Phase I and II trial of 4'-(9-acridinylamino)methanesulfon-m-anisidide in patients with acute leukemia.

Patients with acute leukemia in relapse were given 5'-(9-acridinylamino)methanesulfon-m-anisidide at a dosage of 75 to 200 mg/sq m as a daily bolus infusion of 5 consecutive days. None of the 11 patients treated at 75 to 150 mg/sq m daily for 5 days achieved remission. Ten patients with acute lymphoblastic leukemia and 21 with acute nonlymphoblastic leukemia were given treatment at 200 mg/sq m daily for 5 days. Six of these patients achieved complete remission, three with acute lymphoblastic leukemia and three with acute nonlymphoblastic leukemia. Neutropenia and thrombocytopenia were seen in all patients and in the responders lasted a median of 39 and 41 days, respectively. Stomatitis was the most significant nonhematopoietic toxicity noted. occurring in 80% of the patients. Hyperbilirubinemia was seen in 25% of the patients treated. Since 4'-(9-acridinylamino)methanesulfon-m-anisidide will induce remission in heavily pretreated patients with acute leukemia, consideration should be given to exploring its use in combination with other active drugs.

Phase I and II clinical and pharmacological study of 4-demethoxydaunorubicin (idarubicin) in adult patients with acute leukemia.

Fifty-two adults treated previously with either acute leukemia (43 patients) or blastic-phase chronic myelogenous leukemia (nine patients) received 4-demethoxydaunorubicin (20 to 45 mg/sq m) i.v. over 2 to 3 days. Three of the ten patients with acute lymphocytic leukemia achieved a complete remission (CR) lasting 5 to 7 weeks. Five of the 28 patients with acute nonlymphocytic leukemia achieved a CR lasting 5 to 80 weeks. All remissions were induced with one course of treatment with a median time to CR of 28 days (range, 22 to 40 days). None of the patients with blastic chronic myelogenous leukemia or secondary leukemia achieved a CR. The drug was well tolerated; mucositis (36%), nausea and vomiting (35%), and hepatic dysfunction (26%) were the most common side effects. Pharmacokinetic observations on five patients demonstrated multiphasic clearance of 4-demethoxydaunorubicin and extensive formation and prolonged retention of 4-demethoxy-13-hydroxydaunorubicin; that metabolite accumulated in plasma on repeated daily dosing. 4-Demethoxydaunorubicin has sufficient antileukemic activity in both acute lymphocytic leukemia and acute nonlymphocytic leukemia to warrant a prospective comparison, in combination regimens, against the conventional anthracyclines, daunorubicin and/or doxorubicin.

4-demethoxydaunorubicin (idarubicin) in combination with 1-beta-D-arabinofuranosylcytosine in the treatment of relapsed or refractory acute leukemia.

We conducted a Phase I-II trial of 4-demethoxydaunorubicin (idarubicin, IDR) in combination with 1-beta-D-arabinofuranosylcytosine (ara-C) in 51 patients with relapsed or refractory acute nonlymphocytic leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia in blast crisis. Only 1 of 12 patients treated at the first dose level (idarubicin, 10 mg/m2/day for 3 days and ara-C, 25 mg/m2 i.v. bolus followed by 200 mg/m2 continuous infusion daily for 5 days) achieved aplasia and complete remission. The dose of idarubicin was subsequently increased to 10 mg/m2/day for 4 days with the ara-C dose held constant. Complete remission incidence for this dose schedule was: 7 of 31 patients with acute nonlymphocytic leukemia, 0 of 5 patients with acute lymphocytic leukemia, 0 of 1 patient with chronic myelogenous leukemia in blast crisis, and 1 of 2 patients with biphenotypic leukemia. Nonhematological toxicity included nausea, vomiting, mucositis, and abnormal liver function tests. Detailed pharmacological studies were performed to determine whether ara-C altered IDR metabolism or that of its main metabolite, 13-hydroxyidarubicinol or IDR clearance. A high degree of variability among patients was apparent and no consistent effect could be demonstrated. In summary, 9 of 37 patients (24%) with relapsed or refractory ANLL, including 1 patient with biphenotypic leukemia, achieved remission. We conclude that idarubicin in combination with ara-C is an active combination in patients with relapsed or refractory leukemia.

