K. Van Besien

Dose-intensive chemotherapy in refractory germ cell cancer--a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation.

Between September 1986 and March 1988, 33 patients with refractory germ cell cancer were entered on a phase I/II trial of two courses of high-dose carboplatin plus etoposide with autologous bone marrow support. All patients had extensive prior treatment and had either cisplatin-refractory disease (67%) defined as progression within 4 weeks of the last cisplatin dose or failed at least two cisplatin-based regimens (35%) including a cisplatin-ifosfamide salvage regimen. Patients received a fixed total dose of etoposide of 1,200 mg/m2 with each cycle. The carboplatin dose ranged from 900 mg/m2 to 2,000 mg/m2. Twenty of the 33 patients received the second cycle of therapy. Despite extensive prior therapy with cisplatin, neurotoxicity, nephrotoxicity, or hearing impairment with high-dose carboplatin and etoposide was unusual. The most common nonhematologic toxicity was moderate enterocolitis. The hematologic toxicity of this regimen was substantial at each dose level. All 53 courses were accompanied by granulocytopenic fevers. Seven of the 33 patients (21%) died from treatment. All of these deaths occurred during the granulocyte nadir, and five were related to documented sepsis. Overall, 14 of 32 patients (44%) evaluable for response obtained an objective response, including eight complete remissions. Four patients remain in complete remission, with three patients being continuously free of disease in excess of 1 year. Eight responders (including four complete remissions) had progressed while receiving cisplatin. We conclude that carboplatin and etoposide can be administered in combination at high dosages and this regimen may have curative potential for patients with germ cell tumors resistant to conventional-dose cisplatin-based therapies.

Allogeneic peripheral-blood progenitor-cell transplantation for poor-risk patients with metastatic breast cancer.

PURPOSE To evaluate the feasibility of allogeneic peripheral-blood progenitor-cell (PBPC) transplantation and to assess graft-versus-tumor effects in patients with metastatic breast cancer. PATIENTS AND METHODS Ten patients with metastatic breast cancer that involved the liver or bone marrow were treated with high-dose chemotherapy and allogeneic PBPC transplantation. The median age was 42 years (range, 29 to 55). The median number of metastatic sites was three (range, one to five). The conditioning regimen was cyclophosphamide (6,000 mg/m2), carmustine (BCNU; 450 mg/m2), and thiotepa (720 mg/m2) (CBT regimen). Patients received graft-versus-host disease (GVHD) prophylaxis using cyclosporine- or tacrolimus-based regimens. RESULTS All patients had engraftment and hematologic recovery. Three patients developed grade > or = 2 acute GVHD and four patients had chronic GVHD. After transplantation, one patient was in complete remission (CR), five achieved a partial remission (PR), and four had stable disease (SD). In two patients, metastatic liver lesions regressed in association with skin GVHD after withdrawal of immunosuppressive therapies. The median follow-up time was 408 days (range, 53 to 605). The median progression-free survival duration was 238 days (range, 53 to 510). CONCLUSION We conclude that allogeneic PBPC transplantation is a feasible procedure for patients with poor-risk metastatic breast cancer. The regression of tumor associated with GVHD provides suggestive clinical evidence that graft-versus-tumor effects may occur against breast cancer. Compared with autologous transplantation, allogeneic PBPC transplantation is associated with the additional risks of GVHD and related infections. Allogeneic transplantation should only be performed in the context of clinical trials and its ultimate role requires demonstration of improved progression-free survival.

Management of lymphoma recurrence after allogeneic transplantation : the relevance of graft-versus-lymphoma effect

Donor lymphocyte infusions, by virtue of a graft-versus-tumor effect, have been shown to induce remissions in leukemia that recurs after allogeneic bone marrow transplantation. Similar effects have been postulated to contribute to the decreased recurrence rate observed after allogeneic transplantation in non-Hodgkin’s lymphoma. This lower recurrence rate may be due to a variety of other mechanisms. We aimed to evaluate the role of graft-versus-lymphoma effects in patients in whom lymphomas recur after allogeneic transplantation. At the time of recurrence, immunosuppressive therapy was withheld. Patients with non-responding disease received an infusion of donor lymphocytes. Patients were observed for response and graft-versus-host disease. Disease in four of nine patients responded to withdrawal of immunosuppressive therapy. A minor response was observed in one of three recipients of donor lymphocyte infusions. Responses were observed among two patients with follicular lymphoma, one with large cell lymphoma and one with lymphoblastic lymphoma. A minor response was observed in a patient with prolymphocytic leukemia/lymphoma. We conclude that withdrawal of immunosuppressive therapy and donor lymphocyte infusion can induce durable remissions in patients with recurrent lymphoma after allogeneic transplantation.

