scholarly journals Diaziquone given as a continuous infusion is an active agent for relapsed adult acute nonlymphocytic leukemia

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 182-187 ◽  
Author(s):  
EJ Lee ◽  
DA Van Echo ◽  
MJ Egorin ◽  
MS Nayar ◽  
P Shulman ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Drug Exposure ◽  
Blast Crisis ◽  
Active Agent ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Acute Nonlymphocytic Leukemia ◽  
Nonhematologic Toxicity

Abstract Diaziquone given as a bolus has not been effective in patients with relapsed or refractory leukemia. Because of in vitro data suggesting enhancement of diaziquone-induced cytotoxicity for human and murine leukemia cells with increased duration of drug exposure and the relatively short terminal plasma half-life of diaziquone, 49 patients (34 acute nonlymphocytic leukemia [ANLL], six chronic myelogenous leukemia in blast crisis [CML-B], five acute lymphocytic leukemia [ALL], four 2 degrees ANLL) with leukemia were given diaziquone as a continuous infusion for seven days. The maximum tolerated dose was 28 mg/m2/d for seven days. The dose-limiting toxicity was the duration of bone marrow aplasia (median, 49 days to greater than 500 PMNs in responders; range, 28 to 101 days). Nonhematologic toxicity was minimal. Responses occurred only in patients with relapsed ANLL, of whom 26 were treated at effective doses. There were six complete responses (CR) (23%) and two partial responses (PR) (8%), although five of eight responders never achieved platelet counts greater than 100,000/microL. Thrombocytopenia in these patients was felt to be a manifestation of diaziquone effect, not persistence of leukemia. The median duration of CR was 195 days (range, 88 to 860+). One patient had active CNS leukemia at the start of treatment and has had a durable (28+ month) CR in both sites of disease. Diaziquone produced prolonged aplasia in patients with secondary ANLL and CML-B (five of ten patients died aplastic), whereas patients with ALL all had regrowth of leukemia and two failed to become aplastic. The lack of significant nonhematologic toxicity and the activity in patients with relapsed ANLL render diaziquone of interest as second-line therapy or consolidation therapy in first remission for patients with ANLL.

Diaziquone given as a continuous infusion is an active agent for relapsed adult acute nonlymphocytic leukemia

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 182-187
Author(s):  
EJ Lee ◽  
DA Van Echo ◽  
MJ Egorin ◽  
MS Nayar ◽  
P Shulman ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Drug Exposure ◽  
Blast Crisis ◽  
Active Agent ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Acute Nonlymphocytic Leukemia ◽  
Nonhematologic Toxicity

Diaziquone given as a bolus has not been effective in patients with relapsed or refractory leukemia. Because of in vitro data suggesting enhancement of diaziquone-induced cytotoxicity for human and murine leukemia cells with increased duration of drug exposure and the relatively short terminal plasma half-life of diaziquone, 49 patients (34 acute nonlymphocytic leukemia [ANLL], six chronic myelogenous leukemia in blast crisis [CML-B], five acute lymphocytic leukemia [ALL], four 2 degrees ANLL) with leukemia were given diaziquone as a continuous infusion for seven days. The maximum tolerated dose was 28 mg/m2/d for seven days. The dose-limiting toxicity was the duration of bone marrow aplasia (median, 49 days to greater than 500 PMNs in responders; range, 28 to 101 days). Nonhematologic toxicity was minimal. Responses occurred only in patients with relapsed ANLL, of whom 26 were treated at effective doses. There were six complete responses (CR) (23%) and two partial responses (PR) (8%), although five of eight responders never achieved platelet counts greater than 100,000/microL. Thrombocytopenia in these patients was felt to be a manifestation of diaziquone effect, not persistence of leukemia. The median duration of CR was 195 days (range, 88 to 860+). One patient had active CNS leukemia at the start of treatment and has had a durable (28+ month) CR in both sites of disease. Diaziquone produced prolonged aplasia in patients with secondary ANLL and CML-B (five of ten patients died aplastic), whereas patients with ALL all had regrowth of leukemia and two failed to become aplastic. The lack of significant nonhematologic toxicity and the activity in patients with relapsed ANLL render diaziquone of interest as second-line therapy or consolidation therapy in first remission for patients with ANLL.

Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study.

1992 ◽  
Vol 10 (3) ◽  
pp. 406-413 ◽  
Author(s):  
R Grunewald ◽  
H Kantarjian ◽  
M Du ◽  
K Faucher ◽  
P Tarassoff ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Accumulation Rate ◽  
Blast Crisis ◽  
Maximum Tolerated Dose ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Time Curve ◽  
Cellular Pharmacology

PURPOSE Phase I clinical and in vitro studies of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) have demonstrated that the accumulation rate of dFdC 5'-triphosphate (dFdCTP) in mononuclear and leukemia cells is saturated when plasma or extracellular dFdC levels exceed 15 to 20 mumol/L. Thus, we designed a phase I study to maximize the accumulation of dFdCTP by leukemia cells by administering dFdC at 10 mg/m2/min, a dose rate calculated to produce steady-state plasma dFdC levels that exceed 15 to 20 mumol/L. PATIENTS AND METHODS The treatment intensity was increased in patients (n = 22) with relapsed or refractory acute leukemia or chronic myelogenous leukemia (CML) in blast crisis by prolonging the infusion duration but maintaining the same rate. Doses of dFdC between 1,200 mg/m2 and 6,400 mg/m2 were administered weekly for 3 weeks. RESULTS The maximum-tolerated dose was 4,800 mg/m2 infused over 480 minutes. The mean steady-state dFdC level in plasma of all infusions was 26.5 +/- 9 mumol/L (n = 19). The accumulation rates of dFdCTP in circulating leukemia cells varied greatly among patients but remained linear in eight patients infused for 120 to 240 minutes, and up to or beyond 360 minutes in five of eight additional patients. Elimination of dFdCTP was significantly related to its cellular concentration: blasts with greater than 450 mumol/L dFdCTP exhibited biphasic elimination, whereas blasts with lower dFdCTP concentrations exhibited linear kinetics. Biphasic elimination was associated with higher dFdCTP areas under the concentration-times-time curve (AUCs) and greater inhibition of DNA synthesis. CONCLUSION Studies of the cellular pharmacology and pharmacodynamics of dFdC may be useful in optimizing protocol designs for leukemia.

scholarly journals Production of Colony-stimulating Factor by Malignant Leukocytes

Blood ◽  
1974 ◽  
Vol 43 (5) ◽  
pp. 749-756 ◽  
Author(s):  
David W. Golde ◽  
Belina Rothman ◽  
Martin J. Cline
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Csf Production

Abstract There is considerable evidence supporting a role for colony-stimulating factor (CSF) as a humoral regulator of leukopoiesis. Data on CSF levels in the serum and urine of patients with leukemia and on the in vitro responsiveness of leukemic cells to CSF have suggested a basis for considering leukemia as a primary disorder of leukopoietic regulation. We examined the question of leukemic cell production of CSF. Conditioned medium from cultured leukemic cells was tested for colony-stimulating activity against normal human bone marrow using a two-layer agar colony assay technique. The cells from patients with acute myelogenous leukemia and a patient with chronic myelogenous leukemia in blast crisis did not elaborate CSF nor did acute lymphocytic leukemia cells. CSF production was documented with cells obtained from patients with chronic myelogenous leukemia in the chronic phase and two patients with acute myelomonocytic leukemia. In acute leukemia the cellular production of CSF correlated closely with morphologic and functional maturation along the monocyte-macrophage line. Evidence was obtained that the adherent cells within the leukemic population were primarily responsible for CSF production. We interpret these data to indicate that neoplastic hematopoietic cells may produce CSF in relation to their capacity for mononuclear leukocyte differentiation.

scholarly journals Separation of lymphoid and myeloid blasts in the mixed blast crisis of chronic myelogenous leukemia: no evidence for Ig gene rearrangement in CALLA-positive blasts

