Acute Nonlymphocytic Leukemia Patients Research Articles

The Toxicity of Cytarabine

The principal toxicity of standard induction regimens for acute non-lymphocytic leukemia (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.(ABSTRACT TRUNCATED AT 400 WORDS)

Impact of Advanced Age on the Management of Acute Nonlymphocytic Leukemia: A Study of 103 Patients

Treatment and outcome of 103 consecutive patients aged greater than or equal to 60 with de novo acute nonlymphocytic leukemia (ANLL) were reviewed. Twenty-three cases (22%) were not suitable for induction chemotherapy because of very poor presenting general conditions and could receive supportive care alone. The majority of them died within 1 month. Twenty-eight patients (27%) aged greater than or equal to 70 and/or with concurrent nonhematologic disorders underwent mild induction chemotherapy, which produced 3 complete remissions. The median survival for this group was 2 months. Only 52 patients (50%) were considered eligible for conventional induction chemotherapy. For this group, response rate was 34.5%, the median survival was 3.5 months, and median survival for responding patients was 13 months. Only intensive chemotherapy seems capable of substantially improving prognosis for older ANLL patients. This approach, however, is feasible only in a minority of patients, due to a high incidence of life-threatening complications.

Multiparametric Evaluation of Retinoic Acid-Induced Terminal Differentiation of Blastoid Cells from Acute Non-Lymphocytic Leukemia Patients in Vitro

Recent findings that retinoic acid (RA) induces terminal granulocytic differentiation of the human promyelocytic leukemia cell line HL-60 in vitro and blast cell maturation in patients suffering from acute non-lymphocytic leukemia (ANLL) prompted an investigation on the ability of this agent to induce terminal maturation in blast cells from ANLL patients in vitro. We tested the ability of RA at 3 x 10(-6) M, 3 x 10(-7) M and 3 x 10(8-) M concentrations to induce differentiation in blastoid cells from 16 patients with ANLL using cytochemical and cytologic parameters, in addition to cytofluorometric methods. Leukemic cells in primary culture from all the patients underwent cytochemical and biochemical changes after treatment with RA. However, the extent of differentiation-positive cell clones (D+ clones) varied from patient to patient. Morphologic maturation was observed in a significant number of bone marrow samples. Leukocyte alkaline phosphatase and NBT reduction ability of cells, which are biochemical markers of granulocytic differentiation, were also significantly increased with a simultaneous decrease in DNA and RNA synthesis (which was estimated using a Phywe ICP-11 impulse flow cytometer).

Interleukin-3, GM-CSF, and G-CSF Receptor Expression on Cell Lines and Primary Leukemia Cells: Receptor Heterogeneity and Relationship to Growth Factor Responsiveness

AbstractRecombinant human granulocyte-macrophage (GM) colony-stimulating factor (GM-CSF), G-CSF, and interleukin-3 (IL-3) labeled with 12*l were used to study the characteristics and distribution of receptors for these factors on in vitro cell lines and on cells from patients with acute nonlymphocytic leukemia (ANL) and acute lymphocytic leukemia (ALL). Receptors for GM-CSF and G-CSF were restricted to a subset of myelomonocytic cell lines whereas IL-3 receptors were also found on pre-B- or early B-cell lines. Receptors for all three CSFs were broadly distributed on ANL cells, with considerable variability in levels of expression. Measurement of the colony-forming ability of ANL cells in response to the CSFs showed that there was no direct correlation between the ability of the cells to respond to a growth factor and the absolute number of receptors expressed for that growth factor. Binding of radiolabeled IL-3 and GM-CSF to ANL cells produced complex biphasic curves. Further analysis showed that both IL-3 and GM-CSF were able to partially compete for specific binding of the heterologous radiolabeled ligand to cells from several ANL patients, suggesting that heterogeneity may exist in human CSF receptors. These results provide new insights into the complex role that CSFs may play in ANL.

Interleukin-3, GM-CSF, and G-CSF receptor expression on cell lines and primary leukemia cells: receptor heterogeneity and relationship to growth factor responsiveness

Recombinant human granulocyte-macrophage (GM) colony-stimulating factor (GM-CSF), G-CSF, and interleukin-3 (IL-3) labeled with 125I were used to study the characteristics and distribution of receptors for these factors on in vitro cell lines and on cells from patients with acute nonlymphocytic leukemia (ANL) and acute lymphocytic leukemia (ALL). Receptors for GM-CSF and G-CSF were restricted to a subset of myelomonocytic cell lines whereas IL-3 receptors were also found on pre- B- or early B-cell lines. Receptors for all three CSFs were broadly distributed on ANL cells, with considerable variability in levels of expression. Measurement of the colony-forming ability of ANL cells in response to the CSFs showed that there was no direct correlation between the ability of the cells to respond to a growth factor and the absolute number of receptors expressed for that growth factor. Binding of radiolabeled IL-3 and GM-CSF to ANL cells produced complex biphasic curves. Further analysis showed that both IL-3 and GM-CSF were able to partially compete for specific binding of the heterologous radiolabeled ligand to cells from several ANL patients, suggesting that heterogeneity may exist in human CSF receptors. These results provide new insights into the complex role that CSFs may play in ANL.