Autologous Transplantation for Diffuse Aggressive Non-Hodgkin’s Lymphoma in Patients Never Achieving Remission: A Report from the Autologous Blood and Marrow Transplant Registry

PURPOSE To evaluate the results of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (autotransplants) in patients with diffuse aggressive non-Hodgkins lymphoma (NHL) who never achieve a complete remission with conventional chemotherapy. PATIENTS AND METHODS Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 184 patients with diffuse aggressive NHL who never achieved a complete remission with conventional chemotherapy and subsequently received an autotransplant were evaluated. Transplants were performed between 1989 and 1995 and were reported to the ABMTR by 48 centers in North and South America. RESULTS Seventy-nine (44%) of 184 patients achieved a complete remission or a complete remission with residual imaging abnormalities of unknown significance after autotransplantation. Thirty-four (19%) of 184 had a partial remission and 55 (31%) of 184 had no response or progressive disease. Eleven patients (6%) were not assessable for response because of early death. The probabilities of progression-free and overall survival at 5 years after transplantation were 31% (95% confidence interval [CI], 24% to 38%) and 37% (95% CI, 30% to 45%), respectively. In multivariate analysis, chemotherapy resistance, Karnofsky performance status score less than 80 at transplantation, age > or = 55 years at transplantation, receiving three or more prior chemotherapy regimens, and not receiving pre- or posttransplant involved-field irradiation therapy were adverse prognostic factors for overall survival. CONCLUSION High-dose chemotherapy and autologous hematopoietic stem-cell transplantation should be considered for patients with diffuse aggressive NHL who never achieve a complete remission but who are still chemotherapy-sensitive and are otherwise transplant candidates.

Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results.

PURPOSE This study was undertaken to evaluate the feasibility and therapeutic effect of high-dose chemoradiotherapy with autologous or allogeneic bone marrow transplantation (BMT) in patients with advanced chronic lymphocytic leukemia (CLL) who relapse after fludarabine treatment. PATIENTS AND METHODS Twenty-two patients with advanced CLL received high-dose cyclophosphamide, total-body irradiation, and BMT. Eleven patients with relapsed CLL received autologous BMT with marrow collected during a prior fludarabine-induced remission; leukemia cells were depleted from the autologous marrow in seven patients using an anti-CD19 monoclonal antibody and immunomagnetic separation. Eleven patients received allogeneic or syngeneic BMT, seven of whom had refractory Rai stage III or IV disease. RESULTS Six autologous transplant recipients achieved a complete remission (CR), four a nodular CR (nCR), and one a partial remission (PR). Two recurred with CLL, and three developed Richters transformation. Two patients had recurrence of immune cytopenias while in morphologic remission; one of these patients died of cytomegalovirus pneumonia. Six of 11 patients survive in remission 2 to 29 months following BMT. Of the 11 patients who received allogeneic or syngeneic BMT, seven achieved a CR, two a nCR, and one a PR; 10 survive 2 to 36 months following BMT. CONCLUSION These data indicate that high-dose chemotherapy with allogeneic BMT is effective at producing CRs in patients with CLL. Autologous transplantation in CLL is feasible and is capable of producing remissions in patients with advanced CLL. Further studies are warranted to assess the role of BMT in the treatment of CLL.

Autotransplants for Hodgkin's disease in first relapse or second remission: A report from the autologous blood and marrow transplant registry (ABMTR)

Although patients with relapsed Hodgkins disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkins disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7–64) years. Median time from diagnosis to relapse was 18 (range, 6–219) months; median time from relapse to transplant was 5 (range, <1–215) months. Most patients received high-dose chemotherapy without total body irradiation for conditioning (n = 370). The most frequently used high-dose regimen was cyclophosphamide, BCNU, VP-16 (CBV) (n = 240). The graft consisted of bone marrow (n = 246), blood stem cells (n = 112), or both (n = 56). Median follow-up was 46 (range, 5–96) months. One hundred-day mortality (95% confidence interval) was 7 (5–9)%. One hundred and sixty-five of 295 patients (56%) transplanted in relapse achieved CR after autotransplantation. Of these, 61 (37%) recurred. Twenty-four of 119 patients (20%) transplanted in CR recurred. The probability of disease-free survival at 3 years was 46 (40–52)% for transplants in first relapse and 64 (53–72)% for those in second remission (P < 0.001). Overall survival at 3 years was 58 (52–64)% after transplantation in first relapse and 75 (66–83)% after transplantation in second CR (P < 0.001). In multivariate analysis, Karnofsky performance score <90% at transplant, abnormal serum LDH at transplant, and chemotherapy resistance were adverse prognostic factors for outcome. Progression of Hodgkins disease accounted for 69% of all deaths. Autotransplantation should be considered for patients with Hodgkins disease in first relapse or second remission. Future investigations should focus on strategies designed to decrease relapse after autotransplantation, particularly in patients at high risk for relapse. Bone Marrow Transplantation (2001) 27, 387–396.

Fludarabine-based conditioning for allogeneic transplantation in adults with sickle cell disease.

