Status of allogeneic bone marrow transplantation in childhood in the GDR

Of 25 HLA-identical, MLC negative transplants 10 patients had acute lymphoblastic leukaemia (ALL), 8 acute nonlymphoblastic leukaemia (ANLL), 3 severe aplastic anaemia, 2 malignant histiocytosis, 1 patients neuroblastoma and 1 Fanconi anaemia. 3 HLA nonidentical, MLC positive transplants were performed, two children had malignant infantile osteopetrosis and 1 child had a severe combined immunodeficiency disease. Patients with ALL and ANLL received cyclophosphamide and single dose total body irradiation. 3 patients received fractionated TBI. The results for the allogeneic group overall indicate that the actuarial disease free survival rate is 0.62. 16 of 25 patients are in continuous complete remission (CCR) periods of 3-78 months posttransplant. All three transplanted children with severe aplastic anaemia alive disease-free for periods of 21-81 months. 10 patients with ALL were transplanted (2 in first remission for high risk ALL, 8 in second remission). 7 of 10 patients are alive and disease-free (CCR rate 0.67). 8 patients underwent BMT for ANNL while in first remission in 7 patients and in third partial remission in 1 patient. 4 of 8 patients are alive and disease-free for periods of 25-56 months (CCR rate 0.50). 1 patient with neuroblastoma stage IV survives 24 months, 1 child with Fanconi anemia died on day +25 of GVHD and septicaemia. 1 of the 2 patients transplanted for malignant histiocytosis relapsed 3 months posttransplant, 1 patient is alive and disease-free 5 months posttransplant. In none of the HLA-nonidentical and MLC positive transplantations T-cell depleted marrow engrafted.     

Plasma Insulin during Remission in Juvenile Diabetes Mellitus

Three juvenile diabetics in partial remission were studied before and after the recurrence of overt diabetes. The remissions were partial because glucose tolerance never returned to normal. However, it improved sufficiently to cause the discontinuance of insulin therapy for at least four months.The insulin output in response to double glucose tolerance tests was increased during remission. The degree of remission seemed to be related to the magnitude of the insulin response to glucose. In two of the patients the increase was low and the response very slight. The third patient, however, had a delayed hyper-response and his carbohydrate tolerance during the remission was much more improved than those of the other patients.     

The so-called partial synchronization in the treatment of malignant lymphomas. A clinical study

In a randomized study the effectiveness of a modified MOPP scheme (CVPP scheme) and a so-called partial synchronisation treatment (vincristine or vinblastine respectively and cyclophosphamide) was compared in 72 patients predominantly pretreated with Hodgkin lymphomas and non-Hodgkin lymphomas. From 49 patients affected with lymphogranulomatosis of stage IIIB and IV, 24 were treated according to CVPP scheme; in 10 of them a complete remission was achieved and in 4 of them a partial remission. 25 patients were treated in the control group with synchronization therapy. In 13 of them a complete remission and in 12 of them a partial remission was achieved. With CVPP therapy the mean remission time amounted to 14.4 months and with synchronization therapy 9.2 months. There was no significant statistical difference. From 23 patients with advanced non-Hodgkin lymphomas of a high malignancy 11 received a therapy with CVPP scheme; 2 of them came into a complete remission and 3 of them into a partial one. 12 patients received a synchronization therapy; 7 of them came into a partial remission. With CVPP therapy the mean remission time amounted to 14.4 months, with partial synchronization therapy--10.8 months. Even in non-Hodgkin lymphomas there was no significant difference between the forms of therapy used. Even a comparison of the two survival times of both forms of treatment does not reveal any significance. Thus, both procedures of treatment seem to be comparable in their therapeutic efficaciousness, even if the number of complete remissions during the treatment with CVPP scheme was greater in our investigations. The assumed lower toxicity of synchronization therapy could not be confirmed by our study. In addition to the controversial synchronization effect, the good efficaciousness of treatment according to the so-called synchronization therapy may be due to sensibilizing phenomena and recruitment phenomena.     

