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A four-year experience with anthracycline, cytosine arabinoside, vincristine and prednisone combination chemotherapy in 325 adults with acute leukemia

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Abstract

Combination chemotherapy with an anthracycline, Adriamycin or rubidazone, cytosine arabinoside, vincristine and prednisone resulted in a complete remission rate of 62% in 325 consecutive unselected adults with acute leukemia. The results by morphologic categories were 58% for acute myelogenous leukemia (AML), 70% for acute undifferentiated leukemia (AUL), and 77% for acute lymphoblastic leukemia (ALL). The median survival was 43 weeks. Ten percent of all patients are projected to be alive and in remission at five years. The median remission duration for the whole group was 51 weeks, durations being significantly longer for AML (60 wks) than ALL (30 wks) and AUL (21 wks). Central nervous system involvement was uncommon in AML (4%), but much more common in patients with AUL (37%) and ALL (32%). One in five complete responders with AML is projected to be in their first remission at five years off all chemotherapy. Age, sex, morphology, cytogenetic pattern, temperature of presentation, and presence of a documented preceding hematologic abnormality are found to be significant variables for response and survival.

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... 23,24 . The presence hypoalbuminaemia has been widely confirmed in the malignant lymphomas 25 , prostatic cancer 26 , melanoma 27 , colorectal cancer 28 and leukemia 29 It is well established that the acute phase reaction, usually involved interleukins, tumor necrosis factor (TNF), and C-reactive proteins causing a reduction in the concentration of albumin is associated with the risk and development of cancer 30 . ...
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AML in elderly patients is a heterogeneous disease which is characterized by a number of unfavorable features such as development, cytogenetics, blast cell differentiation, and poor treatment response. Specifically, the association between a higher incidence of unfavorable cytogenetic abnormalities in elderly patients and poor prognosis has been well documented. Low treatment response may be due to the specific biology of AML in this patient group, but also to host-specific factors such as higher treatment-related morbidity and mortality. Treatment tolerance cannot be judged on grounds of chronological age alone; risk factor analysis with regard to performance status, organ function, and underlying systemic disease need to be considered as well. For effective induction treatment in elderly patients, instant and intensive chemotherapy appears to be necessary, while delayed treatment or administration of supportive care alone provide unsatisfactory results. Standard-dose ara-C/anthracycline-containing regimens are the treatment of choice in patients with good performance status. However, patients with a WHO grading of greater than 3 might rather benefit from reduced regimens such as low-dose ara-C. At present, greatest improvement of AML treatment in elderly patients can be expected from an improvement of supportive care.
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The principal toxicity of standard induction regimens for acute non-lymphocytic leukaemia (ANLL) [including cytarabine (ARA-C) 100 mg/m2 for 7 days plus an anthracycline] is myelotoxicity, leading to death in at least 25% of cases during induction in non-selected patients. The complete remission rate is less than 35% in patients over 65 years of age, due in part to an age-related increase of myelotoxicity. The other important adverse effect of standard-dose cytarabine is gastrointestinal toxicity, especially oral mucositis, diarrhoea, intestinal ulceration, ileus and subsequent Gram-negative septicaemia. Idiosyncratic reactions like exanthema, fever and elevation of hepatic enzymes are relatively frequent, but do not represent therapeutic problems. Intermittent high-dose cytarabine (3 g/m2 in 8 to 12 doses) is extremely myelosuppressive. Similarly, the gastrointestinal toxicity is formidable and dose-limiting. Severe, and sometimes irreversible, cerebellar/cerebral toxicity in 5 to 15% of courses of treatment limits the peak dose of cytarabine. The pathogenesis, prophylactic and therapeutic measures are unknown. These major toxicities are age-related and prohibitive to the use of high-dose cytarabine therapy in patients older than 55 to 60 years. Subacute noncardiogenic pulmonary oedema occurs in some patients, with an incidence of about 20%, and seems to have an intriguing coincidence with precedent streptococcal septicaemia; high-dose systemic steroids may be beneficial. Corneal toxicity is very frequent in high-dose cytarabine therapy but is always reversible. It is largely preventable with prophylactic steroid or 2-deoxycytidine eyedrops. Fever, exanthema and hepatic toxicity have an incidence similar to that in standard dosage. The maximum tolerable cumulated dose of cytarabine is significantly lower when the agent is administered as a continuous infusion, due to myelosuppression and gastrointestinal toxicity. Conversely, continuous infusion may be less neurotoxic. The antileukaemic effect of continuous infusion high-dose cytarabine is less well established. The only significant toxicity of low-dose cytarabine is myelosuppression. Given the generally poor condition of leukaemia patients, low-dose cytarabine therapy is well tolerated, although occasional cases of diarrhoea, reversible cerebellar symptoms, peritoneal and pericardial reactions, and ocular toxicity have been reported. Continuous infusion may be more toxic than the usual intermittent dosage. It is concluded that the toxicity of the standard induction regimen for ANLL is acceptable in patients younger than 60 to 65 years with no concurrent disease. Low dose cytarabine is tolerable for virtually all ANLL patients, but the overall therapeutic efficacy still needs to be defined and compared to standard therapy in the relevant age groups. High-dose cytarabine is valuable, even though it is extremely toxic, in relapsed and refractory acute leukaemia in patients younger than 55 to 60 years. It is not recommended as induction therapy, due to its toxicity. The regimen seems to be slightly more tolerable as consolidation therapy but cases of severe toxicity with lethal outcome cannot be avoided; doses of 0.5 to 1.0 g/m2 may have comparably favourable pharmacological properties with less toxicity, but need more clinical documentation.
Following the introduction of anthracyclines and cytosine arabinoside (Ara-C) into clinical practice in the late 1960s, response rates of 50%–80% in previously untreated patients with acute myeloblasts leukemia (AML) have been obtained [1, 2]. Despite a variety of postremission treatments the remission duration remains 12–15 months, with 20%–25% of patients staying in long-term disease-free state and possibly being cured [3, 4]. One-third of the patients who failed to achieve an initial complete remission do so because of persistence of leukemia cells [5], and 75%–80% of patients who achieve a remission have recurrence of leukemia [3, 4]. Both of these patient populations are eligible for salvage therapy.
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The role of amsacrine in inducing remission in patients with cardiac disease and acute leukemia was evaluated. There were 17 patients with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL), and one with biphenotypic leukemia. In this series of 24 patients whose disease had relapsed and who had reduced left ventricular ejection fraction, nine had a complete remission, seven with AML and two with ALL. In addition, four of six with newly diagnosed acute leukemia and reduced left ventricular ejection fraction also responded. Among nine patients who underwent endomyocardial biopsy, none had morphologic changes of sufficient degree to account for drug-induced heart failure. Patients with preexisting arrhythmias received amsacrine without incident if their serum potassium level was higher than 4.0 mEq/1 at the time of drug administration. Amsacrine is safe and effective therapy for patients with acute leukemia and cardiac disease.
Article
Between 1965 and 1982, 105 patients with a diagnosis of Philadelphia chromosome-negative chronic myelogenous leukemia were referred to our institution with minimal or no prior therapy. The median age was 63 years and 64% were males. The overall median survival from time of referral was 14 months; 53% of patients survived 1 year and only 10% survived beyond 5 years. At the time of analysis, 92 patients (88%) were dead, 56% of deaths being preceded by a blastic crisis. Compared with Philadelphia chromosome-positive disease, patients with Philadelphia chromosome-negative chronic myelogenous leukemia were older and had a significantly higher incidence of anemia, thrombocytopenia, monocytosis, marrow blasts, decreased marrow megakaryocytes and a lower incidence of basophilia and thrombocytosis. Chromosomal abnormalities occurred in 33% of patients and consisted most frequently of trisomy 8, or an additional chromosome C, loss of the Y chromosome, or abnormalities in chromosomes #5 and #7. Of nine pretreatment characteristics significantly associated with poor survival, a multivariate analysis identified four to have independent additive prognostic significance: severe thrombocytopenia, hemoglobin levels less than 10 g/dl, increasing peripheral blasts and promyelocytes, and age 60 years or older. Monocytosis was not of prognostic significance. The derived prognostic model divided patients into three risk groups, low, intermediate, and high, with median survivals of 36, 16, and 3 months, respectively. The authors conclude that Philadelphia chromosome-negative chronic myelogenous leukemia is a distinct entity among the myeloproliferative syndromes with characteristic clinical and laboratory features and a poor prognosis. Prognostic factors and related risk categories were demonstrated within this disease entity.