Although allogeneic transplantation can be curative for patients with sickle cell disease, the toxicity of conditioning regimens has precluded its use in adults with significant end-organ damage. Newer conditioning regimens have been developed that are less toxic and that may broaden the applicability of allogeneic transplantation in this disorder. We report two adults with end-stage sickle cell disease, who underwent allogeneic transplantation from an HLA-identical sibling donor after conditioning with fludarabine/melphalan and ATG. Both patients had been extensively transfused and one had multiple RBC antibodies. One of the patients also had end-stage renal disease, and was dialysis dependent. Engraftment occurred promptly in both patients. Both achieved 100% donor chimerism and both were free of pain crises after transplant. The first patient died of a respiratory failure related to chronic graft-versus-host disease (GVHD) on day 335 after transplantation. The second patient developed severe gastro-intestinal GVHD and TTP and died on day 147 after transplantation. Conditioning with fludarabine/melphalan and ATG followed by allogeneic stem cell transplantation resulted in prompt and reliable engraftment in adults with end-stage sickle cell disease. The incidence of severe GVHD was unacceptably high and may be related to the ethnicity of the patients or to the inflammatory state associated with pre-existing sickle cell disease. Bone Marrow Transplantation (2000) 26, 445–449.

Allogeneic blood stem cell transplantation in advanced hematologic cancers

Allogeneic bone marrow transplantation for advanced hematologic cancer is associated with a high risk of early treatment-related morbidity and mortality. To determine the short-term benefits of allogeneic blood stem cell transplants when compared to bone marrow transplants, we reviewed outcomes of 74 adults with advanced hematologic cancer transplanted from HLA-matched related donors after conditioning with thiotepa, busulfan and cyclophosphamide. There were three cohorts: group 1 received bone marrow transplants with cyclosporine (CsA) and methotrexate (MTX) for GVHD prophylaxis; group 2 received bone marrow transplants with CsA and methylprednisolone (MP); and group 3 received blood stem cells with CsA and MP. All patients received filgrastim post-transplant. Median times (range) to neutrophils ⩾0.5 × 109/l were 17 (8–30), 9 (8–16) and 10 (8–13) days post-transplant, and to platelets ⩾20 × 109/l were 28 (14–100+), 19 (13–100+) and 14 (9–86) days post-transplant for groups 1, 2 and 3, respectively (P < 0.05 only for group 1 vs group 3 for both outcomes). Blood stem cell recipients had the least regimen-related toxicity, fewest early deaths and earliest discharge. There was no significant difference in acute GVHD between the three groups. One hundred and eighty-day survivals (95% CI) were 53% (35–72%), 32% (10–53%), and 68% (49–87%) for groups 1, 2 and 3, respectively (P < 0.05 only for group 2 vs group 3). For allogeneic transplantation, use of blood stem cell grafts has substantial advantages over marrow grafts.

Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after HLA-mismatched marrow or blood stem cell transplantation

Thirty adults with leukemia or lymphoma transplanted with marrow or blood stem cells from 1-antigen mismatched related donors received tacrolimus and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 42 years (range 18–56 years). Twenty-seven patients had advanced disease, and 13 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/day i.v. by continuous infusion from day −2, converted to oral at four times the i.v. dose following engraftment, and continued to day 180 post-transplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6 and 11. Mild nephrotoxicity was common before day 100; 69% of patients had a doubling of creatinine, 56% had a peak creatinine greater than 2 mg/dl, and two patients were dialyzed. Other toxicities prior to day 100 thought to be related to tacrolimus included hypertension (45%), hyperkalemia (17%), hyperglycemia (14%), seizures (13%), headache (3%) and hemolytic uremic syndrome (3%). Grades 2–4 GVHD occurred in 59% (95% CI, 38–70%), and grades 3–4 GVHD in 17% (95% CI, 1–32%). Overall survival at 1 year was 29% (95% CI, 12–45%). We conclude that tacrolimus and minidose methotrexate is active post-transplant immunosuppression for patients with 1-antigen mismatched donors.

High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma: mediastinal localization predicts for a favorable outcome.

PURPOSE This study was performed to evaluate the outcome of high-dose chemotherapy and autologous transplantation in patients with diffuse B-cell large-cell lymphoma, and, specifically, to evaluate the impact of primary mediastinal localization on the outcome of high-dose chemotherapy. PATIENTS AND METHODS A retrospective review was performed of all patients with diffuse large B-cell lymphoma who underwent autologous marrow or peripheral-blood stem-cell transplantation at our institution between January 1 986 and December 1995. RESULTS Ninety patients were identified, of whom 31 (34%) had a primary mediastinal B-cell large-cell lymphoma (PML). Cumulative probabilities of disease-free survival, overall survival, and disease progression are 40% (95% confidence interval [CI], 29 to 51), 42% (95% CI, 31 to 53), and 52% (95% CI, 40 to 64), respectively. By univariate analysis, low lactate dehydrogenase (LDH) level and low Ann Arbor stage at transplant were associated with improved survival and disease-free survival. There was a trend for improved disease-free survival and survival for patients with PML. Multivariate stepwise Cox regression analysis showed that LDH level, Ann Arbor stage, and primary mediastinal localization were independent favorable prognostic factors for disease-free survival and survival. LDH level and Ann Arbor stage were also predictive for the risk of disease progression. CONCLUSION Our results indicate that patients with PML may display an increased susceptibility to high-dose chemotherapy compared with other types of B-cell large-cell lymphoma. These findings, if confirmed, may have implications for the initial management of patients with PML.