Treatment Of Acute Nonlymphocytic Leukemia Research Articles

Comparison of Three Remission Induction Regimens and Two Postinduction Strategies for the Treatment of Acute Nonlymphocytic Leukemia: A Cancer and Leukemia Group B Study

Patients with acute nonlymphocytic leukemia were randomized to receive remission induction therapy consisting of seven days of cytosine arabinoside and three days of daunorubicin (“7 + 3”) or to receive the same regimen intensified by either the addition of 6-thioguanine or by extension of the administration of cytosine arabinoside to ten days. Additionally, all patients were randomized to receive or not to receive cotrimoxazole antibacterial prophylaxis during the remission induction phase. Neither an increase in intensity of chemotherapy nor the antibacterial prophylaxis increased the remission rate above the 53% for patients treated with the standard “7 + 3” regimen. The second part of this study addressed the issue of the utility of long-term maintenance chemotherapy. To this end, patients were randomized to discontinue all treatment after 8 months of maintenance chemotherapy or to continue maintenance therapy for a total of 3 years. Although there was a transient increase in the relapse rate for patients who discontinued therapy, the proportion of long-term remitters was identical in the two patient groups. Additionally, there is a suggestion of a survival advantage for patients randomized to discontinue all therapy at 8 months.

Treatment Of Acute Non-Lymphocytic Leukemia With 5-Azacitidine

5-azacitidine (5AZA), a 5-methyltransferase inhibitor that demethylates and unsilences genes is a novel medication with epigenetic mechanism of action approved for therapy of myelodysplastic syndromes. There are few reports in the literature regarding use in acute non-lymphocytic leukemia (ANLL) some indicating efficacy and others lack of efficacy. Since January 3, 2010, we treated 6 patients in various stages of ANLL with 5AZA. Data is summarized in table.AgeCytogeneticsUseResponseDuration (Months)Survival (Months)63 (male)45,XY,add(5)(q13),-7,+11,add(16)(q12),-17,-18,+22Induction FailureCR8+Alive 8+65 (male)46,XY,t(16:21)(q24;q11.2),del(20)(q11.2)Induction FailurePR8Dead 993 (male)46,XYPrimary RX/MaintenancePR12Dead 1368 (male)46,XY/NPM1Dysplasia 2o to ANLL inductionPR14Alive 14+86 (male)46,XYMaintenanceCR32+Alive 32+72 (male)46,XY/NPM1RAEB-2/ANLL Primary RX/MaintenancePR8Dead 19We treated 2 patients ages 63 and 65 with primary induction failure to standard 3+7 anthracycline/AraC, both with complex cytogenetics. One patient achieved hematological improvement following 1 cycle and complete remission at 3 months following 2 cycles of therapy. He continues to receive monthly 5AZA, is alive and in complete hematological remission (bone marrow not repeated) at 8+ months. The second patient achieved a partial remission at 1 month following 5AZA that remained stable on monthly 5AZA for 8 months at which time ANLL progressed resulting in death. We used 5AZA as induction and maintenance for a 93 year old with ANLL with normal cytogenetics. He achieved a partial then stable improvement with monthly 5AZA. At 12 months, ANLL progressed resulting in death. We treated a 68 year old with NPM1 positive normal cytogenetics ANLL who achieved remission with standard 3+7 therapy but at 6 months post induction developed secondary myelodysplasia. He achieved a stable partial response with monthly 5AZA for 14 months at which time ANLL relapsed. He is alive at the time of preparation of this abstract. We used 5AZA as maintenance for an 86 year old with ANLL with normal cytogenetics who achieved a complete remission with standard 3+7 therapy. This individual continues to receive 5AZA (monthly then every 6 weeks) and remains in complete remission 32+ months following diagnosis of ANLL. We treated a 72 year old with borderline RAEB-2/ANLL with NPM1 positive normal cytogenetics with 5AZA as primary induction therapy. He achieved a hematological response following 4 monthly cycles of 5AZA with normalization of platelets and decreased need for RBC support. ANLL relapsed at 8 months at which time he was treated with standard chemotherapy and lived an additional 11 months. This data indicates that 5AZA is useful for individuals with ANLL even with high risk cytogenetics with potential efficacy as primary therapy, for individuals with disease primary refractory to standard chemotherapy, and for maintenance of ANLL remission. Formal studies to more clearly define the role of 5AZA in various stages of ANLL are warranted. Disclosures:Off Label Use: 5-azacitidine for therapy of ANLL.

