Arturo Molina

Pivotal Phase III Trial of Two Dose Levels of Denileukin Diftitox for the Treatment of Cutaneous T-Cell Lymphoma

PURPOSEnThe objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions.nnnPATIENTS AND METHODSnPatients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured.nnnRESULTSnOverall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity.nnnCONCLUSIONnDenileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-free and overall survival.

PURPOSEnTo examine the predictive value of tumor- and treatment-specific prognostic indicators of relapse-free survival (RFS) and overall survival (OS) in patients with high-risk breast cancer (HRBC) treated with high-dose chemotherapy (HDCT) and stem-cell rescue.nnnPATIENTS AND METHODSnBetween June 1989 and September 1994, 114 patients with HRBC (stage II with > or = 10 axillary lymph nodes involved, stage IIIA, and stage IIIB inflammatory carcinoma) received adjuvant chemotherapy followed by HDCT with etoposide, cyclophosphamide, and either doxorubicin (CAVP) or cisplatin (CCVP). Variables analyzed included stage, tumor size, number of axillary nodes involved, grade and receptor status, and types of adjuvant chemotherapy and radiation therapy and HDCT.nnnRESULTSnWith a median follow-up time of 46 months (range, 23 to 93), Kaplan-Meier estimates of 3.5-year OS for stage II, IIIA, and IIIB HRBC are 82% (95% confidence interval [CI], 67% to 97%), 79% (95% CI, 67% to 91%), and 72% (95% CI, 53% to 91%); RFS estimates are 71% (95% CI, 56% to 85%), 57% (95% CI, 43% to 72%), and 50% (95% CI, 29% to 71%) irrespective of the HDCT regimen. In univariate analysis, the risk of relapse was lower for patients with progesterone receptor (PR)-positive tumors (risk ratio [RR], 0.43; 95% CI, 0.22 to 0.81; P = .01) and higher for patients with inflammatory carcinoma (RR, 2.20; 95% CI, 1.02 to 4.76; P = .05). OS was better for patients with PR (RR, 0.16; 95% CI, 0.05 to 0.55; P = .003) and estrogen receptor (ER)-positive tumors (RR, 0.42; 95% CI, 0.17 to 1.02; P = .05); OS was worse for patients with high-grade primary tumors (RR, 4.08; 95% CI, 1.21-13.7; P = .02). In multivariate analysis, PR positivity was associated with improved RFS (P = .01) and OS (P = .001).nnnCONCLUSIONnHDCT in selected patients with HRBC is safe and warrants further evaluation. Patients with receptor-negative, high-grade, or inflammatory tumors require improvement in their therapeutic options. Better assessment of the role of HDCT awaits completion of ongoing randomized trials.

Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: Results of a prospective double-blind randomized trial

We have previously demonstrated a decrease in the incidence of acute graft-versus-host disease (GVHD) with the addition of methotrexate (MTX) to cyclosporine (CSP) and prednisone (PSE) chemotherapy in patients with leukemia. We have now completed a prospective randomized trial comparing the 3-drug regimen (CSP/MTX/PSE, including 3 doses of MTX) to the standard 2-drug regimen (CSP/MTX, including 4 doses of MTX) to investigate the benefit of PSE used up front for the prevention of acute and chronic GVHD. In the trial, 193 patients were randomized and 186 were included in the final analysis. All patients received a bone marrow graft from a fully histocompatible sibling donor. The preparatory regimen consisted of fractionated total-body irradiation (fTBI) and etoposide in all but 13 patients, who received fTBI and cyclophosphamide. The patients were randomized to receive either CSP/MTX/PSE or CSP/MTX. The 2 groups were well balanced with respect to diagnosis, disease stage, age, donor-recipient sex, and parity. In an intent-to-treat analysis, the incidence of acute GVHD was 18% (95% confidence interval [CI] 12-28) for the CSP/MTX/PSE group compared with 20% (CI 10-26) for the CSP/,MTX group (P = .60), with a median follow up of 2.2 years. Overall survival was 65% for those receiving CSP/MTX/PSE and 72% for those receiving CSP/MTX (P = .10); the relapse rate was 15% for the CSP/MTX/PSE group and 12% for the CSP/MTX group (P = .83). The incidence of chronic GVHD was similar (46% versus 52%; P = .38), with a follow-up of 0.7 to 6.0 years. Of interest, 21 patients went off study due to GVHD (5 in the CSP/MTX/PSE group and 16 in the CSP/MITX group [P = .02]), and 11 patients went off study because of alveolar hemorrhage (3 in the CSP/MTX/PSE group and 8 in the CSP/MTX group [P = .22]). The addition of PSE did not result in a higher incidence of infectious complications, bacterial (66% versus 58%), viral (77% versus 66%), or fungal (20% versus 20%), in those receiving CSP/MTX/PSE versus CSP/MTX, respectively. These data suggest that the addition of PSE was associated with a somewhat lower incidence of early posttransplantation complications but did not have a positive impact on the incidence of acute or chronic GVHD or event-free or overall survival.