Article
Sixteen patients with refractory acute non-lymphcytic leukemia (ANLL) were treated with 2 different therapeutic regimens including aclarubicin (ACR) and cytosine arabinoside (ara-C). ACR, 45mg/m², was administered daily by intravenous rapid infusion from, day 1 to 3 in Regimen 1, and the same dose of ACR, divided into 2 doses, was administered every 12 hours by intravenous infusion from day 1 to 3 in Regimen 2. Ara-C, 80mg/m², divided into 2 doses, was given every 12 hours by intravenous infusion from day 1 to 7 in Regimen 1 and 2. Seven of 10 patients, 70%, obtained a complete remission (CR) with Regimen 1, and 1 of 6 patients, 16.7%, with Regimen 2. The days required for CR ranged from 22 to 55 days (median: 40 days). The duration of CR ranged from 2 to 13 months (median: 9.3 months), and the survival from the initiation of therapy was from 9 to 41.3 months (median 19.6 months) in responders. Side effects on the digestive system such as nausea and vomiting were seen in 14 of 16 patients, 87.5%, but they were all controllable. The combination of ACR and ara-C, particularly Regimen 1, was also found to be more effective in the clinical management of refractory ANLL than a NCDVP (neocarzinostatin, area-C, daunorubicin, vincristine and prednisolone) regimen.
Article
Historically, the treatment of adults with acute myelogenous leukemia (AML) has evolved through a number of phases. In the initial phase we saw the accumulation of information on the natural history of acute leukemia and study of the patterns of survival [1, 2]. Analysis of survival data in patients with acute leukemia who were treated with supportive care only was adequately documented and showed that half of all patients would die in less than four months and less than one patient in ten would live for one year. The early literature was concerned with documentation of spontaneous remissions, and up until 1960, there was no evidence that chemotherapy-induced remissions were of longer duration [1, 2] than those which occurred spontaneously. In addition, no accurate estimate of the response rate to chemotherapeutic agents was available, despite the fact that the ‘chemotherapy era’ in acute leukemia had been ushered in by Farber in 1949 [4].
Article
An equation was developed to describe the kinetics of leukemic cell destruction in bone marrow during induction chemotherapy for acute nonlymphocytic leukemia (logZ=K1t⁴+K2t³+K3t²+K⁴, where Z=leukemic cell number, t=time, and K=a constant). The leukemic cell destruction curve was biphasic; phase I was the period from the initiation of a decrease in cells to the maximum velocity of the decrease, and phase II was the subsequent period to the cessation of decrease. The following parameters were established: duration and acceleration of decrease in phases I and II, maximum velocity of decrease, duration of reduction, and residual volume of leukemic cells. 1. Patients who achieved CR showed a longer duration of phases I and II, a lower acceleration of the decrease in phase II, and smaller residual leukemic cell volume than patients who did not achieve CR. there were no significant differences of parameters related to FAB classification, type of induction therapy, or the age of the patients. 2. This equation could be adapted to explain erythroblast kinetics during induction chemotherapy. There were no significant differences of the parameters with respect to the effect of induction therapy and patient age. 3. Patients with high acceleration of the decrease in phase II had a short duration of CR and survival. The leukemic cell destruction curve was thought to be useful not only for evaluation of the effect of induction therapy, but also for establishment of post-remission chemotherapy.
Chapter
Der wesentliche Leitgedanke bei der Abfassung der Therapiekapitel war, die Grundvoraussetzung für die therapeutischen Überlegungen wie Histologie, Grading, Stadieneinteilung und diagnostische Maßnahmen, ebenso wie die Therapiestrategie mit Stellung und Indikation von Chirurgie, Strahlentherapie und Chemotherapie möglichst „gebrauchsfertig“, komprimiert und präzisiert wiederzugeben.
Chapter
The ability to kill leukemic cells is directly related to the dose of irradiation or ‘radiomimetic’ chemotherapeutic agents administered [1–5]. Unfortunately, the dose of systemic chemotherapy or radiotherapy that can be given with safety is limited by toxicity to normal tissues, and for many agents the most sensitive targets are the hematopoietic cells of the marrow.
Chapter
Over the past 25 years considerable progress has been made in the treatment of acute myelogenous leukemia (AML). Multiple factors have contributed to this success. These include the introduction of new drugs, the use of combination chemotherapy, a better understanding of the biology of the disease and bone marrow regeneration, improved supportive care including platelet and granulocyte transfusions and more effective antibiotics. As a result, complete remission rates of 80% have been obtained in some subsets of patients.
Chapter
Over the past decade, marrow transplantation has progressed from a very experimental approach applied only to a handful of endstage leukemic patients to an important therapeutic option appropriate for many patients. In this paper we will describe the role marrow transplantation plays in the treatment of acute nonlymphoblastic leukemia (ANL) in adults. In order to define this role, the outcome of marrow transplantation obviously must be compared to that of more conventional chemotherapy for specific patient groups at given stages of their disease. Such comparisons are best made in prospective studies but only a few such studies have been performed and completed. For many patient groups only retrospective comparisons are possible. Retrospective analyses are inherently flawed and serve only as estimates. For some patient groups not even retrospective comparisons are possible because adequate data are not available.
Chapter
Various intensive induction regimens for adult AML involving a total of 3380 patients produced a median of 60% complete remissions (CR) ranging from 47% to 72% in multicenter [2, 4, 8, 10–12, 14] and major monocenter [5, 6, 9, 13] studies. The probability of continuous CR in these studies ranges from 8% to 45% (median, 24%) at 3 years. Corresponding data projected to 5 years yield a continuous CR rate of 10%–28% (median, 21%). No clear correlation has been found between CR duration and the type of induction or postinduction treatment. In particular, the role of consolidation and long-term maintenance therapy has remained controversial.
Chapter
Acute leukemia was the first malignancy to which the principles of adjuvant therapy were applied. In contrast to adjuvant treatment of solid tumors in which surgery and radiation therapy are usually followed by chemotherapy, hematologists used chemotherapy regimens to treat the presenting disease and render the patient free of identifiable tumor (complete remission) then continue to apply post-remission chemotherapy in an adjuvant setting. The response to chemotherapy before surgery and radiation in many solid tumors predicts for duration of survival after radiation and surgery. Likewise, the quality of response to remission induction therapy predicts for duration of complete remission in adult AML.
Chapter
The challenge of treating acute myelogenous leukemia has shifted over the past decade from studies designed to increase the proportion of patients entering complete remission to studies aimed at prolonging the duration of complete remission. With the introduction of anthracycline antibiotics (1, 2) and cytosine arabinoside (3, 4), with the effective use of these drugs in combination, and with adequate access to platelets and more effective antibiotics, complete remission rates have risen to the range of 55–75% (5–7). Despite this marked improvement in remission induction, the median duration of remission for most large series reported in the literature averages less than a year (8–11). Disease-free survival of five years or more is nevertheless reported in 5–20% of patients who enter remission (12–15). Recent results from a few studies demonstrate that chemotherapy induced remissions can be durable for an even higher proportion of patients (16–17). Super-intensive chemotherapy and radiotherapy followed by allogeneic bone marrow transplantation in first remission appears to offer the highest probability of durable remissions without maintenance chemotherapy (18–20). While at least part of the durability of remission has been ascribed to the immune reaction of the graft against the leukemia cells as a concomitant of graft-versus-host disease (21, 22), cytotoxic therapy alone has induced sustained remissions in patients receiving grafts from their identical twins (23). Some of the more successful chemotherapy regimens and the bone marrow transplantation experience share several features which may impact on curative therapy and which warrant further study.