Implication of raft microdomains in drug induced apoptosis.

DNA damaging agents such as 1-beta-D-arabinofuranosylcytosine (Ara-C) and daunorubicin (DNR) are widely used in the treatment of acute nonlymphocytic leukemia. These drugs have, of course, been the objects of intense basic research, as well as preclinical and clinical study. Although specific biochemical lesions (DNA damage) have been associated with Ara-C- and DNR-mediated cytotoxicity, the pathways leading to the induction of apoptosis remain ill defined. This standpoint has forced investigators to explore a new concept in cell response to cytotoxic stress: apoptosis signaling. The recent identification of a ceramide (CER) mediated apoptotic signaling pathway triggered by antitumor agents offers a new perspective for the treatment of neoplastic cells. Indeed, these agents have been shown to induce apoptosis through the activation of a sphingomyelinase (SMase) responsible for the hydrolysis of sphingomyelin (SM) and the generation of CER. The latter acts as a potent apoptosis mediator, triggering several downstream signaling pathways among which the stress-activated protein kinase cascade (MEKK1-SEK1-SAP/JNK) plays a critical role in apoptosis induction. However, the spacio-temporal organization of the key early signaling events is unclear. The present review delineates what appears to be a critical factor in apoptosis signaling: sphingomyelin enriched plasma membrane rafts. The apparent topological partitioning between DNA damage and apoptosis signaling (integrated into specialized plasma membrane domains) is discussed.

Antitumor antibiotics discovered and studied at the Institute of Microbial Chemistry.

In 1951, we were pioneers in initiating screening of antitumor agents from microbial metabolites. We discovered bleomycin in 1962 and aclacinomycin in 1975. Peplomycin, a derivative of bleomycin, and pirarubicin, a tetrahydropyranyl derivative of doxorubicin, were also studied. All of them have been clinically used for the treatment of cancer. Using new screening methods, we isolated spergualin in 1982. This agent exhibited immunosuppressive activity as well as antitumor activity. Deoxyspergualin, a derivative of spergualin, is now clinically used for the treatment of acute rejection after kidney transplantation. Bestatin was screened as an inhibitor of aminopeptidase B in 1976. It binds to the aminopeptidases located on the cell membrane of immunocompetent cells and modulates immune responses. It is now used for the treatment of acute non-lymphocytic leukemia. Microbial metabolites will become more important as a source of anticancer drugs in the future.

Ubenimex in the treatment of acute nonlymphocytic leukemia in adults

A multi-institutional randomized study for the evaluation of ubenimex (Bestatin) in the treatment of adult acute nonlymphocytic leukemia was performed. One hundred and ninety-five patients were registered from February 1988 to December 1990. Patients who had reached complete remission by one or two courses of remission induction chemotherapy were divided into the ubenimex group or the control group by randomization. Patients of the ubenimex group started to receive 30 mg ubenimex orally once a day when maintenance therapy began and continued as long as possible. Remission duration and survival were analyzed based on the data as of August 31, 1991. Remission duration of the ubenimex group was superior to that of the control group (generalized Wilcoxon test: p = 0.0338). Fifty percent remission duration was 508 days in the ubenimex group and 386 days in the control group. There has been no statistical difference in survival between the two groups as yet.

