Hubert Poliwoda

Long-term gonadal toxicity after therapy for Hodgkin's and non-Hodgkin's lymphoma

SummaryWith the increasing cure rate of patients treated for Hodgkins and non-Hodgkins lymphoma, the evaluation of late effects on gonadal function remains an important issue. The gonadal function of relapse-free long-term survivors with high-grade non-Hodgkins lymphoma (NHL) and Hodgkins disease (HD) were studied; 24 of 119 patients with NHL treated between 1980 and 1990 and 66 of 364 patients with HD treated between 1975 and 1990 at Hannover University Medical School, who were younger than 45 years of age and in complete remission at the time of evaluation for at least 24 months after completion of therapy, were included into the analysis. Of 24 patients with NHL, 1/10 women (10%) and only 3/14 men (21%) showed signs of gonadal dysfunction. Three of these four patients had been treated with combined modality therapy followed by maintenance COP chemotherapy, resulting in high cumulative doses of cyclophosphamide (range: 12–43 g). In comparison, 13/26 (50%) women with HD suffered from premature ovarian failure, and 26/40 (65%) men showed signs of gonadal dysfunction with significant FSH elevations. No significant difference in the incidence of gonadal toxicity existed in patients treated with combined modality who received irradiation to either supra- or infradiaphragmatic radiation fields in combination with chemotherapy (70% versus 62%). A comparison of the chemotherapy regimens used in patients with NHL or HD shows that patients from both groups had received comparable median cumulative doses of cyclophosphamide, vincristine, and adriamycin, but only patients with HD had additionally received a median cumulative dose of 13.3 g of procarbazine per patient. A tendency towards a higher incidence of gonadal toxicity with higher cumulative doses of procarbazine received was found in patients with HD. The frequency of gonadal dysfunctions is markedly lower in patients treated for non-Hodgkins lymphoma than in patients treated for Hodgkins disease, approximately half of whom will be affected by long-term gonadal toxicity. Although the use of more intensive radiotherapy in patients with HD compared with NHL patients makes the evaluation of the influence of radiotherapy on gonadal toxicity more difficult, the current retrospective analysis raises the concern that, in addition to infradiaphragmatic radiotherapy, the use of procarbazine in regimens for the treatment of HD, like COPP or MOPP, may be a possible explanation for the differences in gonadal toxicity observed between patients with HD and those with NHL. Regimens including procarbazine should be avoided in patients wanting to preserve fertility since alternative chemotherapies with at least equal efficacy are available.

Recombinant human interferon (IFN) alpha-2b in chronic myelogenous leukaemia: dose dependency of response and frequency of neutralizing anti-interferon antibodies

Summary. Twenty‐seven patients with Philadelphia chromosome positive chronic myelogenous leukaemia in the chronic phase were treated with low doses of recombinant interferon (IFN) alpha‐2b. Ten patients entered a complete and six a partial haematologic remission with a median duration of 5·8 and 9·1 months respectively. Five minor cytogenetic responses were observed. These results are inferior compared to other studies with higher interferon‐doses. Fever was an acute side effect after injection of IFN, limb pains and fatigue occurred protractedly. Haematologic side effects, nonspecific EEG changes, weight loss, and development of pulmonary infiltrates were observed in later periods of the treatment. Eight patients developed neutralizing anti‐IFN antibodies after 4·2–20·4 months (median 12·8 months). Anti‐IFN antibodies were associated with relapse or refractoriness to IFN treatment: five out of nine patients with rising WBC after initial fall had antibodies, while four did not. Two out of four patients with primary non‐response had IFN‐antibodies. These results may indicate a serious problem in the long‐term treatment of CML with recombinant interferon.