Homoharringtonine: an effective new drug for remission induction in refractory nonlymphoblastic leukemia.

Homoharringtonine (HHT) is a new plant alkaloid originally isolated in the People's Republic of China. Preliminary studies have suggested antitumor activity in several neoplastic diseases. We treated 49 patients with relapsed or resistant acute leukemia with escalating doses of homoharringtonine administered by continuous infusion. Three dose levels were examined: 5 mg/m2 for seven days, 7 mg/m2 for seven days, and 5 mg/m2 for nine days. Of 28 patients with acute nonlymphoblastic leukemia who received cumulative doses of 45 to 49 mg/m2, seven patients (25%) achieved complete remission. Four of these remissions occurred in a subset of ten patients previously resistant to two or more induction attempts with conventional chemotherapy. There were no remissions in three patients with secondary leukemia or in seven patients with acute lymphoblastic leukemia. Reversible hypotension, fluid retention, diarrhea, and tumor lysis syndrome were the major toxic effects of this treatment. Our results indicate that homoharringtonine is an effective new drug for the treatment of acute nonlymphoblastic leukemia and that this drug does not share cross-resistance with conventional antileukemic agents. The recommended dose is 5 mg/m2/d administered by continuous infusion for nine days.

A phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide.

Ten patients with myeloid leukemias were treated in a phase I trial with escalating doses of mouse monoclonal antibody (mAb) M195, reactive with CD33, a glycoprotein found on myeloid leukemia blasts and early hematopoietic progenitor cells but not on normal stem cells. M195 was trace-labeled with iodine-131 (131I) to allow detailed pharmacokinetic and dosimetric studies by serial sampling of blood and bone marrow and whole-body gamma-camera imaging. Total doses up to 76 mg were administered safely without immediate adverse effects. Absorption of M195 onto targets in vivo was demonstrated by biopsy, pharmacology, flow cytometry, and imaging; saturation of available sites occurred at doses greater than or equal to 5 mg/m2. The entire bone marrow was specifically and clearly imaged beginning within hours after injection; optimal imaging occurred at the lowest dose. Bone marrow biopsies demonstrated significant dose-related uptake of M195 as early as 1 hour after infusion in all patients, with the majority of the dose found in the marrow. Tumor regressions were not observed. An estimated 0.33 to 1.0 rad/mCi 131I was delivered to the whole body, 1.1 to 6.1 rad/mCi was delivered to the plasma, and up to 34 rad/mCi was delivered to the red marrow compartment. 131I-M195 was rapidly modulated, with a majority of the bound immunoglobulin G (IgG) being internalized into target cells in vivo. These data indicate that whole bone marrow ablative doses of 131I-M195 can be expected. The rapid, specific, and quantitative delivery to the bone marrow and the efficient internalization of M195 into target cells in vivo also suggest that the delivery of other isotopes such as auger or alpha emitters, toxins, or other biologically important molecules into either leukemia cells or normal hematopoietic progenitor cells may be feasible.

Treatment of acute lymphoblastic leukemia in adults: results of the L-10 and L-10M protocols.

