Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. The Japan Leukemia Study Group.

PURPOSE: We analyzed complete remission (CR), disease-free survival (DFS), and event-free survival (EFS) rates in two groups of patients treated with either N4-behenoyl-1-beta-D-arabinosylcytosine (BHAC) or cytarabine, and analyzed DFS with or without ubenimex, a biologic response modifier. PATIENTS AND METHODS: Newly diagnosed patients with acute myeloid leukemia (AML) were randomized to receive either BHAC or cytarabine as remission-induction combination chemotherapy and two courses of consolidation therapy. After maintenance/intensification therapy, patients in CR were randomized to receive either ubenimex and no drug. RESULTS: Of 341 patients registered, 326 were assessable. The age of assessable patients ranged from 15 to 82 years (median, 48). The overall CR rate was 77%: 72% in the BHAC group and 81% in the cytarabine group, and there was a significant difference between the two groups (P = .035, chi 2 test). The predicted 55-month EFS rate of all patients was 30%: 23% in the BHAC group and 35% in the cytarabine group, with a significant difference between groups (P = .0253). The predicted 55-month DFS rate of all CR patients was 38% and that of CR patients less than 50 years of age was 47%. There was no significant difference in DFS between the ubenimex group and the group that did not receive ubenimex. CONCLUSION: Analyses of our clinical trial showed that the use of BHAC in remission-induction therapy and in consolidation therapy resulted in poorer CR and EFS rates in adult AML patients compared with the use of cytarabine at the doses and schedules tested. Immunotherapy with ubenimex after the end of all chemotherapy did not improve DFS.

All-trans retinoic acid therapy in relapsed/refractory or newly diagnosed acute promyelocytic leukemia (APL) in Japan.

We have conducted four prospective multicenter studies for acute promyelocytic leukemia (APL) using oral 45 mg/m2 all-trans retinoic acid (ATRA) daily. The first three studies were for relapsed/refractory APL, and the fourth study for newly diagnosed APL. In the first study with ATRA alone, 18 (82%) of 22 evaluable patients achieved complete remission (CR). Initial peripheral leukemia cell counts were significantly less in the CR cases (p < 0.01); < 100/microliters in 17 of 18 CR cases, and > or = 200/microliters in all failure cases. In the second study, if initial leukemia cell counts were more than 200/microliters, chemotherapy with daunorubicin and behenoyl cytarabine was first given, and then ATRA was started. Of 42 evaluable patients, 36 (86%) achieved CR. In the third study, if initial leukemia cell counts were more than 200/microliters, chemotherapy was concomitantly given with ATRA, and if during the ATRA therapy leukemia cell counts became more than 1000/microliters, chemotherapy was added. Of 46 evaluable patients, 36 (78%) achieved CR. Patients achieving CR received standard consolidation and maintenance chemotherapy, and the 29-month predicted disease-free survival (DFS) rate is 72% for 41 cases achieving their first CR with ATRA, and 20% for 49 cases achieving their second CR with ATRA. In the fourth study for newly diagnosed APL, if leukocyte counts were more than 3000/microliters, chemotherapy was concomitantly given with ATRA, and if during the ATRA therapy leukemia cell counts became more than 1000/microliters, chemotherapy was added. Of 109 evaluable patients, 97 (89%) achieved CR, and the 19-month predicted event-free survival rate for all patients is 78%, and the DFS rate is 88% for 97 cases achieving CR. ATRA produces a high CR rate in both relapsed/refractory and newly diagnosed APL, and should be incorporated in the first-line therapy of this disease.

Bi-phenotypic t(9;22)-positive leukemia cell lines from a patient with acute leukemia: NALM-20, established at the onset; and NALM-21, NALM-22 and NALM-23, established after relapse.

Four leukemia cell lines; NALM-20, established at the onset of leukemia and NALM-21, -22 and -23 established at the relapse of the disease were found to be t(9;22)-positive leukemia lines having the biphenotypic feature of B cell and myeloid cell characteristics. In addition, a polyclonal Epstein-Barr virus-transformed normal B cell line, B250, was established from the peripheral blood at the onset of the disease.

Allogeneic peripheral blood stem cell transplantation for the treatment of refractory follicular lymphoma.

