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Vascular endothelial growth factor receptor-2 (VEGFR-2), also termed KDR, is a high-affinity vascular endothelial growth factor (VEGF) receptor. VEGFR-2 plays a role in de novo blood vessel formation and hematopoietic cell development. Recently, we found that chronic lymphocytic leukemia (CLL) cells express high levels of VEGF. Therefore, we sought to investigate the role of VEGFR-2 in CLL. Using Western blot analysis, we first determined that VEGFR-2 is present in peripheral blood CLL cells. We then quantified the cellular levels of VEGFR-2 protein using a solid-phase radioimmunoanalysis in peripheral blood cells from 216 patients with CLL. As control, we used peripheral blood mononuclear cells (PBMNCs) from 31 hematologically normal individuals. The median of VEGFR-2 levels detected in the control samples was assigned a value of 1.0, and VEGFR-2 protein levels were normalized to the control median value. The median level of VEGFR-2 in CLL cells was 1.57. Patients with VEGFR-2 levels higher than 1.57 had elevated lymphocyte counts, severe anemia, elevated beta(2)-microglobulin and advanced-stage disease. Elevated VEGFR-2 levels were also associated with statistically significantly shorter survival (35.4 versus 60.1 months; P0.01). Our data indicate that cellular VEGFR-2 levels may serve as a prognostic factor in CLL. Further studies should investigate the biological implications of these findings and the effect of the interaction between VEGF and VEGFR-2 on CLL cell proliferation.

The objectives of this study were to describe cases of avascular necrosis of the femoral head (ANFH) observed in chronic myeloid leukemia (CML) patients who were treated with interferon-alpha and to review the literature.The authors undertook a case review of the M. D. Anderson experience with ANFH occurring in CML patients who were managed with interferon-alpha-based therapy. MEDLINE (from 1966 to November 1999) and CancerLit (from 1983 to November 1999) searches were conducted to identify cases of avascular necrosis (AVN) associated with either CML or interferon-alpha.Three patients with ANFH were identified from the authors' experience. No common features related to the disease or therapy were seen among them, except for the presence of thrombocytosis and loss of response. A literature review revealed seven cases of ANFH associated with CML with or without interferon-alpha-based therapy. ANFH was not reported in association with interferon-alpha use for indications other than the treatment of patients with CML.ANFH may be the result of an interaction between CML and interferon-alpha therapy. ANFH that occurs in patients with CML who are treated with interferon-alpha should be recognized for treatment implications. Thrombocytosis with consequent microvascular thrombi and avascular necrosis manifesting in susceptible vascular or weight-bearing areas (e.g., the femoral head) may be an associated finding along with loss of response to interferon-alpha therapy.

The molecular mechanism for the occurrence of leukemia in multiple members of a family has not been fully elucidated but data support the contribution of highly penetrant mutations in leukemia susceptibility genes. We have investigated the genetic etiology of an unusual three-generation family with apparent autosomal dominant transmission of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) accompanied by somatic loss of the long arm of chromosome 5 and/or loss of heterozygosity (LOH) analysis and fluorescence in situ hybridization (FISH) of leukemia cells have been performed, confirming acquired hemi- and homozygous deletion of the long arm of chromosome 5. However, the chromosome lost in the observed LOH event is from the affected parent, in contradiction to the expectation for a two-hit hypothesis involving a tumor suppressor gene. Furthermore, genetic linkage has been performed at 5q31-33 as well as other loci (21q22 and 16q21-23.2) previously implicated in familial leukemia. In this family, linkage analysis excludes loci at 5q31-33 and 21q22, but localization to 16q21-23.2 cannot be excluded. We observed a maximum multipoint LOD score of 1.19 between marker D16S265 and D16S503 at 16q22 (P = 0.03), suggesting possible linkage to this locus. Considering this family and the previous 16q-linked family together, the linkage of a leukemia susceptibility gene to 16q22 achieved an LOD score of 3.63 at D16S265 with theta = 0. Thus, somatic deletion of the long arm of chromosome 5 appears as a necessary but surprisingly noncausative event for onset of AML and MDS in this family, thereby confirming a multistep etiology in which chromosome 5 plays an important secondary role.

One hundred seventy-four patients with progressive or advanced chronic lymphocytic leukemia (CLL) have received initial therapy with fludarabine as a single agent or fludarabine combined with prednisone. The overall response rate was 78% and the median survival was 63 months. No difference in response rate or survival was noted in the 71 patients receiving fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to progression of responders was 31 months and the overall median survival was 74 months. Patients over the age of 70 years had shorter survivals. Patients with advanced stage disease (Rai III and IV) had a somewhat shorter survival than earlier stage patients. More than half the patients who relapsed after fludarabine therapy responded to salvage treatment, usually with fludarabine-based regimens. Second remissions were more common in patients who had achieved a complete remission on their initial treatment. The CD4 and CD8 T-lymphocyte subpopulations decreased to levels in the range of 150 to 200/microL after the first 3 courses of treatment. Although recovery towards normal levels was slow, the incidence of infections was low in patients in remission (1 episode of infection for every 3.33 patient years at risk) and decreased with time off treatment. There was no association of infections or febrile episodes with the use of corticosteroids or the CD4 count at the end of treatment and a poor correlation with the increase in CD4 counts during remission. Infectious episodes were less common in patients who had a complete response compared with partial responders. Richter's transformation occurred in 9 patients and Hodgkin's disease occurred in 4 patients. Five other patients died from other second malignancies. Fludarabine appears to be an effective initial induction therapy with a reasonable safety profile for patients with CLL.

