor agonist approved for the treatment of chronic ITP. The study being reported in this abstract is a phase I MTD study to evaluate eltrombopag for promoting thrombopoiesis in patients undergoing Stem Cell Transplantation after Total Body Irradiation. Dawson:GlaxoSmithKline: Employment.

Abstract 3295This icon denotes a clinically relevant abstract

No relevant conflicts of interest to declare.

Reduced-intensity conditioning and allogeneic stem cell transplant (RIST), offers an alternative for patients with hematologic malignancies who are not candidates for myeloablative conditioning (MAC) due to the high risk of treatment related toxicity. Despite the reduced “intensity” of RIST preparative regimens, a high incidence of early treatment-related morbidity and mortality persists. The TUFTS regimen represents one such RIST regimen and consists of extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation. The hematopoietic cell transplantation-specific Comorbidity index (HCT-CI) has been reported as an informative predictor of post-transplant survival recipients of fludaribine-based conditioning and SCT, however, its usefulness in patients undergoing allogeneic transplant using alternative conditioning regimens has not been determined. The specific aim of this study was to evaluate the relationship between HCT-CI scores and survival after TUFTS conditioning.The study employed a retrospective, description design. The sample consisted of adults who underwent allogeneic SCT after a TUFTS preparative regimen at the University of Rochester Medical Center from 2001–2006. Indications for transplant included both myeloid and lymphoid malignancies; recipients of stem cells from either related or unrelated donors, and recipients of prior autologous transplant were also included. The TUFTS conditioning was administered as follows: photopheresis on days -6 and -5, pentostatin 4 mg/m2 on days -4 and -3, reduced dose fractionated total body irradiation to a total of 400–600cGy on days -2 and -1, and SCT on day 0. Sixty-three subjects met the study criteria and we collected study defined and de-identified clinical data from the medical records. Subjects received either tacrolimus and mycophenolate mofetil (MMF) or low-dose methotrexate, or sirolimus and MMF as prophylaxis for graft-versus-host disease. For this study, overall survival (OS) was defined as the time elapsed from date of SCT to the date of death. The HCT-CI score was inclusive of 17 comorbid factors and was calculated for each subject. Total HCT-CI scores were trichotomized three categories; low, intermediate, and high.All statistical analyses were performed utilizing SPSS version 15 with an alpha significance set at 0.05. Mean OS was 534.4 days (+/− 515.5). The median survival was 303 days (range 10 to 1673). Subjects were grouped into low (n=7), intermediate (n=20), and high (n=36) HCT-CI score groups. Median survival for each group was 1127, 645, and 181 days, respectively. The Kruskal-Wallis Test was used to evaluate the relationship between trichotomized HCT-CI groups and OS which was re-coded into 6 time-based categories. Mean rank scores for survival were significantly related to HCT-CI categories (p=0.01). A median test on these same variables was also significant where 85.7% (low), 60% (intermediate), and 27.8% (high) of subjects survived to the median survival time point (p=0.004). A Kaplan-Meier survival analysis showed an OS of 46%; HCT-CI group stratification of the survival curve demonstrated that the high CI score group had the lowest survival with a median survival of 202 days (95% CI 64.7, 339.3).Our findings contribute to the validity of HCT-CI as a valuable instrument for assessing risks that impact survival due to comorbidities in patients conditioned with TUFTS prior to SCT. In this sample, OS was inversely proportional to HCT-CI score and median survival was less than 7 months in the high risk group. To our knowledge, this is the first study that has found a statistically significant correlation between survival and HCT-CI groups in subjects conditioned with TUFTS to treat multiple types of malignancies. We conclude that the HCT-CI assessment should be routinely performed to facilitate decision making with patients who are ineligible for MAC and SCT. This assessment will further add to discussions regarding the risks/benefits of RIST, and decision making with patients in the high risk category who are likely to have low actuarial survival. Further prospective studies are needed to confirm these findings and to evaluate the HCT-CI as a predictor of survival in patients with specific malignancies, different histologic/molecular disease-related factors, varying duration of relapse, and remission status at SCT.No relevant conflicts of interest to declare.

