[The hypertensive emergency situation : Recommendations for initial drug therapy management]. / Der hypertensive Notfall : Empfehlungen zum initialen medikamentösen Therapiemanagement.

The hypertensive emergency situation is characterized by an acute-mostly life-threatening-blood pressure derailment with the risk of acute end organ damage. It is an acute manifestation of arterial hypertension, which manifests in a variety of symptoms. The etiology is in most cases long-term (chronic) hypertension as a result of low compliance or inadequate antihypertensive therapy. It can also occur as a first manifestation of arterial hypertension. It requires timely antihypertensive drug therapy, which should be initiated in an intensive or intermediate care unit. The choice of antihypertensive therapy regimen should be based on the underlying end organ damage. Fast-acting, easily controllable and intravenously administered substances should be preferred. The most commonly used substances (groups) are urapidil, nitroglycerin, beta blockers and short-acting calcium channel blockers. With a few exceptions, a deliberate, rapid reduction in blood pressure of no more than 20-25% of the initial value is sufficient for extracerebral causes. A subsequent systolic blood pressure target of 160/100 mm Hg should be aimed for within the next 2-6 h. An overly rapid drop in blood pressure can lead to reduced blood flow to the central nervous system due to changes in autoregulation. Exceptions to this rule are acute aortic dissection and flash pulmonary edema-in these cases, prompt blood pressure normalization should be achieved. The initial acute therapy should be followed by a more detailed investigation of the cause and a long-term therapy setting based on this.

Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial.

In this trial, acute myeloid leukemia patients (pts) aged 61-80 years received MICE (mitoxantrone, etoposide and cytarabine) induction chemotherapy in combination with different schedules of granulocyte colony-stimulating factor administration. Pts in complete remission were subsequently randomized for two cycles of consolidation therapy: mini-ICE regimen (idarubicin, etoposide and cytarabine) given according to either an intravenous (i.v.) or a 'non-infusional' schedule. Among the 346 pts randomized for the second step, 331 pts received consolidation-1 and 182 consolidation-2. A total of 290 events (255 relapses, 35 deaths in first CR) have been reported. The median follow-up was 4.4 years. No significant differences were detected in terms of disease-free survival (median 9 vs 10.4 months, P=0.15, hazard ratio (HR) =1.18, 95% confidence interval (CI) 0.94-1.49) - primary end point - and survival (median 15.7 vs 17.8 months, P=0.19, HR=1.17, 95% CI 0.92-1.50). In the 'non-infusional' arm grade 3-4 vomiting (10 vs 2%; P=0.001) and diarrhea (10 vs 4%; P=0.03) were higher than in the 'i.v.' arm, whereas time to platelet recovery >20 x 10(9)/l (median: 19 vs 23 days; P=0.02) and duration of hospitalization (mean: 15 vs 27 days; P<0.0001) was shorter. The 'non-infusional' consolidation regimen resulted in an antileukemic effect similar to the intravenous regimen, which was less myelosuppressive and associated with less hospitalization days.

On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group.

We report the results of a prospective study in patients more than 65 years of age in whom two different therapeutic strategies were compared: immediate intensive-induction chemotherapy (arm A) versus "wait and see" and supportive care and mild cytoreductive chemotherapy only for relief of progressive acute myeloid leukemia (AML)-related symptoms (arm B). The major objective of the study was to compare survival outcome of both regimens. Thirty-one patients on arm A received one or two courses of daunorubicin, vincristine, and cytarabine for remission induction followed by one additional cycle for consolidation in case of complete remission (CR). Among 29 patients on arm B, cytoreductive chemotherapy (hydroxyurea, cytarabine) had to be initiated for palliation of leukemia-associated complications in 21 patients at a median of 9 days after diagnosis. Overall survival duration for patients treated on arm A was significantly (P = .015) longer than the survival in arm B (median survival, 21 weeks v 11 weeks; projected survival at 2.5 years, 13% v 0%). Eighteen (58%) of arm A patients and none (0%) of arm B patients entered CR. Of the first group, projected disease-free survival at 2 years is 17%. The median percentages of days spent in the hospital by arm A and B patients were 55% and 50%, respectively. This study shows that a strategy based on modern supportive care and a wait and see approach yields extremely poor results. It is not superior in regard to the frequency of hospital admission and is inferior regarding survival outcome.