Polymyositis as a manifestation of chronic graft-versus-host disease.

A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.

High dose therapy and autologous stem cell transplantation for human immunodeficiency virus-associated non-Hodgkin lymphoma in the era of highly active antiretroviral therapy.

The advent of highly active antiretroviral therapy (HAART) has allowed the exploration of more dose‐intensive therapy such as autologous stem cell transplantation (ASCT) in selected patients with human immunodeficiency virus (HIV)‐associated non‐Hodgkin lymphoma (NHL).

Effects of allogeneic bone marrow transplantation on recipient bone mineral density: A prospective study

Allogeneic bone marrow transplant (BMT) recipients have many known risk factors for developing decreased bone mineral density (BMD) after transplantation. We performed a prospective sequential evaluation of BMD in the lumbar spine and nondominant hip using dual-energy x-ray absorptiometry (DEXA) in a cohort of 47 adult patients (median age, 43 years) who were undergoing radiation-based BMT for hematologic malignancies. Baseline DEXA studies were performed before BMT and repeated at 3 to 4 months, 6 to 8 months, and 12 to 14 months after BMT. The majority of patients (60%) had been minimally treated with combination cytotoxic chemotherapy, having received no more than 1 treatment regimen before BMT. Graft-versus-host disease prophylaxis consisted of cyclosporine in combination with either methotrexate or prednisone, or both. Mean lumbar spine and hip BMD were normal before BMT (spine: 1.01 g/cm2, z score = 96%; hip: 0.86 g/cm2, z score = 100%) and gradually decreased (spine: 0.98 g/cm2, z score = 94%; hip: 0.76 g/cm2, z score = 91%) at 12 to 14 months. These declines were statistically significant (P < .006 and < .002 for lumbar spine; P < .001 and < .001 for hip). In addition, the sharpest decline occurred during the first 6 months after BMT and was more marked in the hip than the lumbar spine. These data suggest that BMT adversely affects BMD in this patient population.

Remission of refractory Sezary syndrome after bone marrow transplantation from a matched unrelated donor

Sezary syndrome is a leukemic variant of mycosis fungoides (MF)/cutaneous T-cell lymphoma (CTCL). Bone marrow transplantation (BMT) from a matched unrelated donor was performed in a 22-year-old woman with a 10-year history of Sezary syndrome who had failed treatment with corticosteroids, methotrexate, photochemotherapy, photopheresis, hydroxyurea, interferon-alpha, and cladarabine. At the time of BMT, she had persistent erythrodermic skin disease, adenopathy, circulating Sezary cells and bone marrow (BM) involvement. The patient underwent BMT from a 6/6 HLA-matched unrelated male donor in August 1996. A BM biopsy obtained on day 30 after BMT showed no evidence of lymphoma and complete male donor engraftment. Her skin lesions resolved within 100 days after transplant. Complete staging studies, including T-cell receptor gene rearrangement studies performed at 36 months post-BMT, showed no evidence of recurrent Sezary syndrome. This represents her first durable remission since the initial diagnosis more than 12 years ago. To our knowledge, this is the first patient with refractory Sezary syndrome who has been successfully treated with allogeneic unrelated donor BMT. Our results indicate that this modality may be effective in inducing remission in refractory MF/CTCL, including Sezary syndrome.

Recurrent B-cell neoplasms after Rituximab therapy: an immunophenotypic and genotypic study.