Bilateral testicular tumours: Prevalence and clinical implications

In a series of 773 patients with the diagnosis of a testicular germ cell tumour, treated at Hannover University Medical School between 1972 and 1985 and with a median follow-up of 9 years (60-210 months), bilateral testicular tumours occurred in 27 (3.5%) patients. None of 157 patients receiving chemotherapy for metastatic disease of the first tumour developed a metachronous bilateral tumour. Of 24 patients with metachronous tumours 23 had stage I and 1 patient had stage II at the time of initial diagnosis. The second testicular tumour was stage I in 18 patients, stage II in 5 and stage IV in 1 patient. 3 patients (13%) relapsed after treatment for their second germ cell tumour (surveillance 13 patients, radiotherapy 7 patients, lymph node dissection 2 patients and chemotherapy 2 patients), 1 of which died after refusing further treatment. The cure rate was 96% in patients with bilateral disease. Routine biopsy of the contralateral testis to identify existing carcinoma in situ (CIS) is recommended. Patients with CIS must be informed about their increased risk of a second testicular tumour. Irradiation of CIS or close clinical follow-up might both constitute appropriate strategies for the management of these patients.

Expansion of Peripheral Blood Natural Killer Cells Correlates with Clinical Outcome in Cancer Patients Receiving Recombinant Subcutaneous lnterleukin-2 and Interferon-α-2

Natural killer (NK) cells are believed to contribute to the clinical efficacy of cancer immunotherapy using recombinant interleukin-2 (rIL-2) in humans. In previous trials of high-dose i.v. rIL-2, however, no correlation has been established between circulating NK cells and treatment response. Between January 1989 and October 1990, we treated a total of 47 outpatients with advanced tumors using low-dose s.c. rIL-2 and interferon-alpha-2 (rIFN-alpha). Therapy consisted of a 2-day rIL-2 pulse at 18 million IU/m2/day, followed by 6 weeks of rIL-2 (3.6 x 10(6)-4.8 x 10(6) IU/m2/day x 5 days/week) and rIFN-alpha (5 x 10(6)-6 x 10(6) U/m2 x 3/week). Before and after therapy, we phenotypically evaluated circulating lymphocytes and correlated them with clinical response. During 6-week therapy, peripheral blood lymphocytes bearing the CD56 (NK-cell-associated) surface antigen were increased significantly (p < or = 0.005) in treatment responders [complete response (CR) and partial response (PR), n = 10; 3.8-fold] and stable disease (SD) patients (n = 20; 2.1-fold), while patients with progressive disease (PD, n = 17) exhibited no significant expansion of circulating NK cells (p > 0.1). After one 6-week treatment cycle, CR/PR patients had significantly more peripheral NK cells, when compared with patients in SD (1.6-fold) and PD (1.9-fold) (p < 0.04). The overall number of circulating lymphocytes was also increased upon therapy (1.6-fold; p < or = 0.001), but remained independent of response (p > 0.4). These data demonstrate that s.c. rIL-2 and s.c. rIFN-alpha produce a significant increase in peripheral blood NK cells; this expansion correlates significantly with treatment response in advanced tumor patients receiving long-term combination immunotherapy at outpatient doses.

The development of neutralizing antibodies in a patient receiving subcutaneous recombinant and natural interleukin-2

Systemic administration of interleukin‐2 (IL‐2) in humans may induce antibodies specific to IL‐2. The case is reported of a patient with metastatic rectal carcinoma who was treated with long‐term subcutaneous IL‐2 and a combination of subcutaneous IL‐2 and interferon‐alpha 2b (IFN‐α 2b). This patient developed nonneutralizing and neutralizing anti‐IL‐2 antibodies recognizing both the recombinant and natural cytokine. Detectable serum levels of neutralizing antibodies were accompanied by the inhibition of immune responsiveness to systemic IL‐2 in vivo.

Comparison of the antitumor activity of cisplatin, carboplatin, and iproplatin against established human testicular cancer cell lines in vivo and in vitro.