Chapter
Die folgende Bestandsaufnahme 1983 der Chemotherapie der akuten myeloischen Leukämie (AML) des Erwachsenen kann den Vorteil eines günstigen Zeitpunktes nutzen. Mitte bis Ende der 70er Jahre hat die Polychemotherapie der AML einen besonderen Aufschwung erlebt. Die Studien über damals konzipierte Regime wie 7 + 3 [12], ADOAP [9], DAT [13] und TAD [5] bieten inzwischen eine genügend lange Beobachtungszeit, so daß - über Remissionsrate und Toxizität hinaus - langfristige Therapieeffekte heute zu beurteilen sind.
Article
Acute myelocytic leukemia results from the proliferation of immature myeloid cells whose ability to differentiate is markedly impaired. Failure to differentiate confers an extended reproductive life time on the leukemic cells so that their numbers progressively increase. These cells not only fail to differentiate but their very presence inhibits normal hematopoiesis resulting in anemia, granulocytopenia, and thrombocytopenia. Recent studies have suggested that the conventional view of the kinetics of leukemia cell proliferation should be revised. The low 3HTdR labeling indices reported in the past have been interpreted as indicating that leukemic cells proliferate more slowly than normal immature myeloid elements [1, 2]. Tritiated thymidine suicide studies of leukemic progenitors which clone in vitro have demonstrated that the proportion of clonogenic cells which are synthesizing DNA is comparable to that of normal progenitor cells at a comparable level of maturation and is in fact 3–5 times that which would be projected from conventional labeling index studies [3, 4]. Furthermore, labeling index studies of leukemic cells obtained from bone marrow biopsies as opposed to marrow aspirates have also demonstrated a greater proportion of cells in S phase than had been formerly estimated [5]. Hence, the concept of acute leukemia being a disease of slowly proliferating cells is probably incorrect. It is of interest that in an early report Gavosto attempted to determine the compartment size and turnover time of leukemic cells and concluded that the myeloblast population per se was not self-maintaining and that there had to be a precursor compartment which fed cells into the blast compartment [6]. Perhaps the cloning studies are providing a window for viewing this precursor pool.
Chapter
Since the introduction of chemotherapy for adults with acute nonlymphocytic leukemia, the adverse impact of advancing age on prognosis has been repeatedly demonstrated [1–22]. Age has consistently been one of the most important clinical factors that can predict the outcome of treatment and, consequently, the length of survival [23–30]. The degree to which the age of the patient affects the results of treatment has not remained uniform over time, but perception of it as a major prognostic factor continues to influence the philosophy of treatment. Although it is no longer considered fitting to routinely withhold potentially beneficial treatment from the elderly, there is a residual sentiment to employ only conservative therapy and, thus, not cause the older patient any harm. However, since the identification of an adverse prognostic factor such as advanced age, regardless of importance, does not simultaneously establish the optimal choice among therapeutic options for patients characterized by that specific factor, it becomes relevant to evaluate the reasons elderly patients are perceived to do poorly following treatment and the methods by which therapeutic success for them might be increased.
Article
Many of the conceptual advances in the treatment of advanced cancer have resulted from studies of the hematologic malignancies: The signal importance of complete remission, the complete disappearance of evident disease, as the major contributor to significant palliation; the first studies of adjuvant therapy, that is chemotherapy given to patients free of disease, which demonstrated prolongation of disease-free periods; the first studies of intensification, including early, intermittent, and late; combination chemotherapy; and finally, the important observation that advanced metastatic malignancies can be cured were made in studies of these important diseases. Because of treatment advances that have occurred over the last 10 to 20 years, the majority of patients with adult hematologic malignancies that were once considered universally fatal can be either cured or have substantial palliation. Treatment for adult acute leukemia has advanced such that 15% to 20% of patients have prolonged disease and treatment-free survivorship; in Hodgkin's disease, over 70% of patients can be cured; and for the lymphomas, the majority or 50% to 60% of patients can be cured with available treatments. Major treatment advances in supportive treatment such as allogeneic transfusion and allogeneic and autologous bone marrow transplantation improve the perspective for control of the hematologic malignancies. In addition, the potential for biologic response modifiers or the biologic products of normal cells that are normally involved in the regulation of both proliferation and differentiation show enormous potential for the treatment of advanced disease. Studies of interferon have shown promising early results in chronic granulocytic leukemia and in hairy cell leukemia. A new class of drugs, the acridine analogs, of which AMSA (4′-[9-acridinylamino]methanesulfon-M-anisidide) is a member, has been introduced and has established activity against acute leukemia. VP-16 (etoposide) has just become commercially available and is an important drug both in leukemia and lymphoma. Finally, the discovery of new knowledge about the biochemical pharmacology of drugs such as arabinosyl cytosine has offered a major advance in salvage treatment and the potential for substantial further improvement in the frontline management of these diseases. The rapid advances in both palliative and curative treatment for the hematologic malignancies have generally found broad application to the management of advanced cancer arising from other organ systems.
Chapter
The recognition of Acute Leukemia as a malignancy of the blood cells is usually credited to Virchow [1] as is the term Leukemia (Weisses Blut) [2]. The following century provided extensive details of the pathology and cytology of this disorder. But, the first mention of any attempt to alter its natural history was reported in 1948 by Dr. Farber. He described temporary remissions of the disease and reported that the disease almost invariably recurred despite continuous administration of aminopterin [3]. In 1949, Pearson reported cortisone-induced regressions of lymphoid tumors [4], which was confirmed by Dr. Farber in 1950 showing remissions in childhood acute leukemia [5]. Following the Nobel prize winning research of Hitchings and Elion on the biochemistry of purine analogs [6], Dr. Burchenal reported remissions in acute leukemia with 6-mercaptopurine in 1953 [7]. Despite having three (3) unique molecules effective in inducing temporary remission in patients with acute leukemia, a careful review of the natural history of the disease was published by McMann and Foreman in 1957. They showed that, for over 600 patients studied between 1943 and 1952, the median survival was approximately 6 weeks and 95 % of the patients were dead by 12 months after diagnosis [8]. In 1955, the largest and most authoritative group in hematology, Dr. Wintrobe’s group in Utah reported, “It was not possible to demonstrate that the newer therapies (folic acid antagonists, ACTH, cortisone, and 6-mercaptopurine) significantly increased the total survival in these representative groups” [9]. In fact, the authors recommended that these therapies not be administered to patients since they were simply prolonging the horrible clinical manifestations of a uniformly fatal disease.
Article
Sixty patients with acute promyelocytic leukemia were treated between 1973 and 1984. The overall median survival was 16 months with a five-year survival rate of 31 percent. The complete remission rate was 53 percent and was similar whether they received amsacrine- or anthracycline-based regimens (60 percent versus 51 percent). The median remission duration was 29 months. At five years, 43 percent of patients with responses to treatment had continuous remission and 57 percent were alive. Salvage therapy produced remissions in 53 percent of patients during first relapse, with two long-term survivors after further consolidation with bone marrow transplantation. Early fatal hemorrhage associated with disseminated intravascular coagulopathy during induction therapy occurred in 16 patients (26 percent). Multivariate analysis of the pretreatment patient characteristics significantly associated with an increased risk of fatal hemorrhage identified four that have primary prognostic importance: thrombocytopenia, elevated absolute blast and promyelocyte counts, old age, and anemia. Patients having up to two unfavorable features had a low risk of fatal hemorrhage compared with those who had more than two (5 percent versus 58 percent; p <0.0001). Overall, patients who received heparin had a lower incidence of fatal hemorrhage than those who did not (19 percent versus 32 percent). Heparin therapy was not beneficial to those at low risk but was associated with a trend towards decreased hemorrhagic deaths among high-risk patients (45 percent versus 67 percent). Cytogenetic studies demonstrated the characteristic 15;17 translocation in 73 percent of patients with analyzable metaphases, whereas 12 percent had other karyotypic abnormalities. Remission induction was often associated with a gradual atypical morphologic evolution into remission without intermediate hypoplasia with the interim marrows showing a high proportion of blasts. It is concluded that acute promyelocytic leukemia is a unique disease with a high potential for cure. Knowledge of its prognosis using present frontline and salvage therapy, of the factors related to fatal hemorrhage, and of the unusual patient marrow profiles during remission induction may improve the therapeutic approach.