In vitro synergism of 4-hydroperoxycyclophosphamide and cisplatin: relevance for bone marrow purging

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide (4-HC)-purged bone marrow gives long-term remission in almost half of relapsed acute nonlymphocytic leukemia and non-Hodgkin's lymphoma patients, but relapse of disease is the main cause of failure, suggesting ineffective purging in some cases. Cisplatin (CP) has activity against a variety of human tumors and is not commonly used for initial therapy of leukemia and lymphoma. Using established human leukemia cell lines, combinations of 4-HC and CP were investigated as a potential regimen for improving the ex vivo removal of leukemia cells from bone marrow. The cell lines (K-562 and Raji) were incubated for 1 (4-HC) or 4 h (CP), washed, and assayed for inhibition of colony formation in semisolid media. In both cell lines, CP (4h) was more potent than 4-HC (1 h). Combinations of the drugs in various molar ratios were studied after the cells were sequentially incubated with 4-HC and CP. The effects of the drugs were analyzed using the multiple drug-effect analysis of Chou and Talalay. Analysis of data on in vitro inhibition of colony formation suggested that all combinations studied were synergistic in both cell lines, with the greatest synergism being found in the Raji cell line. In addition, for K-562 cells we could detect at least a 4.6 log reduction in cloning with the CP:4-HC combination (1:10 molar ratio). We conclude that CP is a potential candidate in drug combinations for ex vivo bone marrow purging because of its high potency against human leukemia cell lines, its synergistic activity in combination with 4-HC, and its ability to reduce a high tumor burden when combined with 4-HC.

Periodontal disease and oral microbial successions during myelosuppressive cancer chemotherapy*

Factors contributing to the succession of opportunistic pathogens at oral sites, including the periodontium, during myelosuppressive chemotherapy are poorly understood. This study examined the relation of periodontal disease to qualitative and proportional shifts in the oral microflora of 21 acute nonlymphocytic leukemia patients (7 male and 14 female, mean age (range) = 51.0 (25-81 years) observed during standardized myelosuppressive regimens. Supra- and subgingival microbial plaque specimens were individually collected from 2 contralateral oral sites (distobuccal of teeth 1-6 and 3-6) in each participant at hospital admission (day 1) and during point of maximal myelosuppression (day 14). Periodontal disease indices obtained at day 1 included site-specific measures of attachment loss and clinical assessment of disease status. Using a residualized change score analysis, periodontal disease status and attachment loss were positively correlated with increases in the proportional recovery of Staphylococcus sp. from supragingival sites and total yeast from supra- and subgingival sites. When age-related covariation in the microbial shifts was controlled in the analysis, periodontal disease status and attachment loss demonstrated no significant correlation with increases in total yeast at supragingival sites. These findings suggest that host factors such as periodontal disease may contribute to patterns of oral microbial successions during cancer chemotherapy.

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.

A new rare distamycin A-inducible fragile site, fra(11) (p15.1), found in two acute nonlymphocytic leukemia (ANLL) patients with t(7;11)(p15-p13;p15).

Fragile sites were analyzed in normal peripheral lymphocytes from two acute nonlymphocytic leukemia patients with t(7;11)(p15-p13;p15) leukemic cells. To induce expression of fragile sites, cultures were exposed to folate deprivation (M-F10), BrdU, distamycin A, or Hoechst 33258. Fragility at 11p15.1 was induced by distamycin A and Hoechst 33258 but was not seen in M-F10, BrdU, and control cultures. Fra(11)(p15.1) was found neither in healthy Japanese subjects (0 in 845) nor in patients with leukemia or other hematologic disorders without the t(7;11) (0 in 126). From these results, fra(11)(p15.1) can now be classified as a rare distamycin A-inducible fragile site. Furthermore, this fra(11)(p15.1) coincided with one of the breakpoints of the t(7;11)(p15-p13;p15).