Pharmacokinetics of Mitoxantrone in Plasma and Leukemic Cells During Treatment of Patients with Acute Non-Lymphocytic Leukemia

The pharmacokinetics of mitoxantrone was studied in the plasma and peripheral leukemic cells in 14 patients receiving induction treatment for acute non-lymphocytic leukemia. The disappearance of mitoxantrone from plasma was biphasic with a mean distribution half life of 10.4 minutes and a mean elimination half life of 17.1 hours. At the end of the infusion, the mean mitoxantrone concentration in leukemic cells was 9.6 times (range 2.1-22.7) higher than in plasma and remained relatively stable in the cells until the next infusion following 24 hours after the first. The area under the concentration-time curve (AUC0-20h) in leukemic cells was 23-191 times larger than the AUC0-α in plasma. In the individual patient there was no correlation between the AUC in leukemic cells and AUC in plasma. Since mitoxantrone acts intracellularly, concentrations in the leukemic cells might predict the antileukemic effect better than plasma concentrations.

Granulocyte-macrophage colony-stimulating factor in acute non-lymphocytic leukemia before and after chemotherapy

The introduction of hematopoietic growth factors into the management of leukemia can influence the outcome of treatment in several ways, depending on the sensitivity and the response of normal and leukemic cells. In this paper we report on the effects of the administration of Escherichia coli-produced, human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in 15 adult patients with acute nonlymphocytic leukemia (ANLL) resistant to first-line treatment or in relapse. GM-CSF was given at a dose of 5-10 micrograms/kg/day as a 6-h i.v. infusion, prior to chemotherapy (CHT) (for 7 days) and after CHT (until evidence of failure or of remission). In the pre-CHT period there was a clear trend towards an increase of circulating neutrophils (PMN) and/or blast cell count (median 0.3 vs. 1.0 x 10(9)/l for PMN, and 0.5 vs. 2.3 for blast cells). After chemotherapy, in the patients who achieved complete remission (CR), the median time to a PMN count greater than 0.5 x 10(9)/l and greater than 1 x 10(9)/l was 16 days (range 13-27) and 19 days (range 13-42) respectively. The outcome of treatment was CR for 8/15 (53%), death during induction for 3/15 (20%), and failure for 4/15 (27%). All failures occurred in patients with an increase of blast cell count during pre-CHT GM-CSF administration. Toxicity and side effects were minor, apart from an acute respiratory syndrome that developed twice in the same patient, at doses of 10 and 3 micrograms/kg/day. These data suggest that investigation of GM-CSF in the treatment of ANLL is worth pursuing, with special attention to GM-CSF effects prior to chemotherapy.

Phase II Study of 13-cis-Retinoic Acid in Pediatric Patients with Acute Nonlymphocytic Leukemia—A Pediatric Oncology Group Study

Forty-one patients with refractory acute non-lymphocytic leukemia (ANLL) in relapse were treated with 13-cis-retinoic acid (cRA) as salvage therapy. The cRA was given as a single oral dose of 100 mg/m2/day for 4 weeks. One patient achieved a complete remission and two patients achieved a partial remission with reduction of the bone marrow blast count from 40 to 20% after the first course. We recommend further study of cRA in combination with other agents in the treatment of ANLL in children.

A phase II clinical trial of carboplatin infusion in high-risk acute nonlymphoblastic leukemia.

Carboplatin (CBDCA) is a second-generation platinum drug that has been shown to be useful when used as a continuous infusion in treatment of refractory adult leukemia. We report on the effectiveness of continuous infusion CBDCA, 300 mg/m2/d x 5 days, as evaluated in nine patients with secondary acute nonlymphocytic leukemia (ANLL) (seven previous myelodysplastic syndrome and two treatment-associated ANLL), three ANLL patients in first relapse, six refractory ANLL, and nine patients with blastic phase of chronic myelogenous leukemia (BP-CML). All patients were considered assessable. The response rate was 44% (eight complete remissions [CRs], four partial remissions [PRs]). Median duration of postchemotherapy neutropenia was 36 days (range, 18 to 45). Therapy was well tolerated, and toxicity was mainly hematologic and nondose-limiting. Despite prolonged neutropenia, severe infections were rarely seen, and most patients were managed as outpatients. Twelve patients had nausea and vomiting, two had symptomatic hypomagnesemia, and one patient showed reversible ototoxicity. Because of substantial antileukemic activity and unusual extrahematologic toxicity, CBDCA appears to be an effective second-line agent in the treatment of ANLL and should be considered for upgrading to first-line treatment regimens.