Low dose cytosine arabinoside in refractory anemia with excess of blasts in transformation

Myelodysplastic syndromes (MDS) are heterogeneous diseases. Patients with blast counts of more than 20% of nucleated bone marrow cells have a high risk of short survival. We treated six patients with refractory anemia with excess of blast in transformation (RAEBiT) with low dose cytosine arabinoside (LD Ara-C). We had one partial remission (PR), surviving 16 weeks and two complete remissions (CR), surviving 22 and 55+ months. Myelosuppression was dominant in all patients, but was not as serious as with conventional remission-induction treatments for leukemias. Bone marrow aplasia occurred in all responding patients, but a differentiation effect is possible too. Maintenance therapy with LD Ara-C may be important for the two long-lasting CR.     

Allogeneic bone marrow transplantation for high risk non-Hodgkin's lymphoma during first complete remission

Allogeneic bone marrow transplantation from histocompatible sibling donors was performed in six patients with extranodal involvement of high grade lymphoma during first complete remission. Five patients had lymphoblastic lymphoma and one had diffuse undifferentiated lymphoma. The cytoreductive/immunosuppressive regimen consisted of total body irradiation and high dose cyclophosphamide. Four patients are alive in complete remission at 8 months, 14 months, 21 months and 47 months post transplantation. One patient who relapsed 7 months after his initial transplantation underwent a second transplantation but another relapse 17 months later led to his death. One patient died of chronic graft-versus-host disease and at autopsy there was no evidence of lymphoma. These data demonstrate that allogeneic bone marrow transplantation can produce durable remissions in patients with high grade lymphoma who present with bone marrow, central nervous system and/or skin involvement.     

Results of treating acute myeloblastic leukemia in patients over 60 years of age

An efficiency of the acute myeloblastic leukemia therapy has been assessed in 79 patients aged over 60 years. Twenty six patients out of this group have been treated with usual or reduced doses of doxorubicin and cytarabine (ADR-Ara-C) 35--low doses of cytarabine (LD Ara-C), 11-6-mercaptopurine (6 MP), and 7 patients died before chemotherapy. Complete remission in group treated with ADR-Ara-C was achieved in 23% of patients while partial remission in 42%. Median survival in this group was 5.8 months (range from 0.5 to 16 months). Percentage of the complete remissions in the group treated with LD-Ara-C was 6%, and partial remissions 40%. Median survival was 4.7 months (range from 0.5 to 14.2 months). Partial remission in 5 out of 11 patients treated with 6 MP (36%) and no complete remissions were noted. Median survival was 3.9 months. Therapy with ADR-Ara-C produced marked leucopenia and thrombocytopenia in the majority of treated patients. Vomiting, hemorrhagic complications, and bacterial infections have also been noted. These adverse reactions have been less frequent in patients treated with LD-Ara-C, and 6 MP. Ten patients (38%) treated with ADR-Ara-C and 7 patients treated with LD-Ara-C died during remission inducing therapy.     

131I]metaiodobenzylguanidine therapy after conventional therapy for neuroblastoma.

[131I]Metaiodobenzylguanidine (131I-MIBG) is used for diagnostic scintigraphy and targeted therapy in a range of neural crest tumors, which exhibit an active uptake-1 mechanism at the cell membrane and cytoplasmatic storage in neurosecretory granules. A good and selective concentration and a long retention in the tumor, as is generally the case in neuroblastoma, are the basis for successful 131I-MIBG treatment. At The Netherlands Cancer Institute a phase II study was carried out in 53 patients with progressive recurrent disease after conventional therapy had failed. Despite the unfavorable basis for treatment, 131I-MIBG therapy induced 7 complete remissions, 23 partial remissions and arrest of disease (no change) in 10. Nine patients had progressive disease and one patient was lost to follow-up. The palliative effect of the treatment under these conditions was impressive. The duration of remissions varied from 2 to 38 months. The best results were obtained in patients with voluminous soft tissue disease. In general the treatment was well tolerated by children and the toxicity was mild, provided the bone marrow was not invaded by the disease. It is concluded that 131I-MIBG therapy has a definitive place in the treatment of neuroblastoma after conventional treatment has failed. As the invasiveness and toxicity of this therapy compare favorably with that of chemotherapy, immunotherapy and external beam radiotherapy, 131I-MIBG therapy is the best palliative treatment for patients with advanced recurrent neuroblastoma.     

Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma.

Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.     