Rituximab has been widely used to treat relapsing or advanced stage B-cell neoplasms with an efficacy of about 50%. However, approximately 40-50% of Rituximab treated patients will recur. It is not clear whether these recurrent diseases have the same immunophenotype as that of the original tumors. At the City of Hope, we treated 91 cases of CD20-positive B-cell neoplasms with Rituximab in combination with chemotherapy and hematopoietic stem cell transplantation between August 1999 and December 2000. Thirty-five of 91 patients (38%) experienced recurrence during the time period within one year from treatment. Tumor cells from all of the recurrent patients expressed one or more B cell antigens (CD19, CD20, CD22, CD45RA, or CD79a). However, thirteen of 35 recurrent cases showed aberrant loss of CD20 expression (37%) by immunohistochemical or flow cytometric studies. Pre- and post-Rituximab treated tumor cell DNA was successfully extracted from archival paraffin sections, hematoxylin and eosin (H and E) stained slides, smears, or frozen cells in 10 of 13 CD20 negative recurrent cases. PCR studies for immunoglobulin (Ig) heavy chain gene rearrangements were performed in all these cases. Five cases showed identical Ig heavy chain gene rearrangements in the paired specimens. PCR assay for Ig kappa (κ ) gene rearrangement was performed in the five paired specimens lacking detectable Ig heavy chain gene rearrangements; 2 of them showed identical Ig κ gene rearrangements. Three pairs showed unmatched Ig heavy chain and Ig κ gene rearrangements, probably due to poor quality of recovered DNA. Aberrant loss of CD20 antigens may be a mechanism of treatment resistance and should be considered in the immunophenotyping of recurrent Rituximab-treated B-cell neoplasms; therefore, a panel of B cell markers is recommended for the immunologic diagnosis of recurrent B cell malignancies after Rituximab therapy. Seven of ten pairs of recurrent CD20-negative cases showed identical Ig heavy chain and Ig κ gene rearrangements by PCR assay, strongly suggesting that the pre- and post-Rituxan treated B cell neoplasms are clonally-related.

Interleukin-2 After Autologous Stem-Cell Transplantation for Adult Patients With Acute Myeloid Leukemia in First Complete Remission

PURPOSEnTo determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation.nnnPATIENTS AND METHODSnFifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 x 10(6) U/m(2)/24 h for 4 days, followed by 10 days of IL-2 1.6 x 10(6) U/m(2)/24 h on hematologic recovery.nnnRESULTSnEighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate.nnnCONCLUSIONnThese results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin-mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.

High-dose chemo/radiotherapy and autologous bone marrow or stem cell transplantation for poor-risk advanced-stage Hodgkin's disease during first partial or complete remission

Complete remission rates of 70-90% can be achieved following combination chemotherapy for patients with advanced-stage Hodgkins disease (HD). Patients who present with unfavorable poor prognostic factors, however, have a 5-year disease-free survival of only 40-50%. In an attempt to improve the prognosis of 20 patients with poor-risk advanced-stage HD, we evaluated the role of early high-dose therapy (HDT) and autologous bone marrow/stem cell transplantation (ASCT) during the first complete or partial remission (CR/PR). Patients were eligible for ASCT if they either achieved a PR (defined as > 50% regression) (six patients), or achieved a CR (14 patients) but had presented with three or more of the following unfavorable features: stage IV disease with bone marrow involvement or > or = 2 extranodal sites of involvement; bulky mass > 10 cm or bulky mediastinal mass > 1/3 of mediastina/thoracic ratio; B symptoms; and elevated serum lactate dehydrogenase (LDH) level. The study included 11 men (55%) and 9 women (45%). The median age was 37 years (range 20-57). Seventeen patients (85%) had stage IV disease; 14 (70%) had B symptoms; 13 (65%) had bulky mass > 10 cm; 14 (70%) had > or = 2 extra nodal sites involvement; and eight patients (40%) had elevated LDH levels. All patients were treated with standard four or 7-8 drug combination chemotherapy regimens until they achieved maximal response prior to ASCT with a median of six cycles (range 4-11). Six patients also received involved field radiotherapy to residual bulky mass > 5 cm or bony lesions before ASCT. The median time from diagnosis to ASCT was 8.6 months (range 5.5-18.9). Preparative regimens consisted of fractionated total body irradiation (FTBI) 1200 cGy in combination with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg in all patients except one who had borderline pulmonary function and received lomustine 15 mg/kg instead of FTBI. All patients engrafted and there was no transplant-related mortality. One patient developed congestive cardiomyopathy at 4 years post-ASCT. All patients remain alive and in remission at a median follow-up of 42.8 months (range, 13.2-149.2). These preliminary results suggest that HDT and ASCT can be performed safely during first CR/PR in selected patients with advanced-stage HD who have an unfavorable prognosis. Further randomized studies comparing HDT and ASCT during first CR with conventional chemotherapy and ASCT at relapse in poor-risk advanced-stage HD should be conducted. The prognostic factors and risk groups described recently by an international prognostic study can be used to identify high-risk patients who may be candidates for more intensive therapy.