The role of timing of high-dose cytosine arabinoside intensification and of maintenance therapy in the treatment of children with acute nonlymphocytic leukemia

The Children's Cancer Study Group instituted a pilot study to investigate the use of high doses of cytosine arabinoside (AraC) in the intensification phase of treatment for acute nonlymphocytic leukemia (ANLL). Patients achieving remission and not eligible for allogeneic bone marrow transplantation were treated with four doses of high-dose AraC and L-asparaginase. These drugs were repeated either on or after 28 days (q28 days), after recovery of hematologic parameters (for the first 49 patients entered onto this trial); or after 7 days (q7 days), despite dropping blood counts (for the last 53 patients enrolled). After completing an additional 3 months of intensification therapy, patients were then allocated by physician choice to either discontinue therapy or receive 18 28-day cycles of maintenance therapy, including the daily administration of 6-thioguanine. Despite three deaths associated with the toxicity of the aggressive (q7 days) AraC timing, patients receiving this approach demonstrated equal or better disease-free survival from the end of induction (55% versus 42% actuarially at 3 years [P = 0.52]). Maintenance therapy appeared to play no role in improving outcome for people who received the aggressive timing of AraC cycles. Fifty-nine percent were alive disease free actuarially at 3 years from the decision to not give maintenance therapy (n = 27) compared with 62% for those receiving maintenance therapy (n = 16; P = 0.49). On the other hand, patients who received the less aggressive AraC intensification timing (q28 days) had an improved survival rate if maintenance therapy was administered (n = 17) (65% versus 39% for patients not receiving maintenance therapy [n = 24] at 3 years [P = 0.07]). Maintenance therapy therefore may not improve outcome in patients receiving aggressive timing of high-dose AraC but may be important in less intensive postremission regimens in childhood ANLL.

Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly.

We conducted a randomized multicenter trial comparing low-dose cytarabine (LD ARA-C) (20 mg/m2 for 21 days) with an intensive chemotherapy (rubidazone [a daunorubicin-derived agent], 100 mg/m2 for 4 days, ARA-C 200 mg/m2 for 7 days) in 87 patients over 65 years of age with de novo acute nonlymphocytic leukemia (ANLL). Forty-one patients received LD ARA-C and 46 received intensive chemotherapy. The number of complete remissions (CRs) but also of early deaths was higher in the intensive chemotherapy group, while partial remissions (PRs) and failures were more frequent in the LD ARA-C group (P less than .001). Infectious complications during induction treatment were more numerous and more severe in the intensive chemotherapy group (P less than .01). Patients treated with LD ARA-C required fewer RBC transfusions (P less than .02), fewer platelet transfusions (P less than .01), and had a shorter hospital stay for induction treatment (P less than .01). Overall survival and CR duration were not significantly different in either group. In the LD ARA-C group, the survival of patients with PR and those of patients in CRs was identical. We conclude that in a selected group of elderly patients with de novo ANLL a higher number of CRs may be obtained with intensive chemotherapy, but that with LD ARA-C, the number of early deaths is lower, and long-lasting PRs are obtained, resulting in a similar overall survival.

Nonhematologic toxicities of selected chemotherapeutic agents used in the treatment of adult leukemia

p ROGRESS has been made in the treatment of acute non-lymphocytic leukemia (ANLL), acute lymphocytic leukemia (ALL), and blastic phase of chronic myelogenous leukemia (CMLBC). However, until long-term survival improves, manipulation of drug dose, schedules, and combinations can be expected. With these manipulations, the incidence and severity of nonhematologic toxicities will vary. Because these toxicities can result in dosage alterations or delays in treatment, the prevention, early detection, and objective measurement of these toxicities are essential. There are four chemotherapeutic agents commonly used in the treatment of ANLL, ALL, and CML-BC. These drugs, cytosine arabinoside, mitoxantrone, amsacrine, and daunorubicin, have various gastrointestinal, ophthalmologic, dermatologic, pulmonary, cardiologic, and neurologic toxicities. This article outlines the toxicities of these drugs, used singly and in combination, and describes assessment and intervention strategies for the toxic effects. Because bone marrow hypoplasia is a goal of therapy for these malignancies, myelosuppression will not be addressed.

