Zalmen A. Arlin

The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia.

DNA from 135 patients with chronic myelogenous leukemia (CML) at various clinical stages and Philadelphia (Ph1) chromosome positive acute lymphoblastic leukemia was investigated for alterations in a variety of proto-oncogenes which have been implicated in the evolution of CML from its chronic phase to blast crisis. The most common genetic change found in the evolution of typical Ph1 chromosome positive CML to blast crisis was an alteration of the p53 gene involving either a rearrangement, a deletion, or a point mutation in the coding sequence of the gene. Alterations of the p53 gene were found in the myeloid and the rare megakaryocytic variant of blast crisis but were absent in the lymphoid leukemic transformants. Gross structural alterations were seen in 11 of 54 (20%) of myeloid or unknown phenotypes of blast crisis and in only 1 of 44 chronic phase cases. Eight examples of mutations in the open reading frame of the p53 gene at codons 49, 53, 60, 140, 202, 204, 238, and 239 were observed in blast crisis patients. Mutations in the N-RAS gene were rare in typical blast crisis (2 of 27 cases) but were found in megakaryocytic and Ph1 negative myeloid blast crisis. We concluded that heterogeneous alterations in the p53 gene and occasionally in the N-RAS genes accompany the evolution of chronic phase CML to blast crisis.

Malignant lymphomas in a population at risk for acquired immune deficiency syndrome

Certain neoplasia are closely associated with acquired immune deficiency syndrome (AIDS). To evaluate this relationship the authors reviewed the occurrence of lymphomas in populations at high risk for AIDS; the study population included prisoners from New York State and nonprisoner intravenous drug abusers (IVDA). Non‐Hodgkins lymphoma was diagnosed in 16 prisoners, all of whom were IVDA, and four nonprisoner IVDA. The observed number of prisoners with non‐Hodgkins lymphoma (11) diagnosed between January 1, 1981 and December 12, 1984, significantly greater than the expected number (2.28) based on age adjusted incidence rates for the US population (P < 0.001). The calculated average incidence rate for non‐Hodgkins lymphoma among New York State prisoners aged 20 to 49 years was 21.5/105 to 67.2/105, which was nearly sixfold to 18‐fold higher than the general population. For prisoner IVDA, specifically, this incidence may be as high as 164/105, which represents a 40‐fold increase in the relative risk compared with the general population. It is concluded that, non‐Hodgkins lymphoma is frequently a manifestation of AIDS among IVDA, and is the most common malignancy seen in IVDA with AIDS.

Phase I clinical and pharmacokinetic evaluation of high-dose mitoxantrone in combination with cytarabine in patients with acute leukemia.

PURPOSE To determine the maximally tolerated dose of mitoxantrone in combination with cytarabine in patients with acute leukemia and advanced phases of chronic myelogenous leukemia (CML), and to assess the pharmacokinetics of high-dose mitoxantrone in this patient population. PATIENTS AND METHODS In a phase I study, 68 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and accelerated- and blastic-phase CML received induction therapy consisting of cytarabine 3 g/m2 by infusion over 3 hours daily for 5 days, with escalating doses of mitoxantrone 40 to 80 mg/m2 over 1 to 2 days by intravenous infusion over 15 minutes. Mitoxantrone pharmacokinetics were evaluated by high-performance liquid chromatography (HPLC) in 15 patients given a single dose of mitoxantrone ranging from 40 to 80 mg/m2 in combination with cytarabine. RESULTS Severe, but reversible hyperbilirubinemia (> three times normal) was considered the dose-limiting toxicity, and was observed in 25% of all patients and in 35% of those who received 70 to 80 mg/m2 of mitoxantrone. Other extramedullary toxicity, including cardiac dysfunction, was mild. Myelosuppression was universal and the median time to complete remission (CR) was 28 days (range, 19 to 77). The CR rate for previously untreated and relapsed patients with AML was 85% (17 of 20) and 38% (seven of 18), respectively. Eighty-three percent (15 of 18) of patients with ALL achieved a CR, including all patients with previously untreated disease. Eight of 12 patients with advanced-phase CML achieved a CR. No significant changes in mean mitoxantrone plasma elimination rates (ie, terminal plasma half-life and total-body clearance rate) occurred as the mitoxantrone dose doubled, indicating linear pharmacokinetics. CONCLUSIONS The recommended phase II dose of mitoxantrone is 80 mg/m2 administered over 15 minutes as a single intravenous infusion in combination with cytarabine 3 g/m2/d for 5 days. At this dose, high concentrations of mitoxantrone are achievable in vivo to levels that have been shown to be extremely cytotoxic in vitro.