Treatment of advanced breast cancer with 20 mg toremifene, a phase II study. Preliminary communication

Fourteen postmenopausal women with estrogen-receptor positive advanced breast cancer and no prior cytostatic treatment received 20 mg toremifene daily as a single dose after a loading dose (120----60----60 mg) for the first 3 days. All were evaluable and had undergone at least 6 weeks' treatment. Results were: no complete remissions (CR), 3 partial remissions (PR), 8 no change (NC) and 3 cases of progressive disease (PD). Three patients had mild side effects: nausea, insomnia, sweating and arm pain.     

Combination Chemotherapy using L-Asparaginase,Daunorubicin, and Cytosine Arabinoside in Adults with Acute Myelogenous Leukaemia

Cytosine arabinoside and daunorubicin used in an intensive intermittent regimen have been shown to be an effective combination for the induction of complete remissions in 14 out of 23 adult patients with acute myelogenous leukaemia. This gives an overall complete remission rate of 60%. A further patient had a good partial remission. The addition of L-asparaginase to the regimen has not increased the incidence of remission and there were more side effects in the L-asparaginasetreated group. Of the 10 patients treated with L-asparaginase in addition to cytosine arabinoside and daunorubicin, five achieved a complete remission. Of the 13 patients treated with cytosine arabinoside and daunorubicin without L-asparaginase, nine achieved a complete remission and one a good partial remission.     

Durable remissions are rare following high dose therapy with autologous stem cell transplantation for adults with "paediatric" bone and soft tissue sarcomas

BACKGROUND: The role of high dose therapy (HDT) with autologous stem cell transplantation (AuSCT) for the treatment of bone and soft tissue sarcomas remains investigational. There are few reports examining this strategy focusing on the adult population. METHODS: We retrospectively reviewed our experience of adult patients undergoing HDT and AuSCT for 'paediatric' sarcomas. RESULTS: A total of 17 patients (14 male, 3 female) with median age at transplant of 24 years (range 20 - 41) were identified. The diagnosis was Ewings sarcoma/PNET (10), osteosarcoma (5) and rhabdomyosarcoma (2). Status prior to HDT, following conventional-dose chemotherapy +/- surgery +/- radiotherapy, was complete remission (CR) (6), partial remission (PR) (6), stable disease (1) and progressive disease (4). There was no transplant-related mortality. Two patients remain disease free beyond four years and both received HDT as part of their primary therapy (CR1 and PR1) however, the median progression free survival and overall survival following AuSCT for the entire cohort was only 7 months (range: 2-92 months) and 13 months (range: 2 - 92 months), respectively. CONCLUSION: HDT and AuSCT infrequently achieves prolonged remissions in adult patients and should only be considered in patients who are in a PR or CR following conventional-dose therapy. Further studies are required to define the role of HDT with AuSCT for adult patients with sarcoma.     

Zoledronic Acid Therapy of Patients With Paget Disease of Bone Resistant to or With Unsustained Remission Following Prior Bisphosphonate Therapy

Objective: To evaluate the effect of zoledronic acid (ZA) in patients with Paget disease (PD) who had not had a biochemical remission with prior bisphosphonate therapy or had a remission ≤12 months.Methods: The effects of ZA therapy were studied in 14 patients aged 54 to 90. Serum alkaline phosphatase (ALP) levels were elevated to at least 40% above the normal reference range, and glomerular filtration rates (GFRs) were ≥40 mL/minute. ZA (5 mg) was infused over 15 minutes. ALP and urine N-telopeptide/creatinine (NTx/Cr) were obtained before therapy and at 3, 6, 9, and 12 months, and thereafter at 4-month intervals.Results: At baseline, ALP ranged from 141 to 1,009 U/L. In 13 patients, ALP fell to normal following ZA administration. Remissions occurred in 9 patients who had not previously had a remission. Remissions varied from 12 to 60 months and were more prolonged in 4 patients with prior remissions ≤12 months. ZA failed to induce a remission in 1 patient. Ten to 12 days after therapy in 3 asymptomatic patients, serum calcium levels fell to 7.9, 8, and 8.3 mg/dL. Other than flu-like symptoms in 3 patients after ZA infusion, there were no other adverse effects.Conclusion: Therapy with ZA induced remissions in 13/14 patients and induced more prolonged remissions in patients who previously had remissions ≤12 months. The lack of remission in 1 patient despite 2 courses of therapy is evidence of a continuing therapeutic challenge for some patients with a more resistant form of PD.Abbreviations: ALP = alkaline phosphatase Cr = creatinine NTx = N-telopeptide 25-OHD = 25-hydroxyvitamin D PD = Paget disease ZA = zoledronic acid     