Article
Full-text available
We examined the effects of CI-973 (supplied by Parke-Davis) on several human leukemia cell lines and a Chinese hamster ovary (CHO) line and their drug-resistant counterparts. The cell lines used were HL-60, HL-60/mAMSA, HL-60/DOX, KBM3, KBM3/mAMSA 6, KBM3/mAMSA 6(85), CHO, and CHO/AC-7. DOX, mAMSA, and AC-7 indicate resistance to doxorubicin, amsacrine, or l-/3-t>-arabino- furanosylcytosine, respectively. Cells were incubated with CI-973, and the effect was evaluated by two methods: growth inhibition assay and inhibition of colony formation. All cell lines examined were inhibited by CI-973; two of three amsa- crine-resistant lines and the one cytarabine-resistant line demonstrated collateral sensitivity. At equivalent dosages, a 4-day exposure provided much greater cell kill than a l-li exposure. Clonogenic assay showed exponential killing over 3 log units. Maximum CI-973 levels required to kill 50% of cells were 10-fold lower than the peak plasma levels achieved in a phase I solid tumor study. A continuous infusion phase I study in acute leukemia has been initiated.
Article
We have previously reported that the lethal toxicity of 5-fluorouracil (5-FU) in specific-pathogen-free mice is due to an indigenous infection with Escherichia coli (K. Nomoto, T. Yokokura, Y. Yoshikai, et al. Can. J. Microbiol. 37: 244–247, 1991). In the present study, we demonstrate that nonspecific immunostimulation augments host resistance against the lethal toxicity of 5-FU in tumor-bearing mice. Intravenous administration of a preparation of heat-killed Lactobacillus casei (LC 9018), a nonspecific immunostimulant, at a dose of 20 mg/kg to BALB/c mice augmented their resistance against the lethal toxicity of 5-FU if the preparation was injected into the mice 10–40 days before administration of 5-FU. Injection of LC 9018 into BALB/c mice bearing Meth A fibrosarcoma also enhanced their resistance against the lethality of 5-FU. Systemic infection with E. coli was induced in all of the 5-FU-treated tumor-bearing mice 10 days or more after administration of the drug at a lethal dose of 500 mg/kg, and it was accompanied by an overgrowth of the bacteria in the intestine. Treatment of tumor-bearing mice with LC 9018 resulted in decreased rates of occurrence of systemic infection with E. coli and inhibition of overgrowth of the bacteria in the intestine after administration of 5-FU. A single administration of either LC 9018 or 5-FU significantly inhibited the growth of Meth A cells in vivo, and a combined antitumor effect was shown in the mice treated with both 5-FU and LC 9018. Key words: tumor-bearing mice, fluorouracil, nonspecific immunostimulation, indigenous infection, Escherichia coli.
Article
In the current study, we investigated the cytotoxic ability of peripheral blood mononuclear cells (PBMC) recovered from patients with acute nonlymphoblastic leukemia (ANLL) in complete remission (CR) against natural killer (NK)-sensitive, NK-resistant, autologous and allogeneic leukemic target cells taken at diagnosis. Our purpose was to define the role played by cytotoxic mechanisms in the control of leukemic cell growth in ANLL. Experiments were carried out at resting conditions and after in vitro activation with recombinant interleukin-2 (rIL-2) and anti-CD3 monoclonal antibody (moAb). At resting conditions, PBMC recovered from ANLL patients displayed a NK function that was not significantly different from controls (mean +/- standard error of the mean [SEM]: 21.9% +/- 3.9% versus control values of 27.5% +/- 2.9%; the P value was not significant [NS]), but they were unable to show cytotoxic activity against autologous and allogeneic leukemic cells. After in vitro boosting with rIL-2, PBMC were able to generate lymphokine activated killer (LAK) cells, as demonstrated by an increased killing of NK-resistant Daudi targets (16.3% +/- 2.7%). Although LAK activity was quantitatively lower than in control subjects (mean +/- SEM: 16.3% +/- 2.7% versus control values of 79.8% +/- 3.1%; P less than 0.001), it still exerted a cytotoxic effect against autologous and allogeneic leukemic cells. Similar results were obtained when anti-CD3 moAb was used as a stimulus in vitro. Our data suggest that nonspecific cytotoxic cells may be triggered to exert an in vitro cytotoxic effect on leukemic cells, which could possibly play a key role in vivo in the control of leukemic cell growth regulation.
Article
Zusammenfassung In einer prospektiven multizentrischen Studie wird die Effek”tivität und Toxizität einer Induktionstherapie mit Daunorubicin, Cytosin-Arabinosid und VP 16–213 und einer intensivierten Konsolidationstherapie mit hochdosiertem Cytosin-Arabinosid und Daunorubicin bei Patienten mit akuten myeloischen Leukämien untersucht. In den ersten zwei Jahren wurden 91 Patienten im Alter bis zu 50 Jahren in die Studie aufgenommen. Bei 84 Patienten ist die Induktionstherapie abgeschlossen und auswertbar. Die Rate kompletter Remissionen beträgt 67&percnt;. Die mediane Überlebenszeit sämtlicher Studienpatienten liegt bei 22 Monaten. Fur die derzeit maximale Beobachtungsdauer von 24 Monaten wird eine Überlebenswahrscheinlichkeit von 46&percnt; errechnet. Von den Patienten, die eine komplette Remission erreichten, haben bisher 34 einen oder zwei Stöße der intensivierten Konsolidationstherapie mit hochdosiertem Cytosin-Arabinosid und Daunorubicin erhalten. Diese Patienten haben eine mediane Remissionsdauer von 20 Monaten und eine rezidivfreie Überlebenswahrscheinlichkeit nach 22 Monaten von 46 &percnt;.Copyright © 1988 S. Karger AG, Basel
Article
Injection of a lethal dose of 5-fluorouracil (400 mg/kg) into mice induced an extraordinary increase in the levels of endogenous Escherichia coli in the intestine, systemic translocation of the bacteria to the liver, and loss of body weight. Daily administration of a fermented milk (0.2 ml) containing Bifidobacterium breve strain Yakult, B. bifidum strain Yakult, and Lactobacillus acidophilus strain Yakult (108.5-9.5 CFU/ml) to mice for 7 days before and 9 days after 5-FU prevented the endogenous infection, whereas treatment of mice with water or unfermented milk did not lead to any significant protection against the infection. The levels of indigenous bifidobacteria in the intestinal contents decreased markedly with time after injection of 5-FU in the control groups, and this was associated with a marked decrease in the concentration of total short-chain fatty acids (SCFAs) and an increase in the pH on day 10 after 5-FU administration (pH: 7.3, SCFAs: 40 mM). Administration of fermented milk maintained the concentrations of the total SCFAs at the same levels as before 5-FU administration (120 mM) throughout the experimental period. The pH and concentration of acetic acid in the intestinal contents (pH: 6.7, AA: 90 mM) were found to suppress in vitro growth of an indigenous strain of E. coli These results suggest that the protective effect of oral administration of fermented milk against the endogenous E. coli infection resulted from prevention of any abnormal increase in E. coli levels via normalization of the 5-FU-induced disruption of the intestinal environment.
Article
Sixty-seven unselected adult patients with untreated acute non lymphotblastic leukemia (ANLL) ranging in age from 15 to 80 years received a new induction regimen consisting of Idarubicin, Etoposide and Cytarabine. Patients who entered complete remission (CR) were then allocated to 4 courses of post remission intensification. After this, patients under 50 years of age with a compatible donor were given allogeneic bone marrow transplantation (BMT) or autologous BMT (ABMT) in those without an HLA-compatible donor; the remainder, older than 50, did not receive further therapy. Fifty-six of 67 patients (83.5%) achieved CR (02.5% in young and 70.3% in old patients) and 40 (71 %) after the first course. Seven patients (of whom, 6 were > 50 years) died in aplasia during the induction phase and four additional patients (all elderly) died during post-remission intensification without recurrent disease. Subsequently, the younger patients received transplants (BMT: 4 pts; ABMT: 10 pts). Twelve: of the 52 (23%) who survived post remission intensification (BMT: 1; ABMT: 4; others: 7) are disease free survivors 9-67 months (median, 32 months) after achieving CR. In conclusion, this intensive chemotherapy regimen is highly effective both in young and odder patients but the post-remission intensification may be too aggressive for elderly patients.