A 38-year-old male with follicular lymphoma at clinical stage IV failed to achieve complete remission (CR), and developed leukemic change. After the patient was further treated with intensive chemotherapy for acute lymphoblastic leukemia, lymphoma cells in the peripheral blood and bone marrow disappeared, but the bulky mass persisted. Then, the patient received allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from his human lymphocyte antigen (HL A)-identical brother following high-dose cyclophosphamide and 12 Gy total body irradiation, and the patient achieved CR with the disappearance of Bcl-2 rearrangement. The patient is now alive in continuous CR for more than 19 months after allo-PBSCT.

Superoxide anion (O2-) production by neutrophils in refractory anemia with excess of blasts.

The O2- production by neutrophils was examined in 4 cases of refractory anemia with excess of blasts (RAEB) in order to evaluate the possible causes of enhanced susceptibility to infection and to gain some informations on the differentiation of neutrophils in this hematological disorder. In three of the four RAEB cases there was little O2- production by neutrophils, in addition to there being morphological anomalies of the neutrophils such as a Pelger-Hüet-like anomaly, granular deficiency and binucleated cells. These results suggest that the impairment of O2- production by neutrophils in RAEB is one of the possible causes of susceptibility to infection and also suggest that the differentiation of neutrophils in this hematological disorder is faulty. The estimation of O2- production by neutrophils may be a useful diagnostic method for preleukemia.

Monocyte chemiluminescence and macrophage precursors in the aged.

Age-related alterations in the host defense system have been vigorously investigated because of increased susceptibility to infection and neoplasms in the aged. Although monocyte-macrophages form a major part of the cellular defense against microorganisms, the majority of investigations has been limited to neutrophils and lymphocytes. The present study, designed to determine the influence of age on mononuclear phagocytes, revealed no significant decrease in the absolute number of blood monocytes, but did reveal a tendency for the chemiluminescence of blood monocytes to decrease (p less than 0.10) and a significant decrease in the numbers of macrophage precursors (p less than 0.05) in the aged (over 70 year old), in comparison with controls (under 40 years old). On the basis of these findings, functional alterations of monocyte-macrophages seem to participate in the increased susceptibility to infection in the aged.

Aclarubicin in the treatment of elderly patients with acute nonlymphocytic leukemia.

Thirteen previously untreated patients aged 70 and above with acute nonlymphocytic leukemia were treated with aclarubicin (ACR) alone. Among 10 cases (3, acute myelocytic leukemia; 4, acute myelomonocytic leukemia; 2, acute monocytic leukemia; and one, acute erythroleukemia) in which an evaluation was possible, 5 cases (3, acute myelomonocytic leukemia; and 2, acute monocytic leukemia) obtained complete remission (CR). The CR rate was 83% in 6 patients with acute myelomonocytic leukemia or acute monocytic leukemia. The median CR duration and survival was 7.5 and 10 + months, respectively. Although side effects of the drug on digestive system such as nausea, vomiting and anorexia were observed in all patients, they were controllable by conventional treatments. The results suggest that ACR is effective for the clinical management of elderly patients with acute nonlymphocytic leukemia, especially those with acute myelomonocytic leukemia or acute monocytic leukemia.

Superoxide anion production by neutrophils in myelodysplastic syndromes (preleukemia).

Superoxide anion (O2-) production by neutrophils from 14 untreated patients with acute nonlymphocytic leukemia (ANLL) was significantly less than that of healthy controls (4.93 +/- 1.99 vx 6.20 +/- 1.53 nmol/min/10(6) neutrophils, p less than 0.05). In 10 patients with myelodysplastic syndrome (MDS), however, it was not significantly different from the control level although 6 of the 10 patients had low levels, when individual patients were compared with the lower limit of the control range. An inverse correlation between the O2- production of neutrophils and the percentage of leukemic cells in the marrow existed in ANLL (r = -0.55, p less than 0.01), but not in MDS. Three of 4 MDS patients who died of pneumonia prior to leukemic conversion showed a low level of O2- production. The impaired O2- production by neutrophils from some MDS patients, probably due to the faulty differentiation from leukemic clones, may be one of the causes of enhanced susceptibility to infection.