An update: 12-year follow-up of patients with hairy cell leukemia following treatment with 2-chlorodeoxyadenosine.

Long-term results of both pretreated and previously untreated patients (pts) with hairy cell leukemia (HCL) using uniformly a single 7-day course of 2-chlorodeoxyadenosine (2-CdA) by continuous infusion are reported. In addition, the probability of obtaining another response with this drug in pts who relapsed after 2-CdA treatment will be addressed. A total of 44 consecutive pts (34 males, 10 females) with a median age of 57 years (range 33-77) at the time of initiation of 2-CdA treatment were analyzed. In all, 11 pts were pretreated with either splenectomy (n=6), interferon alpha (n=9) or deoxycoformycin (dCF) (n=3) or all procedures in sequence. Two pts treated with dCF did not respond to dCF, but only 2-CdA. The median time to the start of 2-CdA treatment of the 11 pretreated pts was 47 months (mo) (10-160). Out of 44, 43 (98%) achieved complete response (CR) (13 pts with residual disease-RD), one pt reached a good partial response with a single cycle of 2-CdA. Out of 44 pts, 13 had no nonhematologic toxicities at all. Toxicities (WHO grade I-IV) were mainly of grade I and II, in one pt grade IV infectious complication. Bone marrow biopsies were performed at the time of recovery of hematopoiesis, thereafter at 2-3 mo intervals, thereafter at 6 mo, and finally annually in 35 pts. The median follow-up is 8.5 years (0.1-12.2). Disease-free survival from the start of 2-CdA treatment is 36% at 12 years (median 8.4 years), 17/44 pts relapsed. Nine of these pts were treated with 2-CdA again, eight achieved a second CR (median 2.5 yrs), one pt did not respond. Eight of our cohort had a second malignancy before receiving 2-CdA. Six pts died in CR due to the second malignancy. The overall survival at 12 years after the start of 2-CdA treatment is 79%. 2-CdA is a safe and effective treatment of HCL inducing complete remissions in the majority of pts with only a single cycle of 2-CdA, and a paucity of toxicities. Responses are durable and long-lasting. Pts who relapsed following treatment with 2-CdA responded to subsequent retreatment with 2-CdA.

Multicenter randomized phase II trial of idarubicin vs mitoxantrone, combined with VP-16 and cytarabine for induction/consolidation therapy, followed by a feasibility study of autologous peripheral blood stem cell transplantation in elderly patients with acute myeloid leukemia.