IMMUNOTOXINS FOR EX VIVO MARROW PURGING IN AUTOLOGOUS BONE MARROW TRANSPLANTATION FOR ACUTE NONLYMPHOCYTIC LEUKEMIA

Two potent antimyeloid immunotoxins (IT) were generated by conjugating AML-2-23 (anti-CD14) and MCS-2 (anti-CD13) monoclonal antibodies (mAb) to the ribosome-inactivating phytotoxin, ricin. Both IT selectively bound to target cells, inhibited protein synthesis, and prevented the clonogenic growth of fresh marrow blasts from acute nonlymphocytic leukemia patients as well as KG-1 (ANLL) cells. Cryopreservation did not inhibit IT activity. We conclude that AML-2-23-ricin and MCS-2-ricin show potential for effective ex vivo marrow purging in autologous bone marrow transplantation (ABMT) for ANLL. To our knowledge, this study represents the first evidence of the clinical potential of IT in high-risk ANLL.

Cytogenetic studies on acute nonlymphocytic leukemia in relapse.

Karyotypic abnormalities were compared in 42 acute nonlymphocytic leukemia patients at diagnosis and in relapse. Clonal changes were observed in 21 cases. The types of changes were the appearance of clonal abnormalities in relapse in four patients without clonal changes at diagnosis, the detection of new abnormalities superimposed on preexisting ones in 11 cases, and the selection of an abnormal clone in six others. Nonclonal structural abnormalities, mainly involving chromosomes 17 and 12p, were detected in relapse in 17 patients, compared to seven at diagnosis. The appearance of totally new clonal changes at relapse and the role of individual sensitivity to chemotherapy are discussed.

Use of differentiation-inducing agents in the myelodysplastic syndrome and acute non-lymphocytic leukemia.

The use of chemical agents that induce differentiation of malignant cells to normal cells has held great promise as an adjunct to standard chemotherapy. In vitro data has shown that 13-cis-retinoic acid can differentiate certain leukemia cell lines (e.g., HL-60) into stable granulocyte cells. In this study, oral 13-cis-retinoic acid was administered to four patients with the myelodysplastic syndrome (MDS) and to four patients with acute nonlymphocytic leukemia (ANLL). None of the MDS patients showed an hematologic response to the drug, while three of four ANLL patients responded with normalized peripheral blood counts. The side effects of the drug at 80-120 mg/d (dry skin, cheilitis, epistaxis) were self limiting.

Stem cell apheresis in patients with acute nonlymphocytic leukemia

In patients with acute nonlymphocytic leukemia (ANLL) it has previously been reported that the number of blood-derived hemopoietic stem cells (HSC) is very low during the remission phase. 1,2 However, we and others have recently demonstrated that the concentration of granulocyte-macrophage precursors (CFU-GM cells) in the peripheral blood could be increased to 10- to 40-fold above the mean value in normal subjects during the period of marrow reconstitution following aplasia (or hypoplasia) induced by previous chemotherapy. 1,3 To collect high numbers of circulating HSC, leukocyta-phereses could be performed during this short period of “recirculation” of blood-derived progenitors. However, patients with ANLL may be subjected to different chemotherapy regimens that vary according to the age of the patients, the status of the leukemia, and the therapeutic strategy. The amplitude of the recirculation of CFU-GM cells during remission is influenced mostly by the type of chemotherapy administered to the patient. 1 In order to evaluate this phenomenon, we serially assayed peripheral blood CFU-CM cells in 26 ANLL patients. The mean value of the highest recorded peak (HRP) level was 4370 CFU-GM/mL (1133 to 9066) in 13 patients who achieved complete remission after a single course of induction treatment including cytosine arabinoside (Ara-c) (100 mg/m2 × 10 days) and daunorubicin (DNR) (60 mg/m2 × 3 days). As mentioned in a previous report, HPR levels of CFU-GM cells observed in two patients given a late, intensification treatment (with DNR: 300 mg/m2) were similar to those observed in these latter 13 patients. 1 The recirculation of CFU-GM cells was less marked in seven patients who received two consecutive courses of induction chemotherapy or in four other patients receiving less intensive treatment as consolidation. 1,2 These results confirm the results of our previous report and the data reported by To et al., who studied 13 ANLL patients during the very early remission phase following induction chemotherapy. 3 They found that the mean value of the HRP level of CFU-GM cells was 2796/mL (370 to 14520) and concluded that the early remission period after one single course of chemotherapy could be the best time for collection of circulating HSC in ANLL patients.

