High-dose cytarabine and mitoxantrone in consolidation therapy for acute promyelocytic leukemia.

The objective of our study was to evaluate high-dose cytarabine in consolidation therapy in patients with newly diagnosed acute promyelocytic leukemia (APL). Patients (age 16-60 years) received induction therapy according to the AIDA protocol (all-trans retinoic acid, idarubicin) followed by one cycle of ICE (idarubicin, cytarabine, etoposide) and two cycles of HAM (cytarabine 3 g/m(2) q12h, days 1-3; mitoxantrone 10 mg/m(2), days 2 and 3). From 1995 to 2003, 82 patients were enrolled. In total, 72 patients (88%) achieved a complete remission, and 10 patients (12%) died from early/hypoplastic death (ED/HD). A total of 71 patients received at least one cycle of HAM. Relapse-free survival (RFS) and overall survival (OS) after 46 months were 83 and 82%, respectively. White blood cell count above 10.0 x 10(9)/l at diagnosis and additional chromosomal aberrations were unfavorable prognostic markers for OS, whereas no prognostic markers for RFS were identified including FLT3 mutations. In conclusion, high-dose cytarabine in consolidation therapy for patients with newly diagnosed APL is an effective treatment approach.

Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea.

The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.

A comparison of polychemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma. A prospective trial of the German Myeloma Treatment Group.

406 untreated multiple myeloma patients of stage I (n = 54), II (n = 148) and III (n = 204) were enrolled in the trial. 51/54 stage I and 60/148 stage II patients were asymptomatic and followed without treatment until disease progression (progression free survival: 60% after 4 years for stage I versus 50% after 1 year for stage II). Symptomatic patients of stage I (n = 3/54) and II (n = 88/148) presenting with tumour progression, received melphalan 15 mg/m2 intravenously (i.v.) and prednisone 60 mg/m2 oral days 1-4 (MP). Stage II disease remission rate was 59%, and 50% tumour related survival (TRS) was 59 months. Stage III patients were randomised to receive MP or VBAMDex (vincristine/BCNU/doxorubicin/melphalan/dexamethasone) treatment. 43% of MP treated patients responded compared with 64% of the VBAMDex group. 50% TRS was 36 months in both groups without a detectable difference. 117 responders of stage II and III with stable disease were randomised to receive either IFN-alpha (5 x 10(6) IU, subcutaneous (S.C.) 3 times per week) or no maintenance treatment. The relapse rate in both groups was 50% after 13 months. No survival benefit for IFN alpha treated patients was observed (50% TRS: 45 months).

Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia.

Since January 1989, 56 patients (31 females and 25 males) with de novo acute myelogenous leukemia have been included in the study. Their median age was 43 years (range, 15 to 60 years) with a distribution according to French-American-British morphologic subtypes as follows: six M1, 14 M2, four M3, 19 M4, nine M5, two M6, and two M7. The induction regimen (IDAC) consisted of idarubicin (12 mg/m2/d intravenously [IV] days 1 to 3) in combination with cytarabine (100 mg/m2/d continuous IV days 1 to 7). Patients achieving complete remission (CR) or partial remission received another cycle of IDAC followed by NOVE (mitoxantrone 10 mg/m2/d IV days 1 to 5 and etoposide 100 mg/m2/d IV days 1 to 5). Fifty-four patients are evaluable for response: after two cycles of IDAC, 42 patients had attained CR (78%), while 76% of these had already reached CR after the first cycle. Of the initial 11 nonresponders to IDAC, four obtained CR after NOVE. Thus, 46 of 54 patients (85%) achieved CR after sequential treatment with IDAC and NOVE. In the last 17 patients who entered CR or partial remission after the first cycle of IDAC, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 3 micrograms/kg/d) was administered for 6 days starting 3 days prior to the second cycle of IDAC. For consolidation with NOVE, rhGM-CSF was given according to the same dosage schedule. After 72 hours of rhGM-CSF treatment, the white blood cell count showed a median 3.9-fold increase, without appearance of myeloblasts in the peripheral blood. During sequential chemotherapy, no significant complications (in particular, no major cardiac toxicity) were observed. Postremission, patients were either given bone marrow transplants, received late consolidation with high-dose cytarabine/mitoxantrone, or were followed up without any further treatment. Of the 46 patients evaluable for disease-free survival, 21 patients (45%) remain in CR with a 34% probability of disease-free survival at 37 months. The response-adapted treatment with IDAC/NOVE is effective and very well tolerated. To define the therapeutic impact of rhGM-CSF, a randomized trial will be required.