To compare the antileukemic efficacy of idarubicin and mitoxantrone in elderly patients with acute myeloid leukemia (AML) and to evaluate the feasibility of autologous transplantation using PBSC after consolidation in those with a good performance status, 160 patients (median age 69 years), with AML at diagnosis, 118 of them with de novo AML and 42 with AML secondary to myelodysplastic syndrome or toxic exposure (sAML), received induction treatment with idarubicin, 8 mg/m2/day or mitoxantrone, 7 mg/m2/day, on days 1, 3, and 5, both combined with VP-16, 100 mg/m2/day on days 1 to 3 and cytarabine (araC), 100 mg/m2/day, on days 1 to 7. G-CSF, 5 microg/kg/day, was administered after chemotherapy in patients aged more than 70 years. Patients in complete remission (CR) received one course of consolidation using the same schedule as for induction except the araC administration was shortened to 5 days. Some patients younger than 70 years were then scheduled for autologous stem cell harvest on days 5 to 7 of G-CSF, 5 microg/kg/day, initiated after hematopoietic recovery from consolidation. Autologous transplantation was performed following an additional chemotherapy conditioning. Ninety-five patients (59%) achieved CR, without significant difference between the idarubicin (56% CR) and mitoxantrone (63% CR) group. There was also no significant difference in CR rate between de novo AML (63%) and secondary AML (55%) (P = 0.12). Patients aged < 70 years had 67% CR, while patients aged > or = 70 years had 49% (P = 0.02). There was no significant difference in the duration of aplasia between the two arms. Median time to neutrophil recovery was 22 days in patients who received G-CSF following induction and 27 days in patients who did not (P = 0.006). Severe extrahematologic toxicities of induction did not differ between the two arms and included sepsis (39%), diarrhea (13%), hyperbilirubinemia (8%), hemorrhage (6%) and vomiting (6%). Overall, 14 patients (9%), died from toxicity of induction. First consolidation was administered in 74 patients of whom seven (9%) died from toxicity. Nineteen patients have received transplantation. Median time to recovery of neutrophils > 0.5 x 10(9)/l was 13 days and of platelets > 50 x 10(9)/l 43 days following consolidation. There were two toxic deaths. Median disease-free survival and survival from time of achieving CR of non transplanted patients are 6 and 7 months respectively without difference between the two arms. Fourteen transplanted patients relapsed at a median of 5 months post-transplant. We conclude that this regimen is well tolerated and has a good efficacy to induce CR, without a significant difference in efficacy and toxicity between idarubicin and mitoxantrone. Intensive postinduction, including transplantation, is feasible; however, this procedure did not seem to prevent early relapse in the majority of patients. Neither the high rate of CR nor consolidation nor transplant procedure in a selected group of patients did translate into improved DFS and/or survival.

A randomized phase II study on the effects of 5-Aza-2'-deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group phase II study (06893).

5-Aza-2'-deoxycytidine combined with either amsacrine or idarubicin has been applied in a treatment protocol for patients with a relapse of acute myeloid or lymphocytic leukemia. Sixty-three patients received 5-Aza-2'-deoxycytidine 125 mg/m2 as a 6 h infusion every 12 h for 6 days in combination with either amsacrine 120 mg/m2 as a 1 h infusion on days 6 and 7 (n=30) or idarubicin 12 mg/m2 as a 15 min infusion on days 5, 6 and 7 (n = 33). Twenty-three patients (36.5%) obtained a complete remission (CR); eight of 30 patients treated with amsacrine and 15 of 33 treated with idarubicin. Patients with an interval of more than 1 year between initial diagnosis and start of the protocol achieved CR in 51.4%, compared to 15.4% for patients with an interval of less than 1 year. Patients with normal cytogenetics had a higher CR rate (61%) than those with abnormal cytogenetic findings (15.8%). Digestive tract and hematologic toxicity was prolonged, compared to standard induction schedules. Median disease-free survival was approximately 8 months, with only 20% of patients staying in remission for more than 1 year. 5-Aza-2'-deoxycytidine is a good antileukemic agent with considerable toxicity. Current results merit further investigations in previously untreated leukemia.

The presence of an HLA-identical sibling donor has no impact on outcome of patients with high-risk MDS or secondary AML (sAML) treated with intensive chemotherapy followed by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and GIMEMA Leukemia Groups (EORTC study 06921).

This report used the framework of a large European study to investigate the outcome of patients with and without an HLA-identical sibling donor on an intention-to-treat basis. After a common remission-induction and consolidation course, patients with an HLA-identical sibling donor were scheduled for allogeneic transplantation and patients lacking a donor for autologous transplantation. In all, 159 patients alive at 8 weeks from the start of treatment were included in the present analysis. In total, 52 patients had a donor, 65 patients did not have a donor and in 42 patients the availability of a donor was not assessed. Out of 52 patients, 36 (69%) with a donor underwent allogeneic transplantation (28 in CR1). Out of 65 patients, 33 (49%) received an autograft (27 in CR1). The actuarial survival rates at 4 years were 33.3% (s.e. = 6.7%) for patients with a donor and 39.0% (s.e. = 6.5%) for patients without a donor (P = 0.18). Event-free survival rates were 23.1% (s.e. = 6.2%) and 21.5% (s.e. = 5.3%), respectively (P = 0.66). Correction for alternative donor transplants did not substantially alter the survival of the group without a donor. Also, the survival in the various cytogenetic risk groups was not significantly different when comparing the donor vs the no-donor group. This analysis shows that patients with high-risk myelodysplastic syndrome and secondary acute myeloid leukemia may benefit from both allogeneic and autologous transplantation. We were unable to demonstrate a survival advantage for patients with a donor compared to patients without a donor.