Mitoxantrone, Etoposide and Cytarabine in the Treatment of Acute Nonlymphocytic Leukemia

In a phase I/II study mitoxantrone and etoposide, in combination with cytarabine, were given to 26 patients with refractory, relapsed, and previously untreated acute nonlymphocytic leukemia. Therapy consisted of mitoxantrone 12 mg/m2/day for 3 days, etoposide 100 mg/m2/day and cytarabine 1 g/m2 twice a day for 5 days. A total of 14 complete remissions (CR, 54%) were noted. Among refractory patients 5 of 10 achieved a CR as compared to 5 of 6 in the previously untreated group. A favorable response was also seen in patients with late relapse off treatment (3/4 CR) while patients relapsing on therapy did worse (1/6 CR). The results suggest a high antileukemic activity and a moderate toxicity for this drug combination.

Bone marrow transplantation versus chemotherapy in acute non-lymphocytic leukemia: A meta-analytic review

IN THIS JOURNAL Hermans et al. [l] have performed a retrospective analysis in order to compare alternative therapeutic approaches to the treatment of acute nonlymphocytic leukemia in young adults. They studied the relative efficacy of bone marrow transplantation (BMT) and conventional chemotherapy for patients in first complete remission, using registry information from the European Cooperative Group for Bone Marrow Transplantation, and data from two trials conducted by the European Organization for Research and Treatment ofcancer as controls. They used disease-free survival (DFS) from complete remission (CR) as the primary endpoint. Their analysis involves an adjustment to correct for the bias that is caused by the fact that many patients who might have received transplants are automatically excluded from the BMT series by virtue of an early relapse prior to transplantation. For this purpose they employed the Mantel-Byar procedure [2]. The analysis demonstrates significant superiority for allogeneic BMT over conventional chemotherapy (P = O.Ol), with the results of autologous BMT lying between those of the other two groups. Further analyses using Cox regression with time-dependent covariates demonstrate that the superiority ofallogeneic BMT over conventional therapy is primarily in longer-term disease-free survival, the short-term results being very similar. Less

Alpha-streptococcal septicemia in leukemic children treated with continuous or large dosage intermittent cytosine arabinoside.

During a 2-year period after the introduction of an intensive chemotherapeutic protocol, alpha-hemolytic streptococci accounted for 75% of all episodes of sepsis among children with acute nonlymphocytic leukemia at our institution. Only one case had occurred in the previous 8 years. Fourteen of 15 episodes of streptococcal sepsis occurred after therapy with either continuous or large dosage intermittent cytosine arabinoside. Eleven episodes occurred at two specific treatment points. Septic episodes were complicated by shock (2 of 15), encephalopathy (2 of 15), pneumonia (3 of 15) and death (1 of 15). Oral mucosal lesions may provide a portal of entry for alpha-hemolytic streptococci. These data suggest that children receiving continuous or large dosage intermittent cytosine arabinoside for treatment of acute nonlymphocytic leukemia may be at increased risk for alpha-hemolytic streptococcal sepsis. Empiric antimicrobial therapy in these children when febrile and neutropenic should include antibiotics effective against alpha-hemolytic streptococci.

Adult Acute Nonlymphocytic Leukemia in Saudi Arabia: Experience at King Khalid University Hospital in Riyadh

Twenty-two adult patients with acute nonlymphocytic leukemia (ANLL) were analyzed. There were 15 males (68%) and 7 females (32%). Their median age was 42 years. Thirty-six percent had acute myelomo...

Relapse of acute leukemia after marrow transplantation: natural history and results of subsequent therapy.