Article
Among 35 patients with relapsed or refractory acute myelogenous leukemia (AML) who received salvage chemotherapy, 28 were treated with mitoxantrone (7.5 mg/m2/d intravenously [IV] over 1 hour for 5 days) and etoposide (VP-16) (2 g/m2 over 4 days either as a daily infusion or as two daily doses). Seven patients received mitoxantrone (6 mg/m2/d for 5 days) and VP-16 (1500 mg/m2 over 3 days). The median duration of the initial complete remission (CR) was 6 months and 83% of the patients had initial CR that lasted 12 months or less. Forty-six percent of the patients were undergoing a second or subsequent salvage attempt. Eight patients (23%) achieved CR; seven of these CR were obtained after one course of therapy. Twelve patients (33%) died and 15 patients (42%) had disease that was resistant to treatment. Patients undergoing a first salvage attempt had a higher incidence rate of CR than those undergoing a second or subsequent salvage attempt (37% versus 6%; P = 0.03). CR rates were also higher in patients with a favorable (translocation 8;21 or 15;17) or diploid karyotype compared with other patients (32% versus 8%; P = 0.10). The median survival time was 2 months for all patients and 8 months for patients achieving CR. Mucositis occurred in 74% of the patients and was severe in 32%. Diarrhea and rash occurred in less than 33% of the patients. Fever was noticed in all but 1 of the patients and documented infections occurred in 65% of the patients. Six patients had pancytopenia or thrombocytopenia that lasted more than 42 days from the initiation of treatment. Although mitoxantrone and high-dose VP-16 is an effective antileukemic regimen, it is associated with a high incidence of mucositis. Strategies that are used to limit mucosal damage may improve the tolerance of this combination.
Article
Intensive antileukemic treatment was evaluated in 22 patients with secondary acute myelogenous leukemia (sAML) and 14 patients with myelodysplastic syndrome (MDS). Results of combination remission-induction chemotherapy were compared with 126 patients contemporarily treated for primary AML. The duration of hypoplasia, induced by remission induction chemotherapy, tended to be longer in the sAML and MDS patients when compared to de novo AML, but reached significance only for the duration of thrombocytopenia: 26 days versus 18 days (P less than 0.01). The number of hypoplastic deaths during remission-induction chemotherapy of patients with sAML and MDS was low. Four of the 36 patients treated for sAML or MDS died during hypoplastic phases induced by remission-induction chemotherapy. The complete remission (CR) rates were similar in primary AML (67%), sAML (62%), and MDS (64%). The CR rates of patients younger than 45 years were 75% for de novo AML, 75% for sAML, and 71% for MDS. Remission rates in patients older than 45 years were identical in the three subgroups but significantly (P less than 0.005) inferior to those obtained in younger patients: 56%, 50%, and 57%, in de novo AML, sAML, and MDS, respectively. The remission duration without bone marrow transplant (BMT) was significantly shorter (P less than 0.01) in MDS and sAML when compared with primary AML. Long-lasting CR in MDS and sAML was only obtained in three of the six patients treated with allogeneic BMT. Intensive antileukemic therapy could be considered in young patients with MDS and life-threatening cytopenias or patients with sAML.
Article
All authors contrast the poor prognosis of acute granulocytic leukemias (AGLs) with the progress achieved in acute lymphocytic leukemias (ALLs). However, many advances have already been made in the treatment of this disease: the median survival remains poor with present chemotherapy, but survival has been shown to be directly related to the attainment of a complete remission (CR). The indications for such intensive treatment must be individualized according to the age of the patient and the morphological findings of the leukemia. Cytological classification of AGLs is difficult. The cytology of acute promyelocytic and acute monoblastic leukemias (APLs and AMoLs) is now well characterized, but the term acute myeloblastic leukemia (AML) still includes various cytological variants. We shall deal first with the treatment of AML with an overt maturation arrest (high rate of poorly differentiated cells); then we shall consider the specific problems raised by APL and AMoL and the difficulties
Article
This paper reviews progress in the therapy of acute granulocytic leukemia (AGL) and examines reasons why its results have remained unsatisfactory. For some years there has been no distinct improvement in remission rates, and survival has not lengthened greatly in most patients attaining remissions. However, in a few patients survival is of considerable length. Improvements in supportive therapy have helped raise remission rates in older patients and in those with high leukocyte counts. Resistance to induction therapy is now mainly due to intrinsic resistance of leukemic cells whose growth kinetics are such that only a minority can respond to cycle-specific therapy. Attempts to manipulate the cell cycle have not so far increased remission rates. No clear evidence exists that maintenance therapy prolongs remissions. Relapses are almost certainly due to re-growth of suppressed leukemic clones. Among new forms of treatment, immunotherapy is not yet securely based. Marrow transplantation may become occasionally useful. It is questionable if cytotoxic therapy alone will improve the prognosis of AGL radically. Though there is little to show that progress towards a cure is being made, new approaches based on a better understanding of the pathology of leukemic growth may eventually be translated into clinical success.
Article
One hundred patients were entered in a cooperative study comparing the efficacy of two different regimens in the induction treatment of acute nonlymphocytic leukemia (ANLL). Patients were randomly allocated to receive either the DAT or VAT combination; half of the patients were also randomized to receive CNS prophylaxis including intrathecal methotrexate + prednisone and cranial irradiation. Consolidation and maintenance therapy were uniform in responding patients. Out of 82 evaluable patients 41 (50%) attained complete remission (CR) with no significant difference between the two regimens. Median remission duration was slightly longer in the DAT group (32.5 vs 22 weeks); median survival was 34 weeks for all evaluable patients with no difference between the two schedules. Meningeal relapse occurred only in two patients after 19 and 99 weeks of continuous remission. Fourteen patients are still alive after 61 to ≥ 155 weeks, of whom seven are in their initial remission (six in the DAT and one in the VAT group). We conclude that 1) DAT and VAT are equally effective in inducing CR in a high proportion of ANLL patients; 2) until marrow remission can be prolonged significantly, preventing CNS leukemia will not have any significant impact on the course of ANLL.
Article
SUMMARY A generalization of the Kruskal-Wallis test, which extends Gehan's generalization of Wilcoxon's test, is proposed for testing the equality of K continuous distribution functions when observations are subject to arbitrary right censorship. The distribution of the censoring variables is allowed to differ for different populations. An alternative statistic is proposed for use when the censoring distributions may be assumed equal. These statistics have asymptotic chi-squared distributions under their respective null hypotheses, whether the censoring variables are regarded as random or as fixed numbers. Asymptotic power and efficiency calculations are made and numerical examples provided.
Article
Nineteen patients In continuous complete remission of acute leukemia for at least one year received late Intensification therapy, after which they received no further chemotherapy, but most received BCG Immunotherapy. Five patients have relapsed. The 14 patients still in remission have been followed up for at least 60 weeks after late intensification, with a median time of 98 weeks. The length of complete remission subsequent to a comparable time was 44 weeks for a reference control group and 24 weeks for a matched control group. These results support this type of approach for long-term control of acute leukemia in adults.(JAMA 235:1021-1025, 1976)
Article
In a series of 170 adult patients with acute leukemia, sequential cytogenetic studies were conducted during a period which included either the initial and, at times, the terminal phase of the disease, or the relapse and remission phases. On the basis of morphological similarities in the karyotype changes, the patients carrying aneuploid clones were categorized into several profiles of aneuploidy. Analysis of the survival times determined from the time of diagnosis suggested that some of these abnormal cytogenetic profiles may have definite clinical implications.