Myositis, myoglobinemia, and myoglobinuria associated with enterovirus echo 9 infection.

A 30-year-old man had a "flu-like" syndrome followed by clinical and laboratory evidence of myositis localized in both thighs. Serum neutralization test results were compatible with enterovirus echo 9 infection. Severe myoglobinuria dominated the clinical picture. We discuss other possible manifestations of enterovirus echo 9 infections. To our knowledge, this report is the first describing myositis caused by enterovirus echo 9.

Kinetics of colony-forming cells (CFU-c) in adult acute leukemia and their prognostic relevance.

The in vitro growth pattern of bone marrow and peripheral blood in soft-agar cultures was studied in 50 previously untreated patients with adult acute leukemia. Patients were followed from time of first diagnosis, during induction treatment, in remission at various time intervals, at relapse and during subsequent re-induction therapy. The distribution of granulopoietic progenitor cells was analysed to determine their prognostic significance for remission incidence, remission duration and survival. All patients revealed an abnormal growth. ANLL patients showing a decreased clone number in the marrow but an increased number of clones in the peripheral blood, had a significant higher probability to enter remission and a significant longer remission than those having clones within normal range at first presentation. On the contrary, ALL patients responding to induction treatment, had a better colony and cluster growth in the bone marrow than those failing to respond. No significant correlation was found between in vitro growth and survival. It is concluded that colony-forming cells of both bone marrow and peripheral blood seems to be of some value in predicting the response rate and length of remission in ANLL and ALL, and in possibly selecting patients with a high chance to respond to current cytostatic regimens.

New drugs in the treatment of acute and chronic leukaemia: current role of mAMSA.

Several new cytostatic drugs have entered clinical Phase I-II studies for treatment of leukemia: most promising are pyrimidine analogues such as 5-Azacytosine arabinoside, 5-Aza-2-deoxycytidine, 5-Azacytidine, cyclocytidine, and 2'-2'-difluorodeoxycytidine. They act on different biochemical levels towards DNA-synthesis. Fludarabine is a purin analogue and seems very active in treating CLL. Tiazofurin is an antimetabolite counter-acting nicotinic acid with most promising activity in CML blast crisis. Other substances include deoxycoformycin, an adenosine analogue for treatment of T-cell neoplasias, 1, 25-dihydroxy vitamin D 3 as differentiation inducer, and homoharringtonine, an alkylating agent widely used for treating de novo AML in China. New anthracyclines are THP-adriamycin, fluoroadriamycin, and 4-demethoxydaunorubicin. Amsacrine (mAMSA) finally, is a synthetic aminoacridine with DNA-intercalating properties. The intact acridine ring appears essential for antitumor activity. The plasma clearance of both total amsacrine and unchanged parent species is biphasic. There is a considerable influence of hepatic and renal impairment on plasma clearance. Clinical toxicities include marked myelosuppression, gastrointestinal symptomes, phlebitis, mucocutaneous lesions, occasionally alopecia and neurotoxities. It is a very active drug, particularly in treating AML. Studies using mAMSA alone or in combination revealed comparable results to the anthracyclines. The E.O.R.T.C. Leukemia Cooperative Group has used successfully mAMSA in several trials: relapsed and refractory AML, intensive maintenance treatment during first remission in AML, and, still on-going, during intensive consolidation randomized against BMT in AML-patients under the age of 45 years, and randomized against standard consolidation between the age of 45 and 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of liposomal amphotericin B (AmBisome) versus other lipid-based formulations.