The optimal strategy to mobilize hematopoietic stem cells into peripheral blood for collection has not been defined, and some patients do not successfully mobilize. Failure to harvest the desired number of CD34+ cells results in emotional disappointment for the patient and ineffective utilization of resources. In this study we analyzed various factors influencing CD34+ yields during stem cell collection in patients being considered for autologous transplantation whose peripheral blood CD34+ analysis triggered stem cell collection (usually >10/μ L), and we determined thresholds for successful collection in a single apheresis session.Retrospective chart review of 244 consecutive patients who underwent stem cell collection at the University of Rochester between 2005 and 2008 was conducted. Cells were collected via Cobe semi-automated protocols. For each of the patients, diagnosis, age, gender, type of infusion, marrow status, number of prior chemotherapy treatments, mobilization regimen, CD34+ count/μ l on first day, CD34+/kg after first apheresis, total time of apheresis and volume processed (liters) were recorded. The various mobilization regimens utilized were 1)GCSF, 2)CHEMO (salvage therapy with DHAP, ESHAP, RICE) with GCSF, 3)cyclophosphamide with GCSF, 4)AMD3100 (Plerixafor) with GCSF, and 5) GCSF with GMCSF. The marrow status was defined as no involvement, mild involvement (10-20%), and moderate involvement (>20%). Another factor considered was the number of prior chemotherapy regimens, and the total number of apheresis cycles required to reach targeted yields was recorded. All statistical analyses were conducted using SAS 9.2. All tests were two-sided with p-values ≤ 0.05 considered significant.Analysis revealed a positive linear relationship between the log of initial CD34+ counts and the log transformed number of CD34+ cells/kg on the first day of apheresis (R2= 0.57, p < 0.001). Multivariate analysis suggested that both CD34+ count per μ L blood prior to first apheresis (p < 0.001) and time on the machine (p = 0.08) were positively associated with CD34+ end yield after adjusting for age and gender. A similar analysis on all the mobilization regimens revealed statistical significance for a higher initial CD34 cell count/μ l predicting a higher apheresis yield (p < 0.001). Also, for each of the major diagnoses (AL, HL, MM. NHL), there was a positive relationship between peripheral CD34+ cells/μ l prior to apheresis and CD34+ cells/kg after first apheresis yield (p < 0.001) Another objective of this study was to see if there is a threshold number of CD34+ cells/μ l blood that would predict for lymphoma patients (combined HL, NHL) that at least 4 × 106 CD34+ cells/kg would be reached on the first day of apheresis, and a similar threshold for the multiple myeloma patients (MM) to reach 6 × 106 CD34+ cells/kg on first day. Receiver operating characteristics (ROC) curves were used to determine an optimal initial CD34+ count cutoff and the odds ratio of achieving such a threshold between the two groups was assessed using logistic regressions. Based on the cutoff of 48.3 cells/μ L, lymphoma patients were classified into two groups depending on their initial CD34+ count greater or less than this cutoff. The odds of reaching at least 4 × 106 CD34+ cells/kg on the first day of apheresis when the initial CD34+ count was greater than 48.3 cells/μ L were 24.4 times than those with the initial CD34+ count less than the cutoff (p<0.001). Similarly, for multiple myeloma patients, to reach a threshold of 6×106 CD34+ cells/kg on the first day of apheresis, a cutoff of 90.5 cells/μ L was established. The odds of reaching at least 6×106 CD34+ cells/kg on the first day of apheresis with initial CD34+ count greater than 90.5 cells/μ L were 19.3 times than those with initial CD34+ count less than the cutoff (p<0.001)This study confirmed that the initial peripheral CD34+ count was a good predictor of the CD34+ cells/kg yield on the first day of apheresis, irrespective of disease type or mobilization regimen utilized. A threshold of 48.3 CD34+ cells/μ L for lymphoma patients and 90.5 CD34+ cells/μ L for myeloma patients was established to reach goals of least 4 × 106 CD34+ cells/kg and 6 × 106 CD34+ cells/kg respectively with a single apheresis. These thresholds or others calculated similarly for other collection goals could potentially aid in coordination of apheresis resource utilization.No relevant conflicts of interest to declare.