Article
Twenty-three adult patients (ages greater than 15 years) and 75 children with acute lymphoblastic leukemia were treated with similar intensive, sequential cytotoxic protocols (L-2). The adult patients have a lower remission rate (78%) than the children (98%). The duration of remission and the length of survival are also shorter in adults. The incidence of central nervous system (CNS) relapse in adults (27.7%) is higher than in children (7.1%) suggesting that prolonged prophylactic intrathecal methotrexate as given to the children is more effective than the schedule used for adults where intrathecal methotrexate was given only in the first 2 months of therapy. The low incidence of CNS involvement in children on the L-2 protocol compares favorably with other series reported using a combination of cranial irradiation and intrathecal methotrexate. In both adults and children there seemed to be a higher incidence of CNS involvement in patients with initial white blood cell counts greater than 25,000 cells/mm3.
Article
A prospective study of infectious morbidity in patients with acute myelocytic leukemia receiving chemotherapy was undertaken to test the effects of a reduction of ambient and/or endogenous microorganisms. Patients were randomly allocated to receive: (1) neither barrier isolation nor antimicrobial suppression; (2) antimicrobial suppression (gentamicin, vancomycin, and nystatin) in conventional ward reverse isolation; (3) barrier isolation and filtered air; or (4) barrier isolation, filtered air, and antimicrobial suppression. The presence of infection at the time of randomization was a significant factor (p < 0.02) accounting for an increased death rate. Individuals housed in the isolator who were initially uninfected demonstrated a decrease in the acquisition of severe infections after 23 study days, and fewer respiratory infections throughout the study period. Pseudomonas infections were decreased in isolator patients. Fewer fatalities from infection, but more from hemorrhage, were noted in patients who received endogenous antimicrobial suppression. An increased remission rate was seen in isolated patients not receiving antibiotics for gut flora suppression (not statistically significant). Significant improvement of leukemic remission rate or survival by these environmental manipulations was not found.
Article
Central nervous system (CNS) involvement occurred in 45 of 222 (20.3%) leukemic adults achieving bone marrow (BM) complete remission (CR), including 12 of 23 (52%) acute undifferentiated leukemia (AUL), 12 of 32 (39%) lymphoma leukemia, 5 of 26 (19%) acute lymphoblastic leukemia, and 16 of 142 (11%) acute myelogenous leukemia. Risk factors for CNS disease were lactic dehydrogenase (LDH) ≧600 mU/ml, AUL morphology, and extramedullary involvement, reflecting the importance of disease bulk and biologic idiosyncrasies. For primary CNS relapse, leukocyte count ≧25,000/mm3. AUL morphology, age < 20 years, and extramedullary involvement were most significant. Pattern of CNS involvement varied with morphology. Survival after CNS relapse depended most on BM status and symptoms. Duration of CNS CR was longest for asymptomatic patients with low CSF cell counts. Also important were duration of first BM CR, ease of achievement of initial BM CR, and leukocyte count (original and at most closely antecedent BM involvement), reflecting the common origin of BM and CNS leukemic cells. Central nervous system relapse generally did not shorten BM CR or survival, although early primary CNS relapse was associated with early BM relapse.
Article
28 adult patients with acute myeloid leukaemia (A.M.L.) received T.A.D., a high-dose sequential chemotherapeutic remission-induction regimen consisting of 7-day courses of cytosine arabinoside, 6-thioguanine, and daunorubicin. Overall response-rate was 82%. 22 patients (79%) achieved complete remission, and 1 had a partial remission. Median remission duration was 280 days and median survival 375 days. 10 patients remain in remission. These induction results are superior to those reported in most studies and indicate that disease remission can be achieved in a high proportion of patients with A.M.L. treated with an intensive multi-agent chemotherapeutic regimen, provided support facilities are adequate.
Article
Maintenance chemotherapy consisting of weekly oral 6-thioguanine and intramuscular cytosine arabinoside was administered to 24 adult patients with acute non-lymphocytic leukaemia in complete remission. The median duration of complete remission was 16-5 months, with 9 patients (38%) still in their first remission after 18--56 months. 33% of the patients have been in continuous remission for over 2 yr, 21% for over 3 yr, and 12-5% for over 4 yr. Median survival so far is 22-5 months. This maintenance regimen is well tolerated, is easily administered on an outpatient basis, and produces substantial numbers of long-term remissions.
Article
Active-specific immunization was performed in 26 adult patients with acute leukemia in remission. Fifteen patients, 14 acute myelogenous leukemia (AML) and one acute lymphocytic leukemia (ALL), received pooled allogeneic leukemia associated antigens (LAA) and 11 patients, eight AML and three ALL, received pooled irradiated allogeneic leukemia cells. LAA were prepared from leukemia cells, using hypotonic lysis and low frequency sonication, followed by discontinuous polyacrylamid gel electrophoresis or diethylaminoethyl column chromatography. Immunization was done weekly for three weeks and immunological studies (measurement of in vitro lymphocyte blastogenic responses and delayed hypersensitivity skin test reactions) were done weekly for five weeks. Among the patients who were immunized with LAA, 11 out of 15 showed increased blastogenic responses to LAA after immunization, and eight out of 10 studied showed increased blastogenic responses to irradiated autologous leukemia cells. Significant increases in blastogenic responses to both LAA and autologous leukemia cells were noticed on day 22 (p < 0.05). Among the patients who were immunized with irradiated allogeneic leukemia cells, three out of eight evaluated showed increased blastogenic responses to LAA and five out of seven evaluated showed increased blastogenic responses to autologous leukemia cells. On day 22, significant increases of blastogenic responses to autologous cells (p < 0.05), but not to LAA, were noticed. There was no increased blastogenic response noted to nonspecific mitogens or to the specific mitogenic antigen Streptolysin-O after active-specific immunization. The increase of blastogenic responses to LAA or autologous cells seems to be higher among the patients whose length of remission was over 12 months at the time of immunization. There was no overall significant difference between blastogenic responses in autologous serum or pooled AB(+) serum, although there were some differences in individual cases. Increased skin test reactivity to LAA after immunization was seen in seven out of 14 patients who received LAA, and four out of eight evaluated patients who received allogeneic leukemia cells. Those patients with an initially weak reaction showed increased reactivity after immunization. There was no correlation between blastogenic responses and skin test reactivity.
Article
Thirty evaluable patients with acute leukemia (AL), aged 14 to 48-year-old received remission induction chemotherapy on a protected environment-prophylactic antibiotic program. Twenty-seven (90%) of these patients achieved complete remission and 17 remained in complete remission for 1 to 22 months. Although these patients spent 36% of their time with neutrophil counts less than 100/mm3, they spent only 20% of their time with fever. Major infection was present during only 7% of the days when neutrophil count was less than 100/mm3. No patient died of an infectious complication during remission induction therapy.
Article
Twenty patients with acute myeloid leukaemia (AML) were treated with a combination of chemotherapy which included daunorubicin, cytosine arabino-side and 6-thioguanine (DAT). The complete remission rate was 85% and was achieved, in responsive cases, after an average of 2 courses of therapy. Patients remained in hospital for an average of 37.5 days during remission-induction therapy and 3.7 days per month thereafter. The median remission period was 48 weeks and median survival was 70 weeks. A disappointing feature was the high relapse rate. This feature of the results re-affirms the need for a more effective form of remission therapy.
Article
The clinical characteristics of 10 patients with acute myelogenous leukemia (AML) which developed subsequently to treatment for another neoplasm are described. This disease appears to differ from "spontaneous" AML in being associated with lesser degrees of leukemic infiltration of the marrow and more frequent chromosomal aberrations. Only one of the nine patients who received chemotherapy attained remission status, and the mean and median survivals from the initiation of chemotherapy were 2.7 months and one month respectively. Nine of the 10 patients died as a result of infection. The refractoriness of this form of AML to chemotherapy was borne out by a review of the literature, which revealed only two remissions in 32 treated patients. The implications for the management of this disease are discussed.