Bone marrow changes in acute non-lymphocytic leukemia patients treated with low-dose Ara-C--implications of therapeutic mechanism

Twelve acute non-lymphocytic leukemia patients were treated with low-dose Ara-C with good response. Four patients achieved complete remission and eight partial remission. Bone marrow aspiration and biopsy were performed before and after treatment with one cycle of low-dose Ara-C (14 days to 21 days). By analyzing the change of the bone marrow constituents, we obtained the following results: (A) The mature myeloid cells increased after treatment in four patients. The proportion of mature cells increased from 10.6% before treatment to 46.8% after one cycle of low-dose Ara-C. The cellularity of bone marrow decreased only 10% in these four patients. (B) No prominent mature cells were found after treatment in the other eight patients. The mature cells were replaced by lymphoytes and plasma cells. The cellularity of bone marrow decreased 32% in these patients. The results suggest two kinds of mechanism in the therapeutic effects of low-dose Ara-C. One is the induction of differentiation found in group (A) patients. More mature cells appeared after low-dose Ara-C. Another is the direct cytotoxic effect found in group (B) patients. No prominent mature cells appeared after treatment while the cellularity of bone marrow decreased markedly. The predictive application of low-dose Ara-C for therapy in acute non-lymphocytic leukemia has not yet been established.

Chromosome studies in patients with acute nonlymphocytic or acute lymphocytic leukemia submitted to bone marrow transplantation--results of a European cooperative study.

The chromosomal data of 58 acute nonlymphocytic leukemia (ANLL) patients and of 32 acute lymphocytic leukemia (ALL) patients submitted to bone marrow transplantation and collected from nine institutions are reported. Chromosomal studies were available at diagnosis in 19 cases with ANLL: seven had a partially or completely abnormal pattern. Forty-one patients had a chromosome study before bone marrow transplantation and all had a normal pattern. Thirteen patients with ALL were studied at diagnosis: five had a partially or completely abnormal karyotype. Of 20 cases analyzed before bone marrow transplantation, only one has maintained the abnormal pattern of diagnosis in part of the cells. Karyotypes were available in nine ANLL patients relapsed after bone marrow transplantations. Two showed the same clonal abnormalities seen at diagnosis; in three other cases the leukemic clone of relapse carried an additional chromosome abnormality with respect to the pattern at diagnosis and four more cases presented at relapse complex abnormalities; two of them had a cytogenetically normal pattern at diagnosis. In four of ten relapsed ALL cases chromosomes analyses were available. A relapse in donor cells and a hyperdiploid pattern were observed in two cases, respectively, while a normal, recipient pattern was documented in the other two cases. Serial chromosome studies performed in acute leukemia patients after bone marrow transplantation may allow the detection of different chromosomal patterns of relapse. In those cases who relapsed with a cell clone cytogenetically different from the pattern at diagnosis, a direct role played by the conditioning treatment in the pathogenesis of the relapsing disease may be hypothesized.

Prognostic meaning of chromosome aberrations in acute lymphocytic leukemia and acute nonlymphocytic leukemia patients of the BFM Study Group.

Consistent numerical and structural aberrations of chromosomes are well known as an important additional diagnostic factor in all kinds of leukemia. The prognostic meaning of these abnormalities, however, is still being discussed. To show the influence of chromosomal aberrations on the course of the disease, all cytogenetically investigated patients have to be treated in the same way, for therapy is one of the most important factors of prognosis. The following cytogenetical data were obtained from the analysis of bone marrow blast cells of children treated according to protocols ALL-83 and AML-83 of the BFM study group.KeywordsAcute Lymphocytic LeukemiaMarker ChromosomeBone Marrow SampleStructural AberrationCytogenetic FindingThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Oral succession of gram-negative bacilli in myelosuppressed cancer patients.

Aerobic and facultative gram-negative bacilli (GNB) have been reported to increase on various body surfaces in the seriously ill and debilitated patient. This study examined quantitative aspects of GNB succession at five oral sites in cancer patients before and during myelosuppressive chemotherapy. GNB concentrations increased sharply during chemotherapy at 25 to 50% of the oral sites in both acute nonlymphocytic leukemia and small-cell lung carcinoma patients. Most sites did not exhibit shifts of GNB to levels higher than 0.1% of the cultivable flora. When shifts occurred, all sites sampled in the mouth were usually affected and GNB usually represented more than 10% of the cultivable flora. Low levels of indigenous microflora were observed in most sites exhibiting GNB shifts. None of the subjects harboring high levels of GNB developed the symptoms of acute infection which are commonly observed in myelosuppressed patients. Although Pseudomonas aeruginosa and Klebsiella pneumoniae were recovered from some sites, most GNB were nonpathogenic species of Pseudomonas; Pseudomonas pickettii was the most frequently recovered.