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1404-1408 ◽  
Author(s):  
K Ha ◽  
MH Freedman ◽  
A Hrincu ◽  
D Petsche ◽  
A Poon ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Gene Rearrangement ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Cell Lineage ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
B Lineage

Abstract Recent studies suggest that lymphoid blast crisis cells of chronic myelogenous leukemia (CML) expressing the common acute lymphoblastic leukemia antigen (CALLA) are B precursor cells, based on the demonstration of immunoglobulin (Ig) gene rearrangement similar to common acute lymphocytic leukemia. There is little evidence to suggest whether the cells with similar lymphoid characteristics in the mixed blast crisis of CML are also committed to B cell lineage. A patient in “mixed” blast crisis of CML was studied. On the basis of morphology, cytochemistry, and immunological studies, the blasts were classified as having either lymphoid or myeloid characteristics. A proportion of the leukemic blasts expressed CALLA, whereas others expressed My7 antigen. In order to characterize both populations of cell further, CALLA+ blasts and My7+ (myeloid) blasts were isolated by fluorescence- activated cell sorting. The My7+ cells were highly proliferative in cell culture blast colony assays, retained the Ph1 chromosome, and were indistinguishable from acute myelogenous leukemia blasts. The CALLA+ cells were also Ph1-chromosome positive, but in contrast, were poorly proliferative in vitro. Of particular note was their retention of germline configuration of Ig genes, thus distinguishing them from blasts in the lymphoid crisis of CML. We conclude that the lymphoid component in mixed blast crisis may represent a stage of differentiation prior to commitment to B lineage.

scholarly journals 5-Azacytidine: A New Active Agent for the Treatment of Acute Leukemia

Blood ◽  
1973 ◽  
Vol 42 (3) ◽  
pp. 359-365 ◽  
Author(s):  
Myron Karon ◽  
Lance Sieger ◽  
Suzanne Leimbrock ◽  
Jerry Z. Finklestein ◽  
Mark E. Nesbit ◽  
...  
Keyword(s):  
Complete Remission ◽  
Acute Leukemia ◽  
Acute Myelogenous Leukemia ◽  
Acute Lymphocytic Leukemia ◽  
Active Agent ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Important Addition

Abstract Thirty-seven children with acute leukemia were treated with 5-azacytidine in 5-day courses given every 14 days. Six out of 14 children with acute myelogenous leukemia who were adequately treated achieved an M1 marrow. Five of these subsequently developed complete remissions lasting 8 mo, 6 mo, 3 mo, 2 mo, and 2 mo. Of 22 children with acute lymphocytic leukemia, one achieved an M1 marrow and one an M2 marrow. The former attained a complete remission which lasted 3 mo. The maximum tolerated dose is between 150 to 200 mg/sq m on a daily x 5 schedule given every 14 days. The impressive activity of 5-aza-C in patients with acute myelogenous leukemia resistant to cytosine arabinoside indicates that this drug will become an important addition to the therapeutic armamentaria against this type of leukemia.

scholarly journals The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1684-1690 ◽  
Author(s):  
HG Ahuja ◽  
A Foti ◽  
M Bar-Eli ◽  
MJ Cline
Keyword(s):  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Ras Gene ◽  
Ras Genes

Abstract DNA from 161 patients with various forms of hematologic malignancies were investigated for mutations in exons 1 and 2 of the N-RAS, K-RAS and Ha-RAS gene by direct sequencing of DNA amplified in vitro by the polymerase chain reaction. Mutations involving either codons 11, 12, or 13 of the N-RAS gene were identified in 18 of the 161 patients. The relative frequencies of N-RAS gene mutations in these hematologic disorders was as follows: acute myelogenous leukemia (AML), 15%; acute lymphoblastic leukemia (ALL), 14%; myelodysplastic syndromes, 24%; and myeloid and lymphoid blast crisis of chronic myelogenous leukemia (CML), 3%. No correlation was observed between the presence of mutations and cytologic features or immunophenotype of these malignancies. Mutations involving codons 12 or 13 were equally prevalent, with a glycine to aspartic acid substitution being the most frequently encountered change. A single T-ALL case had a codon 11 mutation resulting in substitution of alanine with threonine. We failed to find mutations in exons 1 and 2 of the K-RAS or Ha-RAS genes in any case except a single AML with a mutation in codon 61 of the K-RAS gene. Also, no mutations were identified in chronic phase of CML, chronic lymphocytic leukemia. Ph1 positive ALL, non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma. These results indicate that RAS mutations, especially those involving exon 1 of the N-RAS gene, are frequent only in a subset of hematologic malignancies.