Article
One hundred and forty-five adults with acute leukemia were randomized to receive remission induction therapy in or out of a protected environment (PE) with prophylactic antibiotics orally (PA) or systemically (SA). Sixty-three patients were randomized in PE and 82 outside a PE. The proportion of patients who survived long enough to receive an adequate trial was higher in the PE (97%) than out (82%) (P = .01). The complete remission (CR) rate was 71% in and 43% out of the PE (P less than .01). Fifty-five patients received PA and 90 received SA. The CR rates were 61% and 45%, respectively. Of the 145 patients, 73 (50%) developed 102 episodes of major infections. Twenty-six of 63 patients in the PE developed major infection compared to 47 of 82 outside a PE (P = .08). The incidence rate of 13% fatal infections in a PE was significantly smaller than the 28% rate outside a PE (P = .04). The number of days with infections at less than 500 neutrophils/mm3 was also significantly lower inside a PE than outside (P less than .01). When comparing patients receiving SA or PA, there was no statistically significant difference in the incidence of infections. Forty-one patients received OAP Chemotherapy and 104 received adriamycin-OAP plus BCG. The CR rate on OAP was 44% compared with 60% on Ad-OAP + BCG. Infection rates were 76% and 40%, respectively (P less than .01). The median survival time was 72 weeks for patients in PE compared with 42 weeks for patients outside a PE (P less than .01). The prophylactic antibiotic regimens were well tolerated by most patients. This prospective randomized study has demonstrated statistically significant advantages for a lowered risk of fatal infection, higher CR rate and longer survival of patients treated in a PE with prophylactic antibiotics compared with patients treated in a conventional hospital room. Also, there was evidence for the superiority of adriamycin-OAP + BCG treatment compared with OAP.
Article
Between January 1973 and February 1975, 77 adults with acute nonlymphoblastic leukemia were treated with a combination of daunorubicin, cytosine arabinoside, 6-thioguanine, prednisone, and vincristine in university-affiliated and private institutions. After 31 patients were treated (regimen 1) the doses of all drugs were significantly increased (regimen 2). Regimes 1 and 2 yielded CR rates of 59% (17 of 29 patients) and 70% (32 of 46 patients) respectively. With regimens 2 the mean number of courses and the median number of days to CR decreased from 3 to 1.4 and from 46 to 29 respectively. Failure to achieve CR was due to persistent leukemia during regimen 1 and fatal infections during regimen 2. With regimen 2 ten of 20 patients (50%) greater than 50 years had CR compared to 22 of 26 patients (85%) less than 50 years. CR rates were similar in community and university institutions.
Article
Reverse isolation and prophylactic oral nonabsorbable antibiotics were evaluated among 64 consecutive noninfected adults with acute nonlymphocytic leukemia admitted for remission induction. Patients were randomly allocated to laminar air flow room reverse isolation with oral nonabsorbable antibiotics (LAF plus A), routine hospital ward care with antibiotics (W plus A), or ward care alone (W). The LAF plus A patients had a significantly decreased incidence of total infection, bacteremias, pneumonias, rectal abscesses, urinary tract infection, and pharyngitis. Infectious deaths were reduced in the LAF plus A group and the time to the first infection or to fatal infection was delayed. The W plus A patients who regularly ingested the antibiotics had a reduction in infections similar to that of the LAF plus A patients but those who could not tolerate the antibiotics had an incidence of infection comparable to the ward patients. The LAF plus A and the W plus A patients also had higher complete remission rates and longer median survival than the unprotected ward patients.
Article
Improvement in the management of acute leukemia in adults has not progressed nearly so rapidly as has the treatment of childhood leukemia. One important difference is that most adults have myeloblastic or related forms of the disease (AML), whereas the majority of children have lymphoblastic leukemia (ALL). However, even adults with ALL fail to respond as well to a similar regimen as do children with the same type of leukemia. In a recent series of patients with ALL who were treated with the complex multiple drug "L-2" protocol, the incidence of complete remission in adults was 78% vs. 99% in children, and the median duration of remission was only 24 months in the adults, whereas it has not yet been reached in the children and is projected to be over 4 years. In AML and the related nonlymphoblastic forms of acute leukemia, therapy is still unsatisfactory in both adults and children. With the best current drug treatment schedules, the incidence of complete remission is now better than 50%, but it is often difficult to compare the exact remission rates in different series because of differences in reporting results. In adults treated with the multiple drug "L-6" protocol, the incidence of remission in previously untreated patients was 56% and the median duration of remission was 10 months. The median survival of all patients (responders and non-responders) was 1 year whereas that of responders only was 2 years. It is encouraging that a significant proportion of those patients with AML who have complete remissions now remain in remission for extended periods; about 45% of patients responding to the "L-6" protocol remained in remission over 1 year, and 18% have been in continuous remission for 2 to over 4 years. Even after discontinuing treatment, some patients with AML stay in remission for long periods, and it is possible that some of them may have been cured. If this proves to be true, it becomes of great importance to determine what is different about the patients who do exceptionally well as compared to the majority who continue to die within a year. However, no consistent nor distinctive favorable prognostic features have yet been identified.
Article
Rubidazone was used as sole chemotherapy in 170 adults and children with acute leukemia and sarcoma. When rubidazone was employed to treat the first attack, complete remission was achieved in : 1) 40 out of 70 patients (57%) with AML; 2) two out of six patients with AML where previous chemotherapy had failed; 3) four out of five patients with ALL; 4) 12 out of 14 patients with acute monoblastic leukemia. When used to treat relapse, rubidazone produced complete remission in : 1) 14 out of 31 cases of AML; 2) 18 out of 39 cases of ALL; 3) 2 out of 3 cases of non-Hodgkin lymphoma. Treatment of a case of rhabdomyosarcoma was unsuccessful. In the treatment of acute myeloblastic and monoblastic leukemias, it may be concluded that rubidazone induces a higher rate of complete remission than any other previously reported drug which was used alone. It also achieves remission rates similar to those resulting from a combination of daunorubicin and Ara-C. Furthermore, when compared with daunorubicin, rubidazone allows better control of the induction of aplasia.
Article
The causes of death were investigated in 315 adults with acute leukemia during a 7-year period (1966-1972). Infection alone or in combination was the most common cause (75%), followed by hemorrhage (24%) and organ failure (9%). Most of the infections were either systemic or pulmonary. Seventy-five percent of the systemic infections and 72% of the pneumonias were caused by bacteria. Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa were the most frequent organisms isolated. After 1968, there was a sharp decrease in the number of fatal infections caused by Pseudomonas aeruginosa and a marked increase in the incidence of fatal infections caused by Klebsiella spp. and E. coli. Infections caused by Gram-positive cocci occurred in only 3% of the cases. The incidence of systemic fungal infections was 13%; most common fungi causing infection were Candida spp. and Aspergillus spp. Eighty-five percent of 159 patients with a terminal neutrophil count of less than 100/mm3 died of infection, compared to 48% of 62 patients with a terminal neutrophil count of greater than 1000/mm3. Hemorrhage was mostly due to thrombocytopenia (61%) and disseminated intravascular coagulation (12%). This study indicates that infection continues to be the most common cause of death in patients with acute leukemia. Although advances in antibiotic therapy have changed the distribution of causative organisms, ultimate control of infection requires further improvements in supportive care measures which rectify impairments in the patients' host defense mechanisms.
Article
A regime of treatment of acute non-lymphoblastic leukemia in adult, employing DMCP protocol, especially two step method consisting of daunorubicin, cytosine arabinoside, 6-mercaptopurine and prednisolone is described. Out of 32 adult patients with ANLL treated with DCMP regime 26 (81.3%) achieved complete remission. The median durations of complete remission and survival were 53 weeks and 54 weeks, respectively. The longest duration of complete remission was more than 220 weeks, and 3 cases are still maintaining initial complete remission more than 3 years.
Article
Sixty-six newly diagnosed patients with acute nonlymphocytic leukemia received either daunorubicin alone or a combination of daunorubicin, cytosine arabinoside, 6-thioguanine, and pyrimethamine for remission-induction therapy. The two treatment groups were comparable with respect to the two major prognostic factors in this disease, which were age and presence or absence of infection on admission. The two therapies produced similar results with respect to CR rate and median survival results. Single-agent therapy was associated with less frequent utilization of hospital inpatient facilities and fewer platelet transfusions. The four-drug combination did not decrease the incidence of meningeal leukemia. Patients who achieved CR were treated with two half-dose consolidation courses of the successful remission-induction regimen. Subsequently, all patients received cyclophosphamide and guanazole monthly for maintenance therapy. Median durations of remission for both induction-treatment groups were similar (6.8 and 5.6 mos). The therapeutic results with the single agent in this study were not inferior to those obtained with the drug combination tested, as well as most other previously reported combinations of antileukemic drugs.