To lower amphotericin B-associated toxicity, amphotericin B may be integrated into liposomes (AmBisome) or can be administered in Intralipid 20% emulsions (Ampho-B/Lipid). The present study compares the pharmacokinetic characteristics of standard amphotericin B dissolved in glucose 5% (Ampho-B/G) (n = 6) to the alternative formulations Ampho-B/Lipid (n = 8) and Ambisome (n = 10). Ampho-B/G and Ampho-B/Lipid were infused at a dose of 1 mg/kg, while the dose of AmBisome was increased to 3 mg/kg. Infusion duration was 1 h. Pharmacokinetics of Ampho-B/G, AmB/Lipid and AmBisome showed striking differences, specifically with regard to the respective Cmax and AUC values. In fact, after application of AmB/Lipid mean Cmax values were reduced to 39% and mean AUC values were lowered to 57% compared with application of Ampho-B/G in the same patients. This compares with a 1.8-fold greater Vss for Ampho-B/Lipid and a clearance rate which was 2.1-fold faster. By contrast, application of AmBisome (at a three-fold greater dose) resulted in Cmax and AUC values eight-fold and 12-fold greater than those reached by Ampho-B/G. The higher Cmax values achieved by AmBisome relate to a four-fold smaller Vss compared with Ampho-B/G. Assuming a linear relationship between AmBisome dose and Cmax, it was concluded that even at equal doses the liposomal formulation of amphotericin B would result in significantly greater Cmax and AUC values than Ampho-B/G or Ampho-B/Lipid.

Phase II-trial of double-consolidation following intensive induction treatment for improvement of survival in elderly patients with acute myeloid leukemia.

Thirty-two consecutive, unselected acute myeloid leukemia (AML) patients (pts) of all FAB-subtypes with a median age of 68 years were treated with intensive induction chemotherapy consisting of one or two cycles of daunorubicin 30 mg/m2 day 1-3 and Ara C 100 mg/m2 as continuous infusion day 1-7. The overall CR rate was 50%, 14/24 (58%) in de novo AML, and 2/8 (25%) with preceding MDS. One patient achieved a PR of 21 months duration, 3 pts died within 7 days of the induction treatment (ED), 6 died during hypoplasia (HD), and 6 remained refractory to 2 cycles of induction. Four pts died after achieving CR. Of the remaining 12 responders, 11 pts received 2 cycles of consolidation consisting of daunorubicin 30 mg/m2 day 1, and Ara C 100 mg/m2 continuous IV infusion day 1-7. No deaths were observed during consolidation. DFS and survival of responders were 7 and 13 months respectively, survival of all pts, responders and non-responders, was 7 months. Large cooperative trials are necessary to identify those elderly pts who may benefit from intensified consolidation treatment.

Long-term outcome of postremission chemotherapy for adults with acute myeloid leukemia using different dose-intensities.

The long-term results of postremission chemotherapy for 122 consecutive, unselected adults (15-65 years) with acute myeloid leukemia (AML) were assessed in two sequential prospective studies involving an identical 3/7-type induction regimen, and in those achieving remission, another course for early consolidation using 1 day of daunorubicin instead of three. Forty-one patients reaching C.R. during the first study period, were treated with an intensive ablative maintenance ("IM") program for a period of 9 months. They were randomized to either 6 cycles of induction-type regimen or to 6 cycles of an alternating-type regimen consisting of high-dose (HD)-Ara C/AMSA or 5-azacytidine/AMSA every 6 weeks. There was no difference in disease-free survival (DFS) or survival. Results are compared with 27 patients reaching C.R. on the subsequent protocol where IM was replaced by intensive, short-term consolidation ("IC") using 1 cycle of intermediate-dose Ara C plus AMSA and 1 cycle of HD-AraC/AMSA. Fifteen patients received both courses of IC as scheduled, 12 refused the second cycle. There was no significant difference in DFS or survival. Seventeen out of the 122 patients refused either IM or IC following early consolidation ("refusals"). They received no further treatment and served as control. Fourteen percent of all patients underwent autologous or allogeneic bone marrow transplantation (BMT) at different stages of their disease, equally distributed amongst the IM and IC-group. Median DFS was 3.3 months in the refusal group, 12.4 months in the IM-group, and 18.4 months in the IC-group when censored for BMT (p = 0.01) with 6%, 12%, and 40% in C.C.R. at 50 months. Accordingly, median survival was 5.4, 20 and 47 months (p = 0.001) with 6%, 15%, and 45% of patients alive at 5 years. There was a definite trend (p = 0.14) for a higher proportion of long-term survivors in the IM-group when BMT was performed (not censored), while long-term survival was identical in the IC-group whether BMT was considered for analyses (not censored) or not (censored). Median follow-up for both studies is 5.6 years, the longest, 10 years. In conclusion, progressive increments in the intensity of postremission therapy yields in a graded, significant improvement of remission duration and survival.