scholarly journals The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1684-1690 ◽  
Author(s):  
HG Ahuja ◽  
A Foti ◽  
M Bar-Eli ◽  
MJ Cline
Keyword(s):  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Ras Gene ◽  
Ras Genes

DNA from 161 patients with various forms of hematologic malignancies were investigated for mutations in exons 1 and 2 of the N-RAS, K-RAS and Ha-RAS gene by direct sequencing of DNA amplified in vitro by the polymerase chain reaction. Mutations involving either codons 11, 12, or 13 of the N-RAS gene were identified in 18 of the 161 patients. The relative frequencies of N-RAS gene mutations in these hematologic disorders was as follows: acute myelogenous leukemia (AML), 15%; acute lymphoblastic leukemia (ALL), 14%; myelodysplastic syndromes, 24%; and myeloid and lymphoid blast crisis of chronic myelogenous leukemia (CML), 3%. No correlation was observed between the presence of mutations and cytologic features or immunophenotype of these malignancies. Mutations involving codons 12 or 13 were equally prevalent, with a glycine to aspartic acid substitution being the most frequently encountered change. A single T-ALL case had a codon 11 mutation resulting in substitution of alanine with threonine. We failed to find mutations in exons 1 and 2 of the K-RAS or Ha-RAS genes in any case except a single AML with a mutation in codon 61 of the K-RAS gene. Also, no mutations were identified in chronic phase of CML, chronic lymphocytic leukemia. Ph1 positive ALL, non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma. These results indicate that RAS mutations, especially those involving exon 1 of the N-RAS gene, are frequent only in a subset of hematologic malignancies.

scholarly journals Separation of lymphoid and myeloid blasts in the mixed blast crisis of chronic myelogenous leukemia: no evidence for Ig gene rearrangement in CALLA-positive blasts

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1404-1408
Author(s):  
K Ha ◽  
MH Freedman ◽  
A Hrincu ◽  
D Petsche ◽  
A Poon ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Gene Rearrangement ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Cell Lineage ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
B Lineage

Recent studies suggest that lymphoid blast crisis cells of chronic myelogenous leukemia (CML) expressing the common acute lymphoblastic leukemia antigen (CALLA) are B precursor cells, based on the demonstration of immunoglobulin (Ig) gene rearrangement similar to common acute lymphocytic leukemia. There is little evidence to suggest whether the cells with similar lymphoid characteristics in the mixed blast crisis of CML are also committed to B cell lineage. A patient in “mixed” blast crisis of CML was studied. On the basis of morphology, cytochemistry, and immunological studies, the blasts were classified as having either lymphoid or myeloid characteristics. A proportion of the leukemic blasts expressed CALLA, whereas others expressed My7 antigen. In order to characterize both populations of cell further, CALLA+ blasts and My7+ (myeloid) blasts were isolated by fluorescence- activated cell sorting. The My7+ cells were highly proliferative in cell culture blast colony assays, retained the Ph1 chromosome, and were indistinguishable from acute myelogenous leukemia blasts. The CALLA+ cells were also Ph1-chromosome positive, but in contrast, were poorly proliferative in vitro. Of particular note was their retention of germline configuration of Ig genes, thus distinguishing them from blasts in the lymphoid crisis of CML. We conclude that the lymphoid component in mixed blast crisis may represent a stage of differentiation prior to commitment to B lineage.

Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.

1994 ◽  
Vol 12 (3) ◽  
pp. 575-579 ◽  
Author(s):  
P McLaughlin ◽  
F B Hagemeister ◽  
F Swan ◽  
F Cabanillas ◽  
O Pate ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Active Agent ◽  
Large Cell ◽  
Maximum Tolerated Dose ◽  
Low Grade ◽  
Overall Response ◽  
Nonhematologic Toxicity ◽  
High Fraction

PURPOSE Fludarabine is an active agent for patients with low-grade lymphoma (LGL) but has mainly been used as a single agent. This trial was designed to define the maximum-tolerated dose (MTD) of a combination of fludarabine, mitoxantrone, and dexamethasone (FND), to identify the toxicities of these agents in combination, and to make preliminary observations about the efficacy of this combination. PATIENTS AND METHODS Twenty-one patients with recurrent LGL or follicular large-cell lymphoma were treated, in cohorts of three, at stepwise escalating doses. Patients were required to have adequate marrow function and normal renal, hepatic, and cardiac function. RESULTS The MTD of the combination was found to be as follows: fludarabine, 25 mg/m2/d (days 1 to 3); mitoxantrone, 10 mg/m2 (day 1); and dexamethasone, 20 mg/d (days 1 to 5). Each course was administered monthly, and up to eight courses were given. Dose-limiting toxicities were neutropenia and infections. Thrombocytopenia was modest. Nonhematologic toxicity was very modest. Responses were seen at every dose level. The overall response rate was 71%, with a 43% complete remission (CR) rate. The median duration of CR was 18 months (with follow-up duration from 13 to 28+ months). CONCLUSION FND was well tolerated in this population. While our primary aim was to define the MTD, our preliminary observations on the efficacy of the regimen were favorable. The overall response rate was high, there was a high fraction of CRs, and our early impression is that these responses are durable.

scholarly journals Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia [published erratum appears in Blood 1989 Aug 15;74(3):1180]

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1720-1728 ◽  
Author(s):  
KM Sullivan ◽  
PL Weiden ◽  
R Storb ◽  
RP Witherspoon ◽  
A Fefer ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Host Disease ◽  
Graft Versus Host

Abstract To assess the influence of graft-versus-host disease (GVHD) on recurrent leukemia and survival after allogeneic marrow transplantation, we studied 1,202 patients with acute nonlymphocytic leukemia (ANL), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML) given unmodified marrow grafts from HLA- identical siblings. Proportional hazards regression models using acute GVHD and chronic GVHD as time-dependent covariates demonstrated a significant association of GVHD with a decreased relative risk (RR, 0.33 to 0.42) of relapse in patients with ANL, ALL, and CML transplanted in advanced disease. Among patients developing either acute or chronic GVHD, treatment failure (that is, mortality or relapse) was decreased in patients with ALL transplanted in relapse (RR = 0.70, P less than .033) and CML in blast crisis (RR = 0.37, P less than .009). This effect was independent of age, sex, preparative regimen, GVHD prophylaxis, or length of follow-up. Five-year actuarial estimates were derived for the subset of 657 patients who survived in remission 150 days after transplant and were at risk for development of chronic GVHD. Among patients with ANL in first remission or CML in chronic phase, GVHD had an adverse effect on survival and no apparent influence on relapse. Among patients with ANL and ALL transplanted in relapse, the probability of relapse after day 150 was 74% without [corrected] GVHD, 45% with acute and chronic GVHD, 35% with [corrected] only acute GVHD, and 34% with only chronic GVHD (P less than .001). Actuarial survival in these four GVHD groups was 25%, 34%, 59%, and 62%, respectively (P less than .009). Among patients with CML in acceleration or blast crisis, the probability of relapse after day 150 was 65% without GVHD and 36% with acute and/or chronic GVHD (P less than .017). We conclude that acute and chronic GVHD were associated with a durable antileukemic effect and improved survival in patients transplanted in advanced stages of ALL and CML.

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