Article
Daunorubicin induces complete remissions in about 50% of patients with acute promyelocytic leukemia. The median duration of these remission is 26 mo. Failures are mainly due to hemorrhages as a result of disseminated intravascular coagulation during the first 5 days (25%) or due to sepsis during the second and third week (25%). Long-term survivals are more frequent than in the other acute granulocytic leukemias.
Article
In a series of 170 adult patients with acute leukemia, sequential cytogenetic studies were conducted during a period which included either the initial and, at times, the terminal phase of the disease, or the relapse and remission phases. On the basis of morphological similarities in the karyotype changes, the patients carrying aneuploid clones were categorized into several profiles of aneuploidy. Analysis of the survival times determined from the time of diagnosis suggested that some of these abnormal cytogenetic profiles may have definite clinical implications.
Article
Earlier studies of cytosine arabinoside (Ara C) infusion for 5 days and dauborubicin (DNR) for 2 days suggested that longer treatment at the same doses could be tolerated. Infection acquisition in patients with acute myelocytic leukemia (AML) during remission induction prior to marrow recovery occurs at a constant rate. By intensifying the induction regimen and producing rapid bone marrow depression, a reduction in the patient's time at risk can be safely achieved. In this study, intravenous Ara C, 100 mg/m 2/day continuously for 7 days and DNR, 45 mg/m 2/day by rapid injection for 3 days was given to 8 previously untreated adult patients with AML. All 5 out of 8 less than 60 yr of age sustained complete remission. The 3 failures in the previously untreated group were elderly 67, 76, 78). Over one half of these patients were managed in an open ward and the remainder in laminar flow isolators. The period of hospitalization required to accomplish remission induction (a median of 35 days), was reduced compared to past experience with other regimens. One patient with previously untreated acute plasma cell leukemia remained in remission for a period of 21 mth. Five out of 8 patients from 26-60 yr of age, who had received prior treatment for their AML, achieved a remission. The combined remission rate for both previously treated and previously untreated AML patients was 63%. Using the schedule of daunorubicin and continuous cytosine arabinoside, remission was achieved in 65% of all of the patients with a substantial reduction in hospitalization time. This program rapidly produces aplastic bone marrows without excessive toxicity. This pilot study served as the basis for a further comparative evaluation.
Article
To reduce the frequency of infection in acute leukemia, we employed isolation and air-filtration facilities ("protected environment") and a prophylactic regimen that included oral nonabsorbable antibiotics. Eighty-eight randomized patients received identical remission-induction chemotherapy within one of three groups: protected environment combined with the prophylactic regimen (Group 1); oral nonabsorbable antibiotics alone (Group 2); and neither isolation nor prophylaxis (Group 3). The groups were comparable in factors that might influence the course of leukemia and susceptibility to infection. Environmental maneuvers. were effective in reducing the potential inoculum of ambient micro-organisms. Patients in Group 1 had 1/2 as many severe infections as those in Groups 2 and 3. Whereas approximately 1/4 of the patients in Groups 2 and 3 died of infection while on study, none in Group 1 died for that reason. Despite fewer infections in Group 1, no intergroup differences were found in remission rat...
Article
Two hundred and two adult patients with acute leukemia were analyzed to determine pretreatment and treatment factors that could predict for duration of bone marrow remission. Several factors had a significant effect on remission duration, including morphologic diagnosis (AML greater than ALL greater than AUL), initial blast cell count, age, serum LDH, fibrinogen level, labeling index, and in vitro agar colony growth. Patients who attained a remission quickly or in whom leukemic cells in blood and bone marrow were rapidly cleared had long remissions. After applying regression model fitting methods, the six major factors, in order of significance, were the initial serum LDH level, pretreatment fibrinogen level, the number of courses of treatment to obtain a remission, morphologic diagnosis, the halving rate of leukemic cells in the blood, and the age of the patient. The model derived from this study was applied to the 202 patients and suggested that patients likely to have short or long bone marrow remission can be identified.
Article
A distribution-free two-sample test is proporesearch-articlesed that is an extension of the Wilcoxon test to samples with arbitrary censoring on the right. The test is conditional on the pattern of observations. The null hypothesis is H0: F1(t) = F2(t) (t ≤ T) against either H1: F1(t) <F2 (t ≤ T) or H2: F1(t) < F2(t) or F1(t) > F2(t) (t ≤ T), where F1, F2 are cumulative distributions (discrete or continuous) of the observations and T is their upper limit. The test is shown to be asymptotically normal and consistent against one-sided alternatives F1(t) < F2(t) (t ≤ T) and against two-sided alternatives where either F1(t) < F2(t) or F2(t) > F2(t) (t≤T). The asymptotic efficiency of the test relative to the efficient parametric test when the distributions are exponential is at least 0.75 and increases with degree of censoring. When H0 is true, the test not seriously affected by real differences in the percentage censored in the two groups. Some comparisons are made for five cases of varying degrees of censoring and tying between probabilities from the exact test and those from the proposed test and these suggest the test is appropriate under certain conditions when the sample size is five in each group. A worked example is presented and some discussion is given to further problems.
Prognostic factors in acute leukemia
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  • Freireich EJ
Prediction of progression and survival of untreated acute leukemia
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Improved survival in adult acute lymphocytic leukemia
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Five year survival and remission duration in adult acute myelogenous leukemia (AML)
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Remission induction therapy with a rubidazone-containing combination (ROAP) in acute leukemia
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The chemoimmunotherapy of acute leukemia. (CIAL): A cooperative group study
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A generalized Wilcoxon test for comparing arbitrarily singly-censored samples Prognostic factors in acute leukemia Combination chemotherapy of acute nonlymphoblatic leukemia in adults Fatal Adriamycin cardiomyopathy (CMY): Prevention by dose limitation
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Five year survival and remission duration in adult acute myelogenous leukemia (AML) Proc Am Assoc C n n c o Resiproc Am Sue Clin O n c d
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Keating MJ. Bodey GP, McCredie KB, Freireich EJ. Five year survival and remission duration in adult acute myelogenous leukemia (AML). Proc Am Assoc C n n c o Resiproc Am Sue Clin O n c d 1979: 20:416. C-517 (abst).
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Treatment of acute leukemia in protected environment units. Cuncer 5. Breslow N. A generalized Kruskal-Wallis test for comparing K samples subject to unequal patterns of censorship
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Treatment of acute leukemia in protected environment units. Cuncer 5. Breslow N. A generalized Kruskal-Wallis test for comparing K samples subject to unequal patterns of censorship
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Bodey GP, McCredie KB, Keating MJ, Freireich EJ. Treatment of acute leukemia in protected environment units. Cuncer 5. Breslow N. A generalized Kruskal-Wallis test for comparing K samples subject to unequal patterns of censorship. BioiniJfriXtr 1970: 57:579-594.
Improved survival in adult acute lymphocytic leukemia
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Combination chemotherapy of acute nonlymphoblatic leukemia in adults
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Remission induction therapy with a rubidazonecontaining combination (ROAP) in acute leukemia
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Keating MJ, Benjamin RS. McCredie KB. Bodey GP, Freireich EJ. Remission induction therapy with a rubidazonecontaining combination (ROAP) in acute leukemia. Proc Anr Assoc Cuncrr ResiProc An1 Soc Cliri Oncol 1977; 18:180, 719 (abst). 1979; 44:431-436.
Five year survival and remission duration in adult acute myelogenous leukemia (AML)
  • M J Keating
  • G P Bodey
  • K B Mccredie
  • E J Freireich
Keating MJ. Bodey GP, McCredie KB, Freireich EJ. Five year survival and remission duration in adult acute myelogenous leukemia (AML). Proc Am Assoc C n n c o Resiproc Am Sue Clin O n c d 1979: 20:416. C-517 (abst).