Successful treatment of accelerated and blastic phase of chronic myeloid leukemia with high-dose interferon alpha and hydroxyurea: a novel approach.

Six patients with either acceleration or blast crisis of transformed chronic myeloid leukemia (CML) were treated with high-dose interferon alpha in combination with hydroxyurea. All patients responded to the treatment by reversal to stable chronic phase. Two of these patients responded repeatedly during their course of disease. Median time for return to chronic phase was 4 weeks. Adverse side-effects such as nausea, vomiting, hairloss, fever, prolonged cytopenia were not observed.

Managing fungal and viral infection in the immunocompromised host.

The increasing number of opportunistic fungal infections in neutropenic cancer patients has become of major concern. Postmortem examinations have shown that more than half of the deaths attributed to infection were due to disseminated fungal infections. Candida species are the major pathogens. Unfortunately, the early diagnosis of serious fungal invasion is exceedingly difficult in these patients, since the manifestations of infection are ill-defined and the organisms can only rarely be isolated from blood cultures. Therefore, empirical antifungal therapy in febrile patients early in the course of disease appears necessary to prevent fungal superinfections and to control clinically undetected fungal invasion. Even if a fungal infection is diagnosed, treatment options are limited to a small number of drugs, and the chance of successful treatment is slim. Amphotericin B remains the most effective drug for systemic fungal infection; however, it is also the most toxic antimicrobical in use. Reduction of its toxicity and, simultaneously, improvement of its effectiveness can be achieved by incorporation into liposomes, although liposomal amphotericin B is not yet available commercially. The newer azoles, such as ketoconazole, vibunazole, and itraconazole are orally active and less toxic. Azoles have been successfully used in the treatment of superficial candidal infections; they are not very active in systemic candidiasis. Inhibitors of the cell wall biosynthesis of candida species include inhibitors of chitin and glucan biosynthesis. Echinocandins and papulacandins interfer with the glucan synthesis and show good anticandidal activity. Their therapeutic potential is currently being explored in clinical trials. Neutropenic patients and particularly bone marrow transplant (BMT) recipients are, in addition to fungal infections, at very high risk for herpesvirus infections: herpes simplex virus (HSV) 0-20 days after BMT, cytomegalovirus (CMV) 40-80 days after BMT, varicella zoster virus (VZV) 100-160 days after BMT, and Epstein-Barr virus (EBV) 14-21 days after BMT. Acyclovir and vidarabine are, at present, the only antiviral drugs available for HSV and VZV infections, acyclovir apparently being the more effective. It is also the drug of choice for prevention of HSV infections in severely immunocompromised, i.e., BMT, patients. Bromovinyldeoxyuridine seems to be suitable for systemic treatment of HSV-1 and VZV infections in these patients. Its potency in inhibiting HSV-1 and VZV replication is superior to that of ACV, and in therapeutic doses it is nontoxic to hematopoietic progenitor cells.(ABSTRACT TRUNCATED AT 400 WORDS)

New drugs in the treatment of acute and chronic leukemia with some emphasis on m-AMSA.