Incidence and Treatment of Tumor Lysis Syndrome in Patients with Acute Leukemia

Tumor lysis syndrome (TLS) is a complication associated with electrolyte abnormalities that is observed in patients with acute leukemia who are receiving intense doses of chemotherapy. Forty-one patients with acute leukemia were treated with high-dose combination chemotherapy and were evaluated for TLS. A grading system developed for the evaluation of these patients was applied. Grade I tumor lysis was observed in 22 patients, grade II TLS in 2 patients and grade III in 1 patient. All patients were treated with intravenous fluids, mannitol, allopurinol and in some patients, aluminum-based antacids. Treatment for TLS prior to intensive chemotherapy reduced morbidity and mortality associated with high-dose chemotherapy for acute leukemias.

A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion

Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokinein vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40μg/m2 and was ultimately escalated to 200μg/m2. A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160μg/m2 was defined as the MTD. At 160μg/m2 peak serum levels occurred within 5–20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80μg/m2. This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule.

A phase I study of recombinant human interleukin-2 and alpha-interferon-2a in patients with renal cell cancer, colorectal cancer, and malignant melanoma

Preclinical data suggest synergy of interleukin‐2 (IL‐2) combined with alpha‐interferon (IFN). In addition, toxicities of IL‐2 may be decreased by intermittent continuous infusion. The purpose of this trial was to determine the maximum tolerated dose (MTD) of recombinant IL‐2 combined with alpha‐IFN in patients with renal cancer, colon cancer, melanoma, and malignant B‐cell disease. IL‐2 was given by continuous i.v. infusion at an initial dose of 5 × 105 units (U)/m2/d for 4 days plus IFN at 6 × 106 U/m2/d intramuscularly days 1 and 4 weekly for 4 weeks. Patients who achieved a response or stable disease received an additional 4 weeks of therapy. IL‐2 doses were increased to 1, 2, 3, 5, and 7 × 106 U/m2/d with three to eight patients at each dose level, at each of the two participating institutions. The dose of IFN was 6 × 106 U/m2 days 1 and 4 for all but five patients whose IFN dose was doubled to 12 × 106 U/m2/d. Forty‐three patients were entered on this study with 34 completing at least 4 weeks of therapy. Six patients were taken off study because of Grades III or IV pulmonary, neurologic, or cardiac toxicity; one for progressive disease; one for CNS metastases, and one for personal reasons. All of the toxicities were reversible. Chills and fever were universal, especially on days 1 and 4. Mild and moderate nausea, vomiting, diarrhea, anorexia, malaise, and cutaneous erythema were present in most patients. Fluid retention and occasional pleural effusions were observed at the higher IL‐2 doses but were not dose‐limiting. Significant hypotension associated with oliguria was seen, and these patients were treated with vasopressors and colloids. None of the patients required ICU admission. Thirty‐four patients were evaluable for response. There were 4/18 (22%) renal cell patients who experienced a partial response. No responses were seen in patients with melanoma, lymphoma, or colorectal cancer. The combined debilitating symptoms of fatigue, diarrhea, hypotension, fluid retention, and anorexia defined the MTD as 5 × 106 U/m2/d of IL‐2 and 6 × 106 U/m2 of alpha‐IFN.

Current status of treatment of acute leukemia in adults: An overview of the memorial experience and review of literature