The use of dose-intensified chemotherapy in the treatment of metastatic nonseminomatous testicular germ cell tumors. German Testicular Cancer Study Group.

With the use of a cisplatin-based chemotherapy, metastatic testicular cancer has become a model for a highly curable malignant disease. Current data show that 70% to 80% of patients with this disease will achieve long-term survival following cisplatin/etoposide/bleomycin therapy. The role of high-dose chemotherapy with autologous stem cell support is being investigated in metastatic germ cell cancer in attempts to improve outcome for patients whose disease relapses after standard-dose chemotherapy and for those who present initially with advanced metastatic disease. Prognostic categories for patients receiving high-dose salvage chemotherapy have recently been developed: cisplatin-refractory disease, beta-human chorionic gonadotropin values greater than 1,000 U/L, and primary mediastinal germ cell tumors are factors characterizing patients who will derive less benefit from high-dose chemotherapy than those with chemosensitive disease at relapse. While standard-dose salvage chemotherapy achieves only a 20% long-term survival rate, high-dose salvage chemotherapy may yield a cure rate of approximately 40%. A randomized study comparing high-dose therapy with conventional-dose therapy (IT94 coordinated by the European Group for Blood and Marrow Transplantation) in patients with relapsed disease is ongoing to substantiate this observation. The use of dose-intensive therapy as first-line treatment is currently being studied by several institutions. High-dose therapy may be better tolerated when used first line compared with its use in the salvage situation, and may also achieve a rapid initial cell kill before cytostatic drug resistance develops. The German Testicular Cancer Study Group has developed a sequential high-dose combination regimen of cisplatin/etoposide/ifosfamide given with granulocyte colony-stimulating factor and peripheral blood stem cell support for four cycles every 3 weeks. This ongoing study, started in 1990, had accrued 218 patients with advanced testicular germ cell tumors as of June 1997. Of 141 evaluable patients receiving dose levels 1 through 5, 82 (58%) have achieved complete remission with no evidence of disease and 32 (23%) have achieved partial remission with marker normalization. The early death rate was 8%. Overall and event-free survival rates at 2 years are 78% and 73%, respectively, with a projected 5-year overall survival rate of 74%. Despite favorable preliminary results, this approach cannot be considered standard treatment. Currently, high-dose chemotherapy with peripheral blood stem cell transplantation should be administered to patients with testicular cancer only within controlled clinical trials to allow long-term cure rates and treatment-related late side effects to be evaluated.

Multicentre study on intensified remission induction therapy for acute myeloid leukemia.

In a cooperative study at 13 centres in the Federal Republic of Germany, 213 adult patients with AML were treated for remission induction by a 9-day regimen consisting of cytosine arabinoside, daunorubicin and thioguanine (TAD) according to previously described sequencing. Complete remission was achieved in 70% of all patients. Complete remission rate was 57% in the 49 patients 60 years of age and older and 74% in the 164 patients under 60 years. Sixty-eight per cent of all complete remissions and 75% of those in the higher age group were induced by one induction course. Median survival was 10 months for all patients treated and 16 months for responders. Median remission duration was 13 months with 72 patients still in continuous remission for 1-31 months. Remission duration was not significantly different for patients treated either by monthly maintenance therapy or induction type consolidation without further therapy. However, patients completing two consolidation courses had a significantly longer remission duration of 22 months. Compared to similar multicentre studies on AML therapy the intensified induction regimen applied in this study shows an improvement even in older patients.

Synchronous double primary malignant lymphoma of low grade malignancy and early cancer (collision tumor) of the stomach.

Collision tumors of the stomach are rare tumors, with about 32 cases reported in the English and German literature. In this report the case of a 65-year-old male with a synchronous primary malignant lymphoma (immunocytoma) and an early cancer of the stomach is presented. A total gastrectomy with esophago-jejunostomy was performed. Postoperatively the affected region was irradiated. 30 months later a re-evaluation did not reveal any recurrence of the disease. The diagnostic and therapeutic problems of collision tumors of the stomach and a possible relationship between the two tumors are discussed against the background of the literature.

[Foudroyant course of AIDS-induced cytomegalovirus retinitis]. / Foudroyante Verläufe bei AIDS-bedingter CMV-Retinitis.