131I]metaiodobenzylguanidine therapy of malignant pheochromocytoma: interference of medication

Malignant pheochromocytoma may present as a widespread metastatic disease, which is little or non-responsive to external beam radiotherapy and chemotherapy. The prognosis of these patients is bad due to both the progressive metastasis and the secretion of excess catecholamines which may cause hypertensive episodes. For these conditions [131I]metaiodobenzylguanidine (131I-MIBG) therapy may be an alternative treatment modality to induce both tumor remission and reduction of hormonal activity of the disease. The experience with 131I-MIBG therapy in four patients with metastatic malignant pheochromocytoma at The Netherlands Cancer Institute is reviewed. One patient with abdominal tumor recurrence and metastases to the lymph nodes and lungs had a partial remission of disease for 3 years; a second had a mixed response together with palliation and two other patients had stable disease, but were relieved of bone pain and severe hypertension, respectively. It is essential to be aware of the medication the patient is using, as many drugs are known or may be expected to interfere with the uptake and/or retention of 131I-MIBG by the tumor cells. The case of a significant reduction of 131I-MIBG uptake and retention by Labetalol in one of the patients is discussed. It is concluded that 131I-MIBG therapy may induce objective remission in patients with malignant pheochromocytoma and is certainly meaningful in the reduction of hormonal activity, the control of hypertension and the relief of pain from metastases.     

The results of treatment of selected patients with ANLL with low-dose Ara-C

Low dose Ara-C (10-15 mg/m2) was administered subcutaneously in 1-5 courses of 14 to 21 days to 16 patients with acute nonlymphoblastic leukaemia, mostly in elderly persons and/or with pancytopenia in whom conventional chemotherapy was contraindicated or ineffective. 18 of the 26 patients were females and 8 males. The mean age was 54.9 years ranging from 31 to 81 years. Mean duration of treatment was 15.2 days. Five complete remissions and three partial remissions were obtained. The mean duration of complete remission was 4.7 months and the mean duration of partial remission was 6.7 months. Aggravation of cytopenia during the treatment and hypocellularity of bone marrow aspirates at the end of therapy suggest that low dose Ara-C exerts its main activity by suppression of leukaemic proliferation rather than by induction of differentiation in malignant cells. Our results show that low dose of Ara-C could be valuable alternative treatment in patients with contraindications or ineffectiveness of conventional intensive chemotherapy.     

Is first salvage chemotherapy the last-line chemotherapy in children with Hodgkin's disease? A tentative answer based on long observation of two patients

In 82 children affected with Hodgkin's disease, in whom a complete remission was obtained, the first relapses occurred in 13 patients, their outcome was a follows: one child died of relapse and in 12 others second complete remissions were achieved. They were durable in 10 children (median, 65.5 months). Two remaining children had further relapses, their treatment consisted of four successive salvage chemotherapies. Both patients are now in their fifth complete remission. The third-line chemotherapy was already introduced 78+ months and 39+ months ago respectively. We believe that it is not possible to determine exactly the end-stage of Hodgkin's disease in those children and adolescents who have failed the first-line salvage chemotherapy.     

Intravenous and oral demethoxydaunorubicin (NSC 256-439) in the treatment of acute leukemia and lymphoma: a pilot study

Demethoxydaunorubicin (DMDR), a new anthracycline available both for intravenous and oral administration, was given in 14 cases of leukaemia, non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) replacing either daunorubicin (DNR) or doxorubicin (DOX) in conventional chemotherapy regimes. In acute leukaemia (6 myeloblastic and 1 common lymphoblastic) there were 5 complete (CR) and 2 partial (PR) remissions; one patient, previously brought into remission with a regime including i.v. DMDR was thereafter maintained in CR with oral DMDR. Among the patients treated with the oral DMDR, 2 NHL cases were treated; 1 patient had a sustained remission of 12 months so far, with DMDR alone; another patient had a CR with a combined regime. In MM, one patient with very advanced disease treated with i.v. DMDR/CHOP did not respond, but three cases treated with oral DMDR plus other drugs showed a partial remission. Toxic effects were limited to brief episodes of nausea and vomiting in a few i.v. treated patients; a prolonged bone marrow depression was observed in one case only. No cardiotoxic effect was recorded.     