Several new cytostatic drugs have entered clinical phase I-II studies for the treatment of leukemia: the most promising are pyrimidine analogs such as 5-aza-cytidine, 5-aza-2'-deoxycytidine, 5-aza-cytosine arabinoside, and 2',2'-difluorodeoxycytidine. Fludarabine, a fluorinated purine analog, appears to be active in CLL and multiple myeloma. Deoxycoformycin, an adenosine analog, showed good activity in the treatment of hairy cell leukemia and T-cell neoplasias. 2-chloro-deoxyadenosine has recently been introduced into the treatment of CLL and hairy-cell leukemia refractory to deoxycoformicin. Tiazofurin, an antimetabolite which interferes with nicotine-adenine-dinucleotide (NAD) metabolism, has been applied in CML blast crisis. Other agents include 13-cis retinoic acid and 1, 25-dihydroxy vitamin D3 as differentiation inducers, and homoharringtonine, an alkylating agent which is widely used for ANLL treatment in China. Among new anthracyclines, aclarubicin, idarubicin, THP-adriamycin and fluoro-adriamycin should be mentioned. Mitoxantrone, a substituted anthraquinone, has successfully been applied in the treatment of relapsed and refractory ANLL. Amsacrine (m-AMSA), finally, is a synthetic aminoacridine which intercalates into DNA and inhibits DNA topoisomerase II. m-AMSA is not cross-resistant to anthracyclines and has been particularly active in ANLL treatment. Studies using m-AMSA alone or in combination revealed comparable results to anthracycline--containing regimens. Cardiotoxicity of the anthracycline congestive type has not been observed with m-AMSA. The EORTC Leukemia Cooperative Group has successfully used m-AMSA in several trials prepositioning this drug stepwise: from relapsed and refractory ANLL, into intensive maintenance treatment during first remission in ANLL, and, still on-going, into intensive consolidation.

Phase II-study for treatment of refractory acute leukemia with intermediate-dose cytosine arabinoside and amsacrine.

25 consecutive leukemia patients (21 AML, 4 ALL) with either primary resistance (n = 22) or resistant relapse (n = 3) of all FAB-subtypes were treated with 1 or 2 cycles of ID-ara C (1 g/m2 i.v. q 12h days 1-6) and AMSA (120 mg/m2 i.v. days 5-7). Patients reaching CR received 1 cycle of intensive consolidation using ara C 3 g/m2 i.v. q 12 h days 1-4 and AMSA 120 mgm2 day 5. Two patients received an allograft thereafter and are still alive and in CCR. CR was achieved in 12/25 patients (48%), in 10 after 1 cycle of induction and in 2 after 2 cycles. 10/22 patients with primary resistant disease reached CR, and 2/3 with resistant relapse. 9 patients remained refractory (36%) and 4 died during hypoplasia (16%) Median DFS of the 12 responders was 2.9 months and median survival from time of CR 8.9 mo. Median overall survival of responders and non-responders was 6 mo from time of resistance. The survival advantage of responding patients (n = 12) as compared to non-responders (n = 13) was 10.7 vs. 3.2 mo (p = 0.002). Toxicity of chemotherapy was acceptable. 1 patient experienced pulmonary edema due to ara C, 2 patients developed life threatening systemic fungal infections, one of whom died while in CR.

Intermediate-dose Ara-C/m-AMSA for remission induction and high-dose Ara-C/m-AMSA for intensive consolidation in relapsed and refractory adult acute myelogenous leukemia (AML).

Twenty nine consecutive patients (pts) with either relapsed (n = 23) or primary refractory AML (n = 6) were treated with 1 or 2 cycles of intermediate-dose (ID) ara-C (1g/m2 IV q 12 h days 1-6) and m-AMSA (120 mg/m2 IV days 5-7). Pts reaching complete remission (CR) were consolidated with 1 cycle of ara-C 3 g/m2 IV q 12 h days 1-4 and m-AMSA 120 mg/m2 IV day 5. The median duration of the preceding remission was 9.5 months, median time from last chemotherapy until relapse 3 months. 18/23 (78%) of relapsed pts achieved CR regardless of the type of prior intensive maintenance (HD-ara-C/m-AMSA/5-AZA or DNR/CD-ara-C). 3/23 (13%) pts died during hypoplasia, 2/23 (9%) pts were refractory to 2x ID-ara-C/m-AMSA. 3/23 pts died in CR during hypoplasia after intensive consolidation with HD-ara-C. Predictive factors for remission were the duration of preceding remission and the time from last chemotherapy to relapse. Three pts were transplanted in 2nd CR. 1/6 refractory pts reached CR, 2 pts remained refractory, and 3 died during hypoplasia. The median duration of disease-free survival (DFS) of relapsed pts was 3.3 months without further treatment, median survival of responding pts (18 replased pts, 1 refractory pt) was 4.6 months, the overall survival (n = 29) was 4.8 months. Pts receiving BMT were censured at the time of BMT. Seven pts experienced lung toxicity due to ara-C, four of whom died. The incidence of lung toxicity was clearly related to the extent of ara-C pretreatment during intensive maintenance. In conclusion, ID-ara-C/m-AMSA is a very effective reinduction treatment in these pts with acceptable toxicity; the impact of HD-ara-C during consolidation for DFS and survival is questionable.