Two successive protocols (L-10 and L-10M) employing multidrug induction therapy with vincristine, prednisone, and doxorubicin (Adriamycin) plus an intensive consolidation phase and maintenance program have led to a significant improvement in the prognosis of adult acute lymphoblastic leukemia (ALL). The complete remission (CR) rates for the 34 patients entered on the L-10 protocol and the 38 patients entered on the L-10M protocol were 85% and 84%, respectively. The median duration of remission has not yet been reached for either the L-10 (median follow-up, 5.5 years; range, 3.5-7.5 years) or the L-10M protocol (median follow-up, 2.5 years; range, 1-3.5 years). The median survival time has not yet been reached for the L-10M protocol. Central nervous system prophylaxis with intrathecal methotrexate alone was effective in preventing central nervous system relapse. An analysis of possible prognostic factors indicated that patients less than 25 years of age had a higher CR rate than older patients (p = 0.02). Patients with an initial leukocyte count below 15,000/microL experienced longer remissions than patients with a leukocyte count above 15,000/microL (p = 0.008), and patients who achieved CR within the first month of therapy were in remission longer than those requiring a longer time to achieve CR (p = 0.04). Patients with T cell ALL did not have a poorer prognosis than other patients treated on these protocols. The L-10 and L-10M protocols were well tolerated with minimal morbidity.

Leukemia following treatment of germ cell tumors in men.

We investigated the incidence of leukemia occurring subsequent to the treatment of germ cell tumors in men at our institution over a 30-year interval and found four patients with acute nonlymphocytic leukemia (ANLL) and one patient with chronic myelomonocytic leukemia. The relative risk (observed/expected cases) estimates for the development of leukemia ranged from 13.7 (P = .0005) in the total population to 50.1 (P = .0001) in the group treated with cytotoxic agents alone. All three patients with ANLL treated with contemporary antileukemic therapy had complete responses, with survivals of 7, 29, and 133 + months. In a review of the literature, 14 additional cases of germ cell tumors were found in which the men subsequently developed leukemia. It is concluded that leukemia following germ cell tumors is increased in incidence and is likely to be treatment induced. Complete responses and long-term survival are possible in secondary leukemia and aggressive antileukemic therapy should be given.

Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias.

PURPOSE: Mouse monoclonal antibody (mAb) M195 (anti-CD33) is reactive with most myeloid leukemia cells, monocytes, and hematopoietic progenitors, but not with other hematopoietic cells or stem cells nor with nonhematopoietic human tissues. A therapeutic dose-escalation study of M195 labeled with iodine 131 was conducted in patients with relapsed or refractory myeloid leukemias. METHODS: Twenty-four patients (16 relapsed or refractory acute myeloid leukemias, five blastic myelodysplastic syndromes [MDS], two chemotherapy-related secondary leukemias, and one blastic chronic myelogenous leukemia [CML]), including seven who had failed to respond to prior bone marrow transplantation (BMT), received from 50 mCi/m2 to 210 mCi/m2 of 131I-M195 in divided doses. RESULTS: In 22 patients, whole-body gamma-imaging demonstrated marked uptake of antibody into all areas of bone marrow. Twenty-three patients (96%) demonstrated decreases in peripheral-blood cell counts, with decreased percentage of bone marrow blasts seen in 83% of cases. Eighty-nine percent of bone marrow biopsies examined quantitatively demonstrated substantial decreases in the number of blasts, with greater than 99% of blasts killed in some patients. The two cases that failed to demonstrate leukemic cytoreduction occurred in the first two dose levels. For 131I doses of 135 mCi/m2 or greater, pancytopenia was profound and lasted for at least 12 days. Eight patients had sufficient marrow cytoreduction to proceed to BMT. Three of these achieved marrow remission, one of 6+, and one of 9 months' duration. Two patients in blastic phase temporarily reverted to their original myelodysplastic states. Thirty-seven percent of assessable patients developed human anti-mouse antibody (HAMA). In two patients with HAMA who were re-treated, plasma 131I-M195 levels could not be maintained and no therapeutic effect resulted. Significant nonhematologic toxicity (hepatic) was seen in one patient and the maximum-tolerated dose (MTD) was not reached. CONCLUSION: These data suggest that safe leukemic cytoreduction can be achieved with 131I-M195 even in multiply relapsed or chemotherapy-refractory leukemias. This agent may be useful as part of a preparative regimen for BMT.

The acute monocytic leukemias: multidisciplinary studies in 45 patients.