Conditioning regimens utilized to prepare patients for stem cell transplantation uniformly result in suppression of marrow function, leading to prolonged recovery of neutrophils and platelets. Neutropenia increases the risk of infection while thrombocytopenia and prolonged platelet engraftment time can result in increased risk of bleeding as well as morbidities associated with subsequent transfusions. The variations in duration of cytopenias are affected by multiple factors including regimen intensity and other clinical factors.In this retrospective study of consecutive patients undergoing stem cell transplantation at the University of Rochester between 2005 and 2009 for radiation—containing regimens, and between 2007 and 2009 for non-radiation containing regimens, we assessed the relationship between platelet engraftment times and source of stem cells, type of graft, and the effect of conditioning regimen intensity. Platelet engraftment was defined per standard CIBMTR definitions – platelet engraftment occurred at the first of 3 days of platelet count >20,000/μ L without platelet transfusions for 7 days, and/or the first day of platelet count >100,000/μ L. Guidelines for transfusion support stipulated a 10,000/μ L threshold for platelets in the absence of bleeding and a hemoglobin of 8.0 g/dL for red cells in the absence of other symptoms. The time to platelet engraftment and the number of platelet transfusions required prior to engraftment were analyzed in those patients with platelet nadir <20,000/μ L. Among 507 adult patients (older than 18), 49 did not have a platelet count nadir, and these patients were excluded from the analyses. Of those, 29 had TBI regimens, 16 of which utilized 200 cGy and 13 had radiation dosage 400–800 cGy. 280 of 458 adult patients who had nadir of platelets received conditioning regimens with chemotherapy alone, and 178 received regimens including total body irradiation (TBI). Disease diagnoses for which transplantation was performed in the 458 cases with platelet nadir included ALL (n=34), AML (n=112), CLL (n=17), CML (n=17), NL/NHL (n=189), MM (n=69), and others (n=20).The 25th percentile, median and 75th percentile (days) for the time to platelet engraftment in days, calculated using the method of cumulative incidence for the non-TBI and TBI containing conditioning regimens, are shown below:With conditioning regimens containing TBI or with chemotherapy alone (non-TBI), both donor type (auto, allo, or matched unrelated donor) and graft type (marrow, PBSCs, or umbilical cord blood) had significant effects on platelet engraftment time, with the longest engraftment times occurring in cord blood transplants. With both TBI and non-TBI conditioning regimens, donor and graft type significantly affected platelet transfusion numbers (p<.0001). Radiation dose-level of TBI had a significant effect on platelet engraftment (p=0.004) and the number of platelet transfusions required. Of the 458 patients who had nadir of platelet counts, 58.7% of the population was female. Gender did not affect the platelet engraftment time for all patients, but affected the platelet and red blood cell transfusion frequencies in TBI patients. Female TBI patients received significantly more platelet transfusions (p<.0001) up to 100 days and significantly more RBC transfusions up to 30 days (p=.007), after which no significant differences were noted up to 100 days (p=.24).With non-TBI conditioning regimens, gender did not affect the number of platelet transfusions, but females received significantly more red cell transfusions up to 100 days post-transplant (p=0.003).These data indicate that times to platelet engraftment in stem cell transplant patients in the era of PBSC and reduced-intensity transplant regimens remains longer than two weeks in cases where conditioning regimens result in platelet nadir. This is associated with considerable utilization of transfusion resources. The increased need of RBC and platelet transfusions in females receiving TBI containing regimens and red cells in non-TBI conditioning cases despite similarity in platelet engraftment times is of interest, and underlying causes remain undetermined.No relevant conflicts of interest to declare.

The transformation of indolent non-Hodgkin's lymphoma (NHL) to a more aggressive histology remains a therapeutic challenge. For younger patients with a favorable performance status, high-dose therapy and autologous stem cell transplantation (HD-ASCT) results in a prolonged progression-free survival (PFS) in a substantial subset, based upon retrospective single and multi-institutional experiences. Rituximab improves PFS and overall survival (OS) in both follicular and aggressive NHL when combined with chemotherapy. However, the impact of prior rituximab on outcome of HD-ASCT for transformed NHL has not been elucidated.We therefore analyzed consecutive patients with indolent NHL (including follicular lymphoma and marginal zone lymphoma) who developed histologically confirmed transformation to diffuse large B-cell lymphoma (DLBCL) and subsequently underwent HD-ASCT at the University of Rochester Medical Center between 1998 – 2009. Patients who transformed within 6 months of the diagnosis of indolent lymphoma were excluded from the study. Progression free survival (PFS) was defined as time from HD-ASCT to date of disease relapse, progression, or death due to any cause. Kaplan-Meier survival curves were estimated, and differences in PFS between those who received rituximab prior to transformation versus those who were rituximab-naïve at transformation were assessed using the log-rank test.19 patients were identified, (10 female) who received rituximab-containing therapy at transformation. The median age at HD-ASCT was 59 years (range 40–66). Patients were treated with a median of 3 (range 1–9) chemotherapy regimens prior to HD-ASCT. Median time from the diagnosis of indolent lymphoma to transformation was 55 months (range 8–276). Conditioning regimens at HD-ASCT were BEAM (N=15), BEAC (N=1) and Cy/TBI (N=3). With a median follow-up of 47 months, the 2-year PFS was 58% and the 2-year OS was 84%. There were no treatment-related mortalities. Seven patients relapsed after HD-ASCT (2 with indolent histologies and 5 with DLBCL); 3 of these patients have died. Two additional patients have died of myelodysplastic syndrome-acute myeloid leukemia after HD-ASCT. Eight patients did not receive rituximab for indolent disease prior to transformation; this group had a significantly better PFS at 2 years (86% vs 36%, p = 0.049) compared to 11 patients who were treated with rituximab for indolent disease prior to ASCT. The patients who did not receive rituxmiab prior to ASCT had similar characteristics to patients who received rituximab, except that the time from indolent diagnosis to transformation was longer in the rituximab-naïve group (90 months vs 39 months).HD-ASCT remains an effective therapeutic option for transformed NHL in the rituximab era. However, transformed patients exposed to rituximab prior to HD-ASCT appear to have inferior outcomes, similar to the experience of patients with de novo NHL treated with rituximab prior to HD-ASCT in the recently reported CORAL study (JCO, published online ahead of print July 26, 2010). Patients who transform after rituximab-containing therapy may represent a higher risk group of patients with a unique biology, who may benefit from novel conditioning and maintenance regimens in the setting of HD-ASCT.No relevant conflicts of interest to declare.