Of 455 acute nonlymphocytic leukemia (ANL) patients who underwent marrow transplantation, 95 (21%) relapsed a median of 6.5 months posttransplantation and 62 received further treatment. Twenty achieved remission. Success of therapy was related to the length of time from marrow transplant to relapse and to the use of cytarabine (Ara-C) and daunomycin. Aggressive chemotherapy for patients relapsing within 100 days of marrow transplant was associated with a high incidence of early death (six of 14 patients) and a low probability of remission (one of 14). Of 23 patients who relapsed in excess of 1 year from marrow transplant, 15 achieved a complete remission. The median disease-free survival is 6 months (range, 0.4 to 53+ months). Acute lymphocytic leukemia (ALL) recurred in 130 of 366 patients (36%), and 94 received further therapy. Fifty-two achieved a remission. Remissions were more common in late relapse patients (greater than 1 year from transplantation): 65% v 7% for those relapsing within 100 days from transplant (P less than .05). Testicular relapse occurred in 11 patients and was the sole site of relapse in seven. Three are alive and free of disease 58 to 109+ months after relapse. The median survival for the treated patients is 10.5 months (range, 5 to 109+ months). We propose that reinduction be attempted in all patients relapsing greater than 1 year from marrow transplantation. Ara-C and daunomycin should be employed in the treatment of ANL. The decision for treatment of patients relapsing earlier than 1 year should be made on an individual basis.

Treatment of acute nonlymphocytic leukemia in the elderly with intermediate high-dose cytosine arabinoside.

Effective treatment of the elderly patients (greater than or equal to 65 years) with acute nonlymphocytic leukemia (ANLL) remains elusive and controversial. In the present study, single-agent Cytosine Arabinoside (ARA-C) was administered at an intermediate dose level (500 mg/m2 intravenously [I.V.] 1-hour infusion q12 hours for 12 doses) to 30 newly diagnosed and previously untreated patients. Complete remission was achieved in seven patients after the initial cycle of treatment, in two patients after retreatment, and in one patient after delayed recovery of his peripheral count over a 6-month period. The toxicity of this schedule was primarily hematologic, and the response rate was in keeping with that reported by other groups using aggressive multiagent regimens.

Treatment of "poor risk" acute nonlymphocytic leukemia with continuously infused low-dose cytosine arabinoside.

There is currently little experience using a continuous intravenous infusion of low-dose cytosine arabinoside (LDARA-C) in the treatment of acute nonlymphocytic leukemia (ANLL). We report the results in 12 patients with ANLL described as either relapsed ANLL, ANLL with a preceding myelodysplastic phase, or ANLL in the elderly treated with 14 days of continuous intravenous LDARA-C (20 mg/m2/day). Complete responses (CR) were seen in five patients (42%) and partial responses (PR) in three patients (25%). Treatment resulted in overall and clonal cytoreduction, which was evident by serial bone marrow exams and bone marrow cytogenetic analysis. The ability to obtain a CR correlated with the finding of a low initial marrow cellularity (P less than .05). This study finds that continuous intravenous infusion of LDARA-C for ANLL can achieve response rates comparable to standard induction programs in a subset of patients traditionally defined as having a poor prognosis.

Biologic Characteristics and Treatment of Acute Nonlymphocytic Leukemia in Children: Report of the ANLL Strategy Group of the Childrens Cancer Study Group

Today approximately 75 per cent of children with ANLL can be induced into a complete remission and approximately 40 per cent will have an event-free survival for more than 3 years, irrespective of whether they received a bone marrow transplantation or chemotherapy after induction. In order to achieve these results very intensive therapy is required. The morbidity and mortality of treatment are high. The length of therapy needed after induction of remission is not known. Whether or not maintenance therapy is required is perhaps related most directly to the intensity of the therapy employed. Similarly, the role of bone marrow transplantation in patients in first remission, treatment of CNS leukemia, and treatment of chloromas are controversial. There is general agreement that WBCs over 100,000, acute monoblastic leukemia in infants less than 2 years of age, and certain chromosomal abnormalities are associated with a poor prognosis. Although there has been a dramatic improvement in the treatment of ANLL over the past 15 years, stratification of therapy based on biologic parameters, and alteration of treatment based on the early responses to treatment may be required before further advances will be made.