[Clinical effects of ceftizoxime and latamoxef on infections in acute leukemia].

Ceftizoxime (CZX) and latamoxef (LMOX), new synthetic cephems, are stable against various types of beta-lactamase and highly active against Gram-negative rods, such as H. influenzae, Serratia, Enterobacter and indole (+) Proteus. In this study, we evaluated clinical effects of CZX and LMOX in the clinical management of infections in acute leukemia. Sixteen episodes of infections were treated with CZX or LMOX. Four causative organisms, P. aeruginosa, S. faecalis, K. pneumoniae and A. faecalis, were identified in 2 episodes of infections. Clinical effects were recognized at 75% in 8 episodes treated with CZX and at 71% in 7 episodes treated with LMOX, respectively. The transient evaluation of GOT, GPT and Al-P, recognized in several cases. In conclusion, the clinical effects of CZX and LMOX are promised in clinical management of infections in acute leukemia.

[Successful treatment of refractory anemia with excess of blasts in transformation with cytarabine ocfosfate].

A 58-year-old female was diagnosed as myelodysplastic syndrome (MDS) [refractory anemia with excess of blasts (RAEB)]. Although melphalan was administered, no response was obtained in the peripheral blood. Sixteen months after diagnosis, she developed RAEB in transformation (RAEB-t), and then overt leukemia. White blood cell (WBC) count elevated to 28,600/microliters with 34% of blasts. She was administered cytarabine ocfosfate (200 mg-->300 mg/day) orally, resulting in decrease of WBC count and blasts in peripheral blood. The drug has been given for 11 months, and her hematological data have now remained stable in RAEB. Cytarabine ocfosfate might be a useful drug for the treatment of high risk MDS such as RAEB and RAEB-t.

[Low-dose 4N-behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC) in the treatment of atypical leukemia].

Four cases of hypoplastic leukemia, one of acute myelocytic leukemia (M2) and one of RAEB-t were treated with a low-dose 4N-behenoyl-1-beta-D-arabinofuranosylcytosine (LD-BHAC) regimen, in which 50 mg BHAC was administered daily intravenously by one-hour drip infusion for 14 days. Among the 6 cases, three (2 hypoplastic leukemia and one M2) obtained complete remission and one (hypoplastic leukemia), partial remission. Response rates were 66.6% of all cases, and 75% of cases of hypoplastic leukemia. During treatment, cytopenia was observed in all cases and a decrease in bone marrow nucleated cell counts was recognized in the aged M2 patient with remission. Although side effects of the drug on the digestive system such as anorexia and nausea were observed in some cases, they were all controllable by conventional treatments. The serum concentration of ara-C was measured in 4 cases. The peak level of serum ara-C concentration, 3.62-18.9 ng/ml (mean: 11.74 ng/ml), was observed at the time of cessation of infusion of BHAC, and an ara-C level of 2.75-4.89 ng/ml (mean: 3.54 ng/ml) was still present in the blood 6 hours after the cessation of infusion. It was concluded that LD-BHAC was useful in the clinical management of atypical leukemia and acute myelocytic leukemia in the aged.

[Therapeutic effects of a combination of intermediate-dose cytosine arabinoside, adriamycin and vincristine in relapsed acute leukemia].

Eleven cases of acute leukemia, 8 relapsed and 3 refractory to a conventional induction chemotherapy, were treated with a combination of intermediate-dose cytosine arabinoside (ara-C), adriamycin (ADM) and vincristine (VCR). They consisted of 9 ANLL and 2 ALL. The therapeutic regimen consisted of 1-hour infusion of ara-C of a dose of 500 mg/m2 every 12 hours for 6 days from days 3 to 8, ADM, 40 mg/m2, on day 1 and VCR, 1.4 mg/m2, on day 2. Among 11 cases in which an evaluation was possible, 7 obtained complete remission (CR). The CR rate was 77.8% in the 9 cases of ANLL. The toxicity of this regimen included the following: conjunctivitis in 4 of 11 cases (36%), nausea and vomiting in 9 of 11 cases (91%) and hair loss in all cases, although no toxicities of the central nervous system of liver were observed. The mean level of serum concentration of ara-C was above 10 microM at 15, 30 and 60 minutes after the initiation of infusion. The therapeutic effect of this regimen consisting of intermediate-dose ara-C is expected to be useful not only in induction of refractory and relapsed acute leukemia, but also in the postremission therapy of CR cases.