Effects of Verapamil on In Vitro Intracellular Accumulation and Retention of Daunorubicin in Blast Cells From Patients With Acute Nonlymphocytic Leukemia

The effects of verapamil on the intracellular pharmacokinetics of daunorubicin (DNR) in blast cells from the bone marrows of patients with acute nonlymphocytic leukemia (ANLL) were studied to determine whether verapamil was capable of enhancing intracellular accumulation and retention of DNR in ANLL, as has been observed in murine P388 cells resistant to DNR. Seventeen marrows from ANLL patients were studied, 13 of which were from patients who were considered to be clinically refractory to DNR. We took care to include such patients in this study since, in the P388 model, verapamil enhancement of DNR uptake is observed only in cells resistant to DNR. Intracellular accumulation of DNR was studied by exposing blast cells to DNR (1 microgram/mL) +/- verapamil (6.6 mumol/L) for up to 4 hours. Following a 2-hour exposure of cells to DNR +/- verapamil, intracellular retention of DNR was studied by incubating the cells in DNR-free medium for 3 hours. Intracellular DNR/10(6) cells was quantified by fluorometry. In 12 of 15 patient marrows, verapamil failed to enhance intracellular accumulation of DNR. Three patient marrows had a very small increment in DNR uptake in response to verapamil (approximately 14% greater than DNR alone) that was significant (P less than .05) by paired t test. Intracellular retention of DNR (t 1/2) and the area under the intracellular DNR v time curve (AUC) were studied in 17 patients marrow specimens. No significant alterations in these parameters were observed in response to verapamil. These data indicate either that verapamil did not substantially enhance DNR uptake or retention in blast cells obtained from ANLL patients who are clinically resistant to DNR, or that the frequency of DNR-resistant cells (ie, verapamil-responsive cells) among the blast cells obtained from these patients was too low to influence the population mean of intracellular DNR as measured in these studies.

Effects of verapamil on in vitro intracellular accumulation and retention of daunorubicin in blast cells from patients with acute nonlymphocytic leukemia

The effects of verapamil on the intracellular pharmacokinetics of daunorubicin (DNR) in blast cells from the bone marrows of patients with acute nonlymphocytic leukemia (ANLL) were studied to determine whether verapamil was capable of enhancing intracellular accumulation and retention of DNR in ANLL, as has been observed in murine P388 cells resistant to DNR. Seventeen marrows from ANLL patients were studied, 13 of which were from patients who were considered to be clinically refractory to DNR. We took care to include such patients in this study since, in the P388 model, verapamil enhancement of DNR uptake is observed only in cells resistant to DNR. Intracellular accumulation of DNR was studied by exposing blast cells to DNR (1 microgram/mL) +/- verapamil (6.6 mumol/L) for up to 4 hours. Following a 2-hour exposure of cells to DNR +/- verapamil, intracellular retention of DNR was studied by incubating the cells in DNR-free medium for 3 hours. Intracellular DNR/10(6) cells was quantified by fluorometry. In 12 of 15 patient marrows, verapamil failed to enhance intracellular accumulation of DNR. Three patient marrows had a very small increment in DNR uptake in response to verapamil (approximately 14% greater than DNR alone) that was significant (P less than .05) by paired t test. Intracellular retention of DNR (t 1/2) and the area under the intracellular DNR v time curve (AUC) were studied in 17 patients marrow specimens. No significant alterations in these parameters were observed in response to verapamil. These data indicate either that verapamil did not substantially enhance DNR uptake or retention in blast cells obtained from ANLL patients who are clinically resistant to DNR, or that the frequency of DNR-resistant cells (ie, verapamil-responsive cells) among the blast cells obtained from these patients was too low to influence the population mean of intracellular DNR as measured in these studies.

Chromosomes in acute nonlymphocytic leukemia.

The karyotype of leukemic cells was studied in 88 acute nonlymphocytic leukemia (ANLL) patients. Chromosome abnormalities were discovered in 78.4% of all patients and in 72.5% of the 69 patients studied before treatment. Characteristic abnormalities: translocations 8;21, 15;17, 9;22 or 6;9, rearrangements of 11q, gain of chromosomes 8 or 21, and loss or deletion of chromosomes 5 or 7 were detected in 56 of 69 patients with abnormal karyotypes. Translocation 8;21 was revealed in 27 patients; 20 of them had M2 FAB-form, four had M1, and three had M4. In patients with t(8;21) the incidence of complete remission was higher and the duration of first remission and survival longer than in patients with other abnormalities or with a normal karyotype.