The clinical and laboratory features of 37 patients with variants of acute monocytic leukemia are described. Three of these 37 patients who had extensive extramedullary leukemic tissue infiltration are examples of true histiocytic "lymphomas." Three additional patients with undifferentiated leukemias, one patient with refractory anemia with excess of blasts, one patient with chronic myelomonocytic leukemia, one patient with B-lymphocyte diffuse "histiocytic" lymphoma and one patient with "null" cell, terminal deoxynucleotidyl transferase-positive lymphoblastic lymphoma had bone marrow cells with monocytic features. Another patient had dual populations of lymphoid and monocytoid leukemic cells. The true monocytic leukemias, acute monocytic leukemia (AMOL) and acute myelomonocytic leukemia (AMMOL), are closely related to acute myelocytic leukemia (AML) morphologically and by their response to chemotherapy. like AML, the leukemic cells from the AMMOL and AMOL patients form leukemic clusters in semisolid media. Cytochemical staining of leukemic cells for nonspecific esterases, presence of Fc receptor on the cell surface, phagocytic ability, low TdT activity, presence of surface "ruffles" and "ridges" on scanning EM, elevations of serum lysozyme, and clinical manifestations of leukemic tissue infiltration are features which accompanied monocytic differentiation in these cases.

A new observation in the clinical spectrums of erythroleukemia. A report of 46 cases.

Erythroleukemia is a disease manifested by an abnormal proliferation of erythroid and myeloid precursors, generally consisting of a primary erythroid phase (chronic erythemic myelosis), a transition phase involving erythroid and myeloid precursors (erythroleukemia) and, finally, the purely myeloblastic (acute myeloblastic leukemia) phase. The experience at Memorial Sloan-Kettering Cancer Center is reported. Presenting signs and symptoms are consistent with prior reports. The chemotherapy results in the past have been poor; because of the poor results, chemotherapy is started only if one of the following criteria are present: (1) frequent transfusion requirements; (2) rapidly increasing peripheral white blood cell count or percentage of leukemic blast forms; (3) frequent recurrent infectious and/or hemorrhagic complications. A hitherto unrecognized association of erythroleukemia and symptomatic rheumatic disease and numerous immunologic abberations are reported. The symptoms related to this rheumatic disorder do not seem to be relieved by therapy directed at the leukemic process, but rather by the use of simple anti-inflammatory agents.

Relationship of Auer rods and chromosome findings to outcome in eighty-nine adults with acute nonlymphoblastic leukemia.

We performed cytogenetic analyses using banding techniques on 89 adults with acute nonlymphoblastic leukemia prior to receiving protocol chemotherapy. The relationships of cytogenetic findings both to outcome and to other pretreatment variables (particularly the presence or absence of Auer rods) were analyzed. Patients were followed up to 90+ months. When patients were grouped according to cytogenetic findings (NN: all normal metaphases; AA: all abnormal metaphases; AN: both normal and abnormal metaphases; F: no evaluable metaphases; I: insufficient (less than three) metaphases) no significant differences were noted with regard to age, sex, terminal transferase positivity, complete remission rate, remission duration or survival. The marrow aspirates of patients with only normal (69%) metaphases or no evaluable metaphases (64%) were more likely to display Auer rods than specimens from individuals with only abnormal (26%) or a mixture of normal and abnormal (42%) metaphases (p = 0.03). The presence of Auer rods in the pretreatment marrow aspirate was associated with an increased complete remission rate (71% vs 41%, p = 0.004), median remission duration (12 months vs 9 months, p = 0.02), and median survival (13 months vs 4 months, p = 0.01). Using multivariable analyses, the presence or absence of Auer rods was the pretreatment factor that most significantly predicted response and survival in this group of patients. The presence of a normal karyotype in the initial cytogenetic preparation is associated with the presence of Auer rods. The finding of Auer rods in the initial bone marrow predicts greater response and longer survival in acute nonlymphoblastic leukemia.