[Chemotherapy of chronic myelogenous leukemia--VP(M) regimen initiated during its chronic phase, and evaluation of MCNU in the phase of blastic crisis].

Seventy-four patients in the chronic phase of Ph1-positive chronic myelogenous leukemia (CML) have been treated with busulfan or other alkylating agents in a conventional way. During its chronic phase, 24 of these 74 cases had received additional intermittent therapy every 4 to 6 months, consisting of vincristine 2 mg or vindesine 3 mg per week, prednisolone 20-30 mg per day and partly 6 mercaptopurine 50 to 100 mg, combined with allopurinol 200 to 300 mg per day for 2 to 3 weeks. The 50% survival of these patients using the Kaplan-Meier's method was 73.7 months and 5-year survival was 69.6%, against 40.5 months and 14.4%, respectively, in the remaining patients. Nine patients in the blastic or accelerated phase of Ph1-positive CML have been treated with new regimens including MCNU. All cases had been refractory for usual types of induction chemotherapy. The new regimen consisted of MCNU 50-100 mg, combined with vindesine or 6-MP plus allopurinol or prednisolone. Five out of 9 cases attained complete remission and 1 partial remission. The major adverse effect of this regimen was slight liver damage. MCNU could be regarded as an useful agent in the blastic phase as well as in the chronic phase of CML.

[Clinical effects of K-18 (IgG-melphalan) in hypoplastic leukemia: a case report].

Five cases of hypoplastic acute myelocytic leukemia were treated with an IgG-melphalan conjugate, K-18. Eight tablets of K-18, containing 30 mg per tablet, were given daily. One patient, a 68-year-old female, obtained complete remission with a duration of 1.5 + months. Among the four remaining patients without remission, one showed a decrease in leukemic cells in the peripheral blood. No side effects of K-18 were observed except in one patient, showing a slight increase in serum GOT and GPT levels. Further studies with a large group will be necessary to clarify the effect of this drug on hypoplastic leukemia.

[Effects of interferon and its inducers on neutrophil chemiluminescence].

In order to evaluate effects of interferon (IFN) and its inducers on neutrophil functions, neutrophil chemiluminescence (ChL) was assayed in 12 patients treated with IFN (human lymphoblastoid interferon, 3.0 X 10(6) units/day i.m. daily) or Ge-132 (2,250 mg/day p.o. daily). The peak levels of neutrophil ChL, assayed one week after the initiation of treatment, were increased in comparison to those before treatment, but one month after treatment they were decreased to pretreatment levels in spite of the daily administration of the agent. On the basis of these results, it was concluded that IFN and Ge-132 enhanced the host defence mechanism including the activation of neutrophils, which appeared at the early phase of the host reaction.

[Therapeutic results of 43 cases of adult acute lymphocytic leukemia].

Between July, 1976 and June, 1984, 43 adults with acute lymphocytic leukemia were treated with a V(V') P [vincristine (vindesine), prednisolone] followed by DV(V')MP [daunomycin, vincristine (vindesine), 6-mercaptopurine, prednisolone] and V(V')AP [vincristine (vindesine), 1-asparaginase, prednisolone] regimen. They were all previously untreated and aged 15 and over. Complete remission (CR) was attained in 41.9% of cases by V(V')P alone, the CR rate being increased up to 62.8% by the sequential administration of DV(V')MP, and to 74.4% by the further administration of V(V')AP. The median duration of CR was 5.6 months; it was 10.9 months for patients with the maintenance therapy and 1.3 months for patients without it. For patients who achieved CR, the median survival time (MST) was 21.3 months compared to 2.7 months for those who failed to achieve CR. As for the maintenance therapy, MST was 22.3 months for patients who received it, and 9.5 months for patients who did not. Factors associated with significantly lower rate of CR were: lymphadenopathy and hepatomegaly and/or splenomegaly. The CR rate was somewhat lower for patients aged over 20 and with hyperleukocytosis (above 40,000/cmm). Shorter remissions tended to be associated with ages over 20 and with hepatomegaly and/or splenomegaly. Patients who obtained CR by the sequential administration of the V(V')AP regimen showed somewhat shorter CR duration compared with to those who obtained CR by V(V')P alone and by the sequential administration of DV(V')MP. Survival was significantly shorter for patients who failed to achieve CR, with B-ALL and with hyperleukocytosis. Shorter survival was also observed among patients with ages above 60 compared to those with ages below 20.