Low-dose cytosine arabinoside (LD-Ara C) treatment in dysmyelopoietic syndromes (DMPS) and acute myelogenous leukemia (AML).

The effect of low-dose Ara C (LD-Ara C) (10 mg/m2 q 12 hr s.c.) for a minimum of 10 days was evaluated in 21 patients with acute myeloid leukemia (AML) and 15 patients with dysmyelopoietic syndromes (DMPS). Median age (range) for AML-patients was 47 yrs (19-89), and for DMPS-patients 60 (22-78). From the AML-group, 9 patients were either primary refractory or resistant to intensive re-induction treatment of relapse, 6 others had heavy pretreatment, 1 suffered from myelosclerosis. Five AML-patients had no pretreatment at first presentation and were started on LD-Ara C because of old age (3) or poor condition (2) including 1 patient with a secondary leukemia. DMPS included those with RAEB (8) and RAEB in transformation (7). 12 patients with AML and 4 with DMPS displayed a leukocytosis of greater than 10 X 10(9)/l. Three out of 21 AML-patients reached complete remission (CR), one of them twice, with partial remission (PR) at the third attempt with this type of treatment. Two other AML-patients reached a P.R. of 5 and 1 months duration respectively. Three patients experienced a transient response characterized by improved peripheral blood counts and cessation of transfusion requirements, one of them for 12 months. In 5 AML-patients no effect was seen and 8 pts. died. In the DMPS-group, 5/15 patients reached C.R., one patient twice with the same treatment, 1 patient reached a P.R., 1 improved, 6 showed no effect, and 2 died. In 13 patients final examination of the bone marrow was not performed after treatment because of either early death or obvious progression. Treatment was associated with significant, transient hematologic toxicity. Patients suffering from DMPS had prolonged aplasia and required more blood and platelet support than pts with AML. Responding leukemia patients had a rapid hematologic regeneration. Considering the poor prognosis of both of our treatment groups, this therapeutic approach proved to be of considerable benefit.

Exogenous interleukin 2 (IL 2) reconstitutes deficient in vitro T-cell growth of patients with chronic lymphocytic leukemia of B-cell lineage (B-CLL).

Mechanisms of tumor growth are concerned with the possibility that neoplasms are disturbed in their response to growth factors. Interleukin 2 (IL 2) is secreted by activated T-cells and is required for autocrine T-cell growth. Controversy exists as to the functional capacity of T-lymphocytes in patients with B-cell chronic lymphocytic leukemia (CLL). We studied 14 patients with previously untreated, early CLL. Data were compared to 16 healthy individuals. Immunophenotyping showed that T-cells in B-CLL are highly activated as evidenced by HLA-DR and IL 2 receptor expression. Membrane receptors for IL 2 on the patients' T-cells were overexpressed. The T4:T8 ratio was 1.5. T-cells for in vitro studies were isolated by their ability to form E-rosettes with AET and repeated Ficoll density gradient centrifugation. Purified T-cells were grown on semisolid agar and their capability to form colonies investigated using a variety of exogenous stimulants. It was found that patients with CLL showed a pronounced impairment in forming T-cell colonies. However, colony formation was restored to normal by adding exogenous recombinant IL 2, indicating that endogenous IL 2 production of T-cells is deficient. This finding might have implications for the therapeutical use of IL 2 in CLL patients.