Erythroid progenitors (BFU-e and CFU-e) in acute leukaemia.

Bone marrow erythroid progenitor cells were examined from 50 cases of acute leukaemia and from 20 normal subjects using an in vitro semisolid culture method. Numbers of both primitive erythroid progenitor cells (BFU-e) and later-stage erythroid progenitor cells (CFU-e) were remarkably depressed in patient with acute leukaemia in active phase. However, both BFU-e and CFU-e recovered to within normal range when the patients achieved remission. Peripheral blood BFU-e of children with acute lymphocytic leukaemia in remission were also examined and found to have values not significantly different from those of control subjects. There was no distinct correlation between the numbers of erythroid bursts or colonies and the duration of remission in patients with acute leukaemia in remission. The reduction of BFU-e and CFU-e in active acute leukaemia suggests the involvement of erythropoietic progenitors in the pathophysiology of this type of leukaemia.

Two T lymphocyte populations as effector cells fro IgG dependent cytotoxicity.

The characteristics and proportions of human lymphocyte populations capable of lysing IgG coated target cells were studied. Monolayer of target erythrocytes coated with rabbit IgG were employed to detect and isolate the lytic effector lymphocytes. Normal peripheral blood effector lymphocytes were shown to express IgG receptors, and a total of four cell types possesing different surface markers were identified. An average of 68% (range 51-80%) of the effector lymphocytes had T lymphocytes antigen and were capable of SRBC rosette formation, and 32% of the lymphocytes lacked T lymphocyte markers. Two populations of these T lymphocytes were identified: one possesses SRBC and IgG receptors, and the other possesses SRBC, IgG and complement receptors. The proportion of the former was estimated as 53.2% and the latter as 14.8% of the total effector cell population. Two other cell types were distinguished among the non-T lymphocytes. One type of lymphocytes bear IgG receptors (21.6%) and the other has both IgG and complement receptors (10.4%). The cytolytic capacity of the two T lymphocyte subpopulations is suggested to be an important reaction of the immune reactive T lymphocytes during the immune response.

Philadelphia chromosome positive chronic myelogenous leukemia developing in a patient with acute lymphoblastic leukemia.

A patient with acute lymphoblastic leukemia (ALL) in remission for over five years and with no systemic chemotherapy for over two years developed a peripheral blood and bone marrow granulocytosis. While in remission from the ALL, cytogenetic studies revealed a normal karyotype. With the development of peripheral and marrow granulocytosis, repeat cytogenetic preparations demonstrated the presence of the Philadelphia chromosome. The long interval between the onset of ALL and GML, as well as the normal karyotype during remission from the ALL, causes us to favor the hypothesis that two separate diseases are present.

The role of bone marrow aspiration and biopsy in detecting marrow involvement by nonhematologic malignancies.

A review of the records of the Memorial Sloan-Kettering Cancer Center identified 291 adult patients with nonhematologic malignancies who had undergone simultaneous bone marrow aspiration and biopsy from the same anatomic site. In 236 cases both samples were negative for tumor whereas in 39 both were positive. The biopsy was positive in three patients with a negative aspirate whereas in three others to aspirate was positive with a negative biopsy. The higher rate of tumor detection on aspirate in comparison with previous reports may be due to a thorough initial screening provided by technologists. Both aspiration and biopsy appear to be indicated for full evaluation of bone marrow in cancer patients.

The L-5 protocol: intensive treatment for patients with chronic myeloid leukemia.

An aggressive treatment program combining splenic irradiation, splenectomy and intensive cytotoxic combination chemotherapy was used in 37 patients with Ph1 chromosome positive chronic myelogenous leukemia. Cytogenetic Ph1 chromosome determination on marrow cells revealed a significant but transient decrease in the Ph1 positive cell population in 12/37 (32%) cases. Survival duration appears longer in patients who show a reduction in the Ph1 positive population. Blastic transformation occurred in 18/37 (49%) cases, not different from our historical control.