[Clinical effects of human lymphoblastoid interferon in patients with hematologic neoplasms].

Sixteen patients with hematologic neoplasms were treated with Human Lymphoblastoid Interferon (HL-BI) derived from Namalwa cell line. They were 6 multiple myeloma, 8 acute leukemia and 2 malignant lymphoma patients. All patients were previously treated with anticancer agents except one case with multiple myeloma. HLBI, 3.0 X 10(6) IU/day, was daily administered by intramuscular injection at least for 4 weeks. Three of 6 multiple myeloma responded to HLBI with a decrease of more than 25% in serum myeloma protein level. A case with pleural effusion due to massive infiltration of myeloma cells treated with intrathoratic administration of HLBI, in whom complete disappearance of pleural effusion was recognized. On the other hand, no patients with acute leukemia and malignant lymphoma responded except one case with acute lymphocytic leukemia, in which bone marrow lymphoblasts decreased transiently. Fever episodes, 13 of 16 cases, were more frequently seen but were manageable. Transient leukocytopenia and thrombocytopenia were also observed in 4 and 7 of 8 cases, respectively. No anaphylactoid reaction was seen. Thus, HLBI was expected useful in the clinical management of multiple myeloma.

[Clinical management of acute lymphocytic leukemia in adults. 1. Treatment of acute lymphocytic leukemia with VP (vincristine, prednisolone)--DVMP (daunorubicin, vincristine 6-mercaptopurine, prednisolone) regimen].

Eighteen patients with acute lymphocytic leukemia (ALL) were treated with VP (vincristine, prednisolone) followed by DVMP (daunorubicin + vincristine + 6-mercaptopurine + prednisolone) regimen (VP-DVMP regimen). Patients were all previously untreated. Complete remission (CR) was obtained in 11 of 18 patients (61.1%,) by VP alone and 4 patients, by VP-DVMP. The time required for CR varied from 14 to 60 days with a median of 28 days. The duration of CR and survivals in responders were from 1.2 to 42.3 + months with a median of 24.0 months. The hematological toxicities in VP-DVMP regimen were lower than those in NVP (neocarzinostatin + vincristine + prednisolone) and NVMP (neocarzinostatin + vincristine + 6-mercaptopurine + prednisolone) regimens.

[Comparative evaluation of a combination of daunorubicin and cytosine arabinoside and that of aclarubicin and cytosine arabinoside in remission induction in acute non-lymphocytic leukemia].

A comparative trial of a combination of daunorubicin and cytosine arabinoside (Regimen A) and a combination of aclarubicin and cytosine arabinoside (Regimen B) was performed. Sixteen patients with acute non-lymphocytic leukemia, previously untreated, were entered into this study. Five of 8 patients (62.5%) obtained a complete remission (CR) in Regimen A and B, respectively. The days required for achieving a CR varied from 37 to 46 days in Regimen A and from 22 to 56 days in Regimen B. The total doses of daunorubicin and cytosine arabinoside were from 100 to 240 mg and from 640 to 1,120 mg in Regimen A, respectively. Those of aclarubicin were from 180 to 300 mg and from 660 to 1,000 mg in cytosine arabinoside in Regimen B. In a comparative study on hematological changes, toxic effects on peripheral white blood cell, platelet and nucleated cell counts in bone marrow tended to appear later in Regimen B compared to those in Regimen A. Side effects on digestive system such as nausea and vomiting and vascular pain were more frequently recognized in patients treated with Regimen B, although they were managed by symptomatic treatment. The results indicated the usefullness of aclarubicin in combination chemotherapy for the treatment of acute non-lymphocytic leukemia.