Cisplatin is a backbone of any combination chemotherapy currently in use for the treatment for nonseminomatous germ cell tumors. Recently new platinum analogs with lower toxicity have been developed. The antitumor activity of two analogs, carboplatin (JM8) and iproplatin (JM9) was compared to cisplatin in vitro and in vivo. The 3thymidine incorporation in three established human testicular cancer cell lines was significantly stronger inhibited by cisplatin than by JM8 or JM9. Cisplatin showed a significantly stronger antitumor activity against heterotransplanted human testicular cancer cell lines in the nude mouse than JM8 or JM9 when given at equitoxic doses. Although both analogs only moderately retarded the tumor growth, cisplatin produced a significant reduction of tumor volume in three of four cell lines. From these data it is concluded that the antitumor activity of cisplatin may be significantly superior to JM8 and JM9, and results of preclinical investigations should be awaited before replacement of cisplatin by JM8 or JM9 in the treatment of nonseminomatous germ cell tumors can be considered.

Titanocendichloride activity in cisplatin and doxorubicin-resistant human ovarian carcinoma cell lines.

The activity of a new organometallic compound, titanocendichloride, was evaluated in doxorubicin- and cisplatin-resistant human ovarian carcinoma cell lines in vitro. Titanocendichloride showed no cross resistance to doxorubicin in two multidrug resistant sublines of A2780. Furthermore, the cell line A2780 CP3, which is about 20-fold resistant to cisplatin was only 2.5-fold resistant to titanocendichloride, indicating a lack of cross resistance between the two metal compounds. These results were confirmed in vivo where titanocendichloride showed a much stronger inhibitory effect in cisplatin-resistant human ovarian carcinoma xenografts than cisplatin.

Technical and safety aspects of blood and marrow transplantation using G-CSF mobilized family donors.

An allogeneic transplantation programme using immunoselected blood progenitor and bone marrow CD34+ cells has been established. Thirteen healthy HLA-matched, MLC negative sibling donors received two doses of 5 micrograms kg-1 G-CSF (s.c. daily) for 5 days. On days 4 and 5, large-volume mononuclear cell aphereses were performed (COBE Spectra) and on day 5 one unit of autologous blood was obtained. Mononuclear cells were pooled and cryopreserved after CD34+ cell-immunoselection on day 5. Bone marrow (BM) of the same donors was procured under routine conditions 10-45 days later (median: 27 days). The final graft consisted of blood CD34+ cells with either complete BM (n = 5) or immunoselected BM CD34+ cells (n = 8). The present paper describes the progenitor cell mobilization and apheresis protocol and analyzes the cell loss by BM and peripheral blood progenitor cell (PBPC) donation. Considerably larger amounts of mononuclear cells (CD45+), T-lymphocytes (CD3+) and platelets were lost by the apheresis as compared to bone marrow without apparent immediate clinical consequences for the donors. Owing to cross-cellular contamination of the apheresis concentrate, blood platelet count (PC) significantly decreased (mean PC after the second apheresis 116 x 10 microL-1); furthermore on average 3.04 x 10(10) CD3+ cells were removed by two apheresis sessions. This loss did not lead to long-term total lymphocyte count changes (2370 microL-1 versus 1889 microL-1) as observed during the long-term follow-up of 7/13 donors (mean 290 days). Subjectively, the PBPC collections were better accepted than BM donations in all but one family donor.

Low-Dose lnterleukin-2 in Combination with Interferon-α Effectively Modulates Biological Response in vivo

Phenotypic characterization of peripheral blood lymphocytes was performed in patients with advanced metastatic cancer receiving low-dose recombinant interleukin-2 (rIL-2) and recombinant interferon-α

Treatment with natural human interferon alpha of a CML-patient with antibodies to recombinant interferon alpha-2 b

SummaryA patient with Philadelphia-chromosome positive chronic myelogenous leukemia developed interferon antibodies on treatment with recombinant interferon alpha-2 b. Clinically this event corresponded with progressive disease. No cross-reactivity of antibodies with human leukocyte interferon was found by Western blot. Treatment was switched to human leukocyte interferon with an obvious clinical effect: WBC was reduced and platelet count stabilized, but the effect was transient and no hematologic remission was achieved. Human leukocyte interferon may be an alternative in CML-patients with neutralizing antibodies to recombinant interferon alpha.