Efficacy of lomustine, teniposide, doxorubicin, bleomycin and prednisone (LTABP) or adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in the treatment of malignant lymphogranulomatosis resistant to MOPP]

LTABP regimen was applied to 18 patients in IIB and IV stage of malignant lymphogranulomatosis resistant to MOPP. The obtained results were compared with historical control group of 18 patients with similar stage of the disease treated according to ABVD regimen. In both regimens courses were repeated every 28 days or more rarely, when leucopenia and thrombocytopenia prolonged. Only patients who had received at least 3 courses were analysed. In the LTABP group the complete remission was obtained in 10 cases (55%) while partial remission in 6 (33%). In the group treated with ABVD complete remission was obtained in 4 cases (22%) and partial in 9 cases (50%). In the LTABP group 11 patients are still alive and remain in complete remission, while in ABVD group--4 patients. The most frequent side effects in both groups included leucopenia, thrombocytopenia and symptoms of gastrointestinal intolerance. The LTABP regiment allows to obtain higher percentage of the complete remission than ABVD.     

Therapy with Zoledronic Acid, 5 Mg,for a Patient with Paget Disease of Bone

ObjectiveTo describe the effects of an infusion of zoledronic acid in a patient with Paget disease of bone (PD) who had been treated unsuccessfully with several other bisphosphonates.MethodsThe patient’s treatment history is described, and his response to various bisphosphonates, including zoledronic acid, is discussed.ResultsThe patient was a 61-year-old man when a diagnosis of PD was made on the basis of an elevated serum alkaline phosphatase (ALP) level of 391 U/L (reference range, 45 to 135). Pagetic bone changes were noted on bone scan and x-ray examinations. Treatment with etidronate had no effect on ALP levels. This intervention was followed by 2 courses of intravenous therapy with pamidronate, which decreased ALP levels by 57% and 55% without inducing a remission. Subsequent oral treatment with alendronate and then risedronate yielded unsustained biochemical remissions of 6 months each. Most recently, therapy with an infusion of 5 mg of zoledronic acid induced a remission that is thus far 20 months in duration. With this therapy, the patient has experienced no side effects, and he has noted a decrease in bone pain.ConclusionThis case study shows that a patient with PD who received successive treatments with several bisphosphonates with inadequate responses or only brief remissions was more effectively treated with a single 5-mg infusion of zoledronic acid. This patient’s therapeutic responses illustrate the relative efficacy of available bisphosphonates and the potential for longer-lasting remissions with zoledronic acid in patients with PD. (Endocr Pract. 2008;14:607-610)     

Clinical management of patients with invasive cervical cancer following a negative Pap smear

Among 535 patients with invasive cervical carcinoma seen between January 1975 and June 1986, 26 were found to have developed the disease within six months (65 percent), 35 within 12 months (88 percent), 37 within 13 months (93 percent), and three developed the disease within 17 months after a negative Pap smear. Eighty-eight percent of these 40 patients were under age 40 at diagnosis. Rapidly progressive cancers are highly resistant to radiation therapy. Seven stage IB patients treated only with radiation died within nine to 29 months after initial therapy. By contrast, 15 patients treated by radical hysterectomy and four by radical hysterectomy and post-surgical radiation were alive with no evidence of disease from six to 109 months after surgery (median, 30 months). Six of nine patients with stage II to IV disease treated with radiation have died; the remaining three are alive. One patient is well 14 months after therapy, but two others have developed metastases seven and 12 months after treatment. Surprisingly, 37 of 40 patients had symptoms of pain, bleeding, and discharge at the initial diagnosis, but their physicians had a false sense of security because of a recent negative Pap smear. Early biopsy diagnosis and radical hysterectomy with bilateral pelvic lymphadenectomy is the most effective management for this cancer.     

Phase II clinical study of toremifene in patients with metastatic breast cancer. Preliminary communication

Twelve postmenopausal women with inoperable or metastatic breast cancer were given toremifene at a daily dose of 60 mg. The patients had no prior endocrine or cytotoxic therapy and further inclusion criteria were bidimensionally measurable disease, performance status above 50, expected survival of more than 3 months and estrogen receptor status positive or undetermined. Objective response [complete remission (CR) + partial remission (PR)] was achieved in 6 patients (50%) and stable disease was obtained in 5 patients. No side effects of the treatment were noted.