Stem cell transplantation, better supportive care, and the introduction of “novel agents”, particularly proteosome inhibitors and IMIDS, have improved survival in myeloma. However it is unclear if this improvement is uniform across various demographic subgroups. We present our analysis of a national database which still reveals significant disparities in the outcome of myeloma patients depending on their geographic location and race.Data on incidence and mortality was obtained from SEER database. Data on individual state myeloma rates was obtained from U.S. Cancer Statistics Working Group. Graphs were obtained from Cancer Mortality Maps and Graphs (NCI). Valuable measures of trends in cancer epidemiology include Annual Percent Change (APC) and Joinpoint analyses (JPC) which measure trends over a long period of time. Information regarding APC and JPC was obtained from the SEER Cancer Statistics Review. Disparities were calculated by the SEER health disparities calculator for differences in mortality across racial groups. Differences between the cohorts dichotomized at the introduction of novel agents (before and after 2000) were also calculated. Absolute mortality difference was assessed by the “Between Group Variance” (BGV). Relative disparity outcome across the 2 cohorts was assessed by “mean log deviation” (MLD) and the Theil index.Overall age-adjusted mortality rate was 3.6/100,000 (2002-2006). 5-year relative survival rate was 37% (1999–2005). JPC trends stratified by race indicate a significantly increased JPC modeled incidence of myeloma in blacks to 12.4/100,000 until 1994, declining to 11.2/100,000 in 2006. The mortality rate, with a survival lag effect, also followed the trend in blacks, reaching a peak in 1996 at 7.9/100,000, whereas in whites, the JPC modeled trend was comparatively stable. Significant geographical variation in both incidence and mortality rates of myeloma were observed between different states (see maps). Washington DC and Alabama had the highest mortality rates of 5.3 (SE 0.43) and 4.4 (SE 0.14) per 100,000, whereas Hawaii and Florida had the lowest mortality rates of 2.25 (SE 0.18) and 3.09 (SE 0.05) per 100,000 respectively. The adjusted incidence rate within a state did not significantly correlate with its adjusted mortality rate. State wise comparisons were calculated between black and white races for mortality rates. Differences were found between mortality of blacks and whites in most of the states, which remained nearly constant across both the pre and post novel agent time cohorts. For example, in Washington DC the 1992–2000 and the 2000–2006 cohorts represented a mortality rate of 2.7 and 3.1 respectively for whites, and 7.9 and 7.2 respectively for blacks. An absolute difference in BGV of −21.5 for 2000–2006 cohort compared to 1992–2000 was observed whereas the relative disparity across the 2 cohorts indicated an MLD of −8.57 and a Theil index of -9.45; both indicating an absolute and relative decrease of mortality for the 2000–2006 cohort. When compared to 1992–2000, the percent change in mortality for 2000–2006 was −5.5 in whites and −9.2 in blacks.A wide variation in myeloma incidence and mortality was observed with respect to race and geography. While differences in incidence rates can be attributed to various epidemiological factors, the socioeconomic issues and differences in disease biology may explain the differences in mortality. Based on our results, we hypothesize that variations in clinical practice, due to lack of standardization may also contribute to the disparities in mortality. Previous studies have demonstrated comparable survival between blacks and whites given comparable treatment. While new approaches have contributed to improved mortality within the 2 studied cohorts of pre and post-novel agent era, the disparity in mortality between whites and blacks has remained constant. This is the first study to our knowledge, which has analyzed the inter-state disparities in mortality and disparities between black and white mortality before and after the introduction of novel agents for myeloma, in a representative sample of national dataset. Further studies are necessary to evaluate various factors that are responsible for the observed mortality differences. Age Adjusted Incidence rates 2006 Age-adjusted Mortality rates 2006 No relevant conflicts of interest to declare.

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