Of 57 patients at Karlsruhe Municipal Eye Hospital with manifest acquired immune deficiency syndrome, ocular involvement was found in 34%. In the prefinal stage (on average 6 months ante finem), 25% of these patients developed typical, rapidly progressing cytomegalovirus retinitis with intraretinal hemorrhages and necrosis, which responded well to combined intravenous and intravitreal DHPG therapy. Almost all the patients died of global respiratory insufficiency caused by pneumocystis carinii or atypical mycobacteria.

[Folic acid levels in patients with compensated renal failure and during long-term haemodialysis (author's transl)]. / Folsäurespiegel bei Patienten mit kompensieter Niereninsuffizienz und unter Dauerdialyse.

Folic acid concentration in plasma and erythrocytes and vitamin B12 concentration in plasma were determined by radioassay in 56 patients with chronic renal failure. Compensated retention was present in 31, while 25 were haemodialysed at regular intervals, 14 at home, and 11 in hospital. One patient had megaloblastic anaemia. Mean folic acid concentration in plasma for the whole group was 4.60 microgram/l (normal 8.30 +/- 2.57 microgram/l), in RBC 385 microgram/l (normal 459 +/- 143 microgram/l. Vitamin B12 levels were normal. These was no significant difference in folic acid levels betwwen patients on home or on hospital dialysis. During dialysis there was a fall in folic acid concentration in plasma which was proportional to the intial levels. After a four-week replacement pause folic acid concentration in RBC had not decreased in those patients on long-term dialysis who had previously received folic acid. The decreased folic-acid concentration in plasma of patients in compensated chronic renal failure is not due to the renal failure. Folic acid concentration in RBC is decisive in the assessment of folic acid deficiency.

Polychemotherapy of acute myelogenous leukemia in a patient with acute intermittent porphyria.

The safety of drugs in hepatic porphyrias has largely been established by clinical experience, which is very limited in the case of antineoplastic agents. We administered three cycles of polychemotherapy consisting of daunorubicin, cytarabine and 6-thioguanine, and modified supportive care to a 33-year-old Turkish woman suffering from acute myelogenous leukemia. The urinary excretion of total porphyrins, porphobilinogen, and aminolevulinic acid was continuously monitored. Excretion of these metabolites was permanently elevated, but the values were comparatively low during cytotoxic therapy while peak values were recorded at the onset of fever during bone marrow aplasia; yet there were no clinical signs of porphyritic attacks at that time. A few potentially unsafe drugs were tolerated without an increase in porphyrin excretion. Although the susceptibility to drugs is highly variable in patients with hepatic porphyrias, the treatment of malignancy in these patients seems justified as long as porphyrin excretion under therapy is not grossly elevated over baseline values and appropriately modified supportive care is administered.

[Diagnosis of acute myelogenous leukemia]. / Diagnostik der akuten myeloischen Leukämien.

Acute myeloid leukemia (AML) is a heterogeneous disease. The diagnosis is based on the demonstration of immature myeloid cells in Pappenheim stained blood and bone marrow smears. Using the criteria of the French-American-British Cooperative Group, the myeloid leukemias can be divided into six subgroups (FAB classification). Recently, the development of several new techniques has led to a more detailed cell characterization. This review article will discuss the diagnostic procedure in AML.

[Primary calcification in Hodgkin's disease]. / Primär verkalkte Lymphogranulomatose

A chance radiological observation of a calcified mediastinal tumour in 23-year-old woman led to its operative removal. Histologically it proved to be a Hodgkin's sarcoma in a nodular sclerosing form of Hodgkin's disease. There was no other clinical evidence of Hodgkin's foci and, after radiotherapy, the patient has been without recurrence for over one year.

[Portal vein aneurysm and liver fibrosis in myelofibrosis]. / Pfortaderaneurysma und Leberfibrose bei Myelofibrose.

In a 54-year-old woman with oesophageal varices there were the unusual morphological findings of portal-vein aneurysm and irregular hepatic fibrosis. The patient had been treated for 8 years for polycythaemia vera with transition into myelofibrosis. Histologically the hepatic tissue showed occlusion of intrahepatic portal-vein branches by organised thrombi, as well as angiomatous vessels in the sclerosed portal areas. the increased pressure as well as medial atrophy with portal-vein sclerosis were the cause of the portal-vein aneurysm. Portal hypertension may have been the result of intrahepatic vascular obstruction and of the increased flow through the enlarged spleen. It is suggested that interaction of several factors, related to the basic disease of myelofibrosis led to these complex anomalies of the liver and portal vascular system.