I Strohscheer’s research while affiliated with Freie Universität Berlin and other places

Die reife B-ALL ist mit einem Anteil von 2–4% eine seltene Subgruppe der akuten lymphatischen Leukämie des Erwachsenen. Charakteristische Merkmale der leukämischen Blasten sind eine Morphologie vom Typ L3 nach der French-American-British (FAB-)Klassification (Bennett et al. 1976) sowie die Expression von monoklonalen Oberflächenimmunglobulinen (SIg), die bis auf wenige Ausnahmefälle nachweisbar ist. Spezifische Chromosomentranslokationen bei der B-ALL sind t(8;i4), t(2;8) und t(8;22). Die B-ALL ist charakterisiert durch eine rasche Proliferation der leukämischen Blasten mit großen Tumormassen und häufigem Befall extramedullärer Organe.

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

To compare autologous bone marrow (BM) with peripheral-blood progenitor cells (PBPC) as hematopoietic rescue after high-dose chemotherapy (HDCT). From January 1991 until April 1993, 47 consecutive patients with relapsed or refractory germ cell tumors were randomized to either BM harvest or collection of PBPC mobilized by chemotherapy plus granulocyte colony-stimulating factor (G-CSF). After additional conventional-dose salvage treatment, all patients received HDCT with carboplatin 1,500 mg/m2, etoposide 2,400 mg/m2, and ifosfamide 10 g/m2 with either BM or PBPC rescue. Forty-six patients were assessable for hematologic reconstitution, and one patient died on day +4 before engraftment. Rescue using PBPC resulted in a significantly shorter recovery time to neutrophil counts more than 500/microL (10.0 v 11.0 days, P < .01), neutrophil counts more than 1,000/microL (10.0 v 12.0 days, P = .001), and platelet counts more than 20,000/microL (10.0 v 17.0 days, P < .01), as well as in fewer days to transfusion independence from RBCs (8.0 v 12.0, P < .05) and platelets (9.0 v 12.0, P < .01) and fewer days of intravenous (IV) antibiotics (9.0 v 11.0, P < .05). However, no statistical differences in transfusion requirements or in other clinical outcome variables were observed. Overall survival and event-free survival also were not different in the two study arms. We conclude that the use of PBPC mobilized by chemotherapy plus G-CSF results in sustained trilineage reconstitution after HDCT, which occurs more rapidly as compared with BM. The earlier hematologic reconstitution in patients with PBPC rescue significantly reduces the time to transfusion independence.

This trial evaluated the toxicity and efficacy of high-dose carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in patients with refractory or relapsed germ cell cancer. Between August 1989 and September 1992, 74 patients with refractory or recurrent germ-cell tumors received one cycle of escalating doses of carboplatin (1,500 to 2,000 mg/m2), etoposide (1,200 to 2,400 mg/m2), and ifosfamide (0 to 10 g/m2). Before high-dose therapy, two cycles of conventional-dose cisplatin, etoposide, and ifosfamide were administered to assess tumor responsiveness. Seventy-four patients were assessable for toxicity and 68 for response. The doses of carboplatin 1,500 mg/m2, etoposide 2,400 mg/m2, and ifosfamide 10 g/m2 appeared to be safe. At this dosage, we treated 20 patients and observed World Health Organization (WHO) grade 3 and 4 hematotoxicity (100%), nausea (100%), diarrhea (30%), and hepatotoxicity (10%). All patients developed granulocytopenic fever. At carboplatin doses of 1,500 mg/m2, kidney toxicity was mild, with a median maximum creatinine level of 1.4 mg/dL (range, 1.1 to 3.0 mg/dL). However, at carboplatin doses of 1,750 and 2,000 mg/m2, we observed nonacceptable nephrotoxicity and neurotoxicity. Two (3%) patients died of treatment-related complications. Six patients required hemodialysis, which was temporary in five patients and permanent in one. Objective responses were obtained in 43 of 68 (63%) patients, including 21 (31%) complete remissions (CRs) and 14 (20%) inoperable partial remissions (PRs) with marker normalization. The median observation time of surviving patients was 12 months (range, 2 to 32). The probabilities of overall survival, event-free survival, and the relapse-free survival at 2 years were 44% (SD 8%), 35% (SD 6%), and 67% (SD 9%), respectively. Patients with disease refractory to conventional-dose pretreatment had a poor prognosis, with only one of 23 patients surviving event-free at 7 months after high-dose chemotherapy (HDT). In contrast, 24 of 45 (53.3%) patients with sensitive disease survive event-free with a probability of event-free survival at 2 years of 50% (SD 8%). High-dose carboplatin, etoposide, and ifosfamide plus autologous stem-cell transplantation can be used in refractory and relapsed germ cell cancer with acceptable toxicity, and represents an effective, potentially curative salvage treatment.

Forty patients with germ cell tumors were treated with carboplatin 1500-2000 mg/m2, etoposide 1200-1600 mg/m2 and ifosfamide 0-10 g/m2 plus mesna followed by autologous stem cell reinfusion. A pruritic maculopapular rash was observed in 10 patients usually starting on the last day of chemotherapy. Lesions remained localized to the extremities in four patients. In six they became confluent and progressed also involving the trunk and face. Facial edema and painful swelling of hands and feet also occurred in this latter group. No ulcerations or bullae formation were seen and changes resolved spontaneously in all patients within 3 weeks leaving marked hyperpigmentation in involved areas. Renal function declined in nine of 10 patients concomitantly with evolving cutaneous changes, but recovered in all except one. Cutaneous side effects were more frequent with increasing doses of etoposide and carboplatin and in patients with deteriorating renal function. Plasma concentrations during high-dose chemotherapy should be monitored to avoid excessive serum levels and toxicity, especially in patients at risk of renal dysfunction.

Stimulation of lymphocytes with mitogens and antigens is an established model for in vitro testing of immunoreactivity. Due to the great variability of blastogenic response the interpretation of these results is difficult. Our results suggest that multivariate experiments and statistics improve the interpretation.

Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/46912/1/277_2005_Article_BF02044602.pdf