The results of treatment of 629 previously untreated adults with acute leukemia at Memorial Hospital are reviewed. During the past 14 years, 135 adults (greater than 15 years) with acute lymphoblastic leukemia (ALL) have been treated with one of three successive multidrug-intensive treatment protocols (L2, L10/10M, and L17/17M), each calling for 2.5 to 3 years of systemic chemotherapy and prophylactic intrathecal methotrexate without cranial irradiation. The complete remission (CR) rates were L2 (n = 22) = 77%; L10/10M (n = 69) = 86%; L17/17M (n = 44) = 77%. The median durations of survival and remission were, respectively, L2 = 33 and 30 months; L10/10M = 62 months and not reached; and L17/17M = not reached. Almost all relapses occurred within the first 3 years while still continuing treatment, and there were only rate late relapses after stopping treatment. It appears that approximately half of the patients may have been cured with the latest two protocols. During the last 17 years, 494 adults aged 15 to greater than 70 with acute nonlymphoblastic leukemia (ANLL) were treated with one of five successive multiple drug treatment protocols of varying intensity (arabinosylcytosine + 6-thioguanine [n = 36]; L6 [n = 101]; L12 [n = 104]; L14/14M [n = 121]; and L16/16M [n = 132]). Patients with myelodysplastic syndromes generally were not treated until they developed acute leukemia, but were then entered and included in the results. Secondary leukemias following treatment of other neoplastic diseases were not included. The complete remission rates were fairly constant between 47 and 64% and the median durations of remissions were between 9 and 21 months. The intensive treatment L14 and L16 protocols were associated with more early deaths and did not result in a significantly improved remission incidence or duration or survival. With all protocols, the majority of relapses occurred within the first 2 years, but relapses continued to occur at a decreasing rate for 4 years and occasionally even later. Whereas a small fraction (approximately 10 to 15%) of adults with ANLL are now apparently being cured with combination chemotherapy, despite intensive efforts there has been little improvement during the last decade and more selective and effective forms of treatment are urgently needed.

Amsacrine is safe and effective therapy for patients with myocardial dysfunction and acute leukemia

The role of amsacrine in inducing remission in patients with cardiac disease and acute leukemia was evaluated. There were 17 patients with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL), and one with biphenotypic leukemia. In this series of 24 patients whose disease had relapsed and who had reduced left ventricular ejection fraction, nine had a complete remission, seven with AML and two with ALL. In addition, four of six with newly diagnosed acute leukemia and reduced left ventricular ejection fraction also responded. Among nine patients who underwent endomyocardial biopsy, none had morphologic changes of sufficient degree to account for drug‐induced heart failure. Patients with preexisting arrhythmias received amsacrine without incident if their serum potassium level was higher than 4.0 mEq/1 at the time of drug administration. Amsacrine is safe and effective therapy for patients with acute leukemia and cardiac disease.

Marrow storage techniques: a clinical comparison of refrigeration versus cryopreservation.

Fifty-three patients were evaluated for a comparison of the efficacy, safety, and cost efficiency of bone marrow (BM) transplanted after either refrigeration or cryopreservation. Thirty-eight patients had BM stored at 4 degrees C for an average of 3 days and 15 patients had cryopreserved BM stored for an average of 56 days. The average number of cells harvested was 3.8 x 10(8)/kg. The time to WBC recovery greater than 1 x 10(9)/l was 17 days refrigerated and 23 days for cryopreserved BM. The time to platelet recovery greater than 20 x 10(9)/l was 24 days for refrigeration storage and 51 days for cryopreserved BM. Four of 38 patients with refrigerated vs. 4/15 patients with cryopreserved BM experienced delayed engraftment (p less than 0.05). Refrigeration storage requires no special equipment, is cheaper than and presents a safe and viable alternative to cryopreserved BM in reconstituting hemopoiesis following high-dose chemo-radiotherapy.

Acute Promyelocytic Leukemia: A 5-Year Experience with New Antileukemic Agents and a New Approach to Preventing Fatal Hemorrhage

Forty-six induction courses were administered to 32 patients with acute promyelocytic leukemia. There were 28 males and 18 females with a median age of 39.5 (range 19-68). Twelve patients were previously untreated, 32 were in relapse, and 2 were refractory to primary induction chemotherapy. Heparin 7.5-10 units/kg/h by continuous infusion, 4-6 units of platelets and 1-2 units of fresh-frozen plasma (FFP) every 12 h were given to all patients. Previously untreated patients received either daunorubicin, idarubicin or mitoxantrone in combination with cytarabine (Ara-C). For relapsed and refractory patients, regimens included amsacrine with high-dose cytarabine (Amsa/HiDac), homoharringtonine (HHT) alone, or with Ara-C, mitoxantrone and bisantrene. Hemorrhagic complications occurred in only 1 out of 46 courses (2%). Complete remission rates (CR) were as follows: previously untreated 83% (10/12), relapsed 66% (21/32), primary refractory 50% (1/2). Amsa/HiDac resulted in a 71% (10/14) CR and HHT-based regimens achieved a 46% (6/13) CR. These regimens are effective and the value of their incorporation into primary therapy should be studied. The use of heparin with platelet and FFP transfusions every 12 h reduces the risk of hemorrhage during induction therapy.