A 24-member kindred is described in which four cases of acute myeloid leukemia (AML), and one case of myelodysplastic syndrome (MDS) occurred over three generations. The proband was diagnosed with AML at age 47; within 6 months, her sister, age 41, was diagnosed with MDS. The proband's father, grandfather and a paternal uncle all died of AML, preceded by a pre-leukemic phase. The five cases had several clinical features in common. In the two sisters and their paternal uncle, cytogenetic analyses of bone marrow cells revealed a common abnormality characterized by loss of the long arm of chromosome 5, del(5q). No constitutional cytogenetic abnormality was detected in mitogen-stimulated peripheral blood lymphocytes from the proband. In addition, there was no history of common environmental or occupational exposure in the family. The occurrence of AML and MDS in three generations of this family most likely resulted from a single gene defect with an autosomal dominant pattern of inheritance. The association with the somatic loss of 5q material in the leukemia cells of affected members suggests that a germline mutation of a leukemia suppressor gene located on 5q might be the primary event responsible for hereditary susceptibility to leukemia in this family.

Aberrant expression of the tumor suppressor gene RB1 is associated with a variety of solid tumors and hematopoietic neoplasms. Certain cancer cell lines in which the protein encoded by RB1 (p110RB) is absent have been reported to show decreased growth rate, clonogenicity, or tumorigenicity following insertion of a transcriptionally active RB1 gene. We asked whether these RB-deficient cells could be growth inhibited by direct exposure to purified p110RB. We report a decrease in uptake of tritiated thymidine by 5637 bladder carcinoma cells (RB-negative) when purified recombinant p110RB is added to culture media. Internalization of the protein by cells and translocation to the nucleus are demonstrated by immunohistochemistry, FACS, and detection of radiolabeled protein in subcellular fractions. Next, we chose a well-described leukemia cell culture model to investigate the potential effect of recombinant p110RB in clinical disease. We observed dose-related decreases in cell number of colony formation in vitro in 8 of 20 acute myelogenous leukemia samples, 7 of which did show endogenous p110RB detectable by immunohistochemistry. Histological appearance following exposure to p110RB shows cytoplasmic vacuolization and nuclear lobulation of degenerating cells. We conclude that purified p110RB added to culture media is internalized by cells, translocated to the nucleus, and exerts a growth-inhibitory effect on certain cancer cell types.

Trisomy 21 is the second most common trisomy in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, its clinical and prognostic significance is not known. We analyzed the records of 1187 consecutive patients with untreated AML or MDS. Thirty-seven (3.3%) had trisomy 21: four (0.3%) as the only cytogenetic abnormality and 33 (2.7%) with other cytogenetic abnormalities (-5 and/or -7 in 15, +8 in nine, t(15;17) in three, inv(16) in three, t(8;21) in one, and hyperdiploid with several other additional chromosomes in two). Twenty-eight patients had AML and nine MDS. No patients had megakaryocytic phenotype (M7), common in patients with constitutional trisomy 21 (Down's syndrome) and AML. Overall, 57% achieved complete remission (CR), with median CR duration of 39 weeks, and median survival of 31 weeks. When patients with additional cytogenetic abnormalities were compared to patients with similar abnormalities but no trisomy 21, their clinical features as well as their CR rate, CR duration and survival were similar, with or without trisomy 21. We conclude that trisomy 21 in AML typically presents in conjunction with other cytogenetic abnormalities, especially -5/-7 and +8 whose presence rather than the presence of +21 dictates the clinical outcome.

The nonrandom chromosomal translocation t(8;21)(q22;q22) can be found frequently in acute myelogenous leukemia with maturation (AML-M2). The breakpoint of this translocation has been cloned and characterized, and fusion transcript AML1/ETO has been identified. Reverse transcription polymerase chain reaction (RT-PCR) can be used to amplify the breakpoint site of AML1/ETO in t(8;21)-positive AML-M2 patients. The chimeric transcript can be detected in all 16 (100%) t(8;21)-positive AML-M2 patients. In all samples, the size of the amplified DNA fragments and pattern of restriction digest were identical, indicating that the t(8;21) translocation breakpoint occurs within a single intron of the AML1 and ETO genes. Interestingly, this fusion transcript was also detected in one of 13 AML-M2 patients without the t(8;21) translocation, indicating that a masked translocation involving chromosomes 8 and 21, exists in AML. Minimal residual disease was detected by semi-nested RT-PCR in all four patients tested, who had been in complete remission for 12, 15, 34, and 52 months, respectively. These results indicate that RT-PCR amplification of the AML1/ETO fusion transcript is a powerful tool for diagnosing and monitoring minimal residual disease in AML-M2 patients.

The clinical response and survival of 113 patients with at least 3-year follow-up after treatment with fludarabine as a single agent for chronic lymphocytic leukemia has been evaluated. Seventy-eight patients were previously treated and 35 were untreated. The response to therapy and survival were strongly correlated with the degree of previous therapy, the stage of disease, and whether or not the patients were refractory to alkylating agents. Other characteristics associated with survival were the age of the patient and the serum albumin level at the start of therapy. The median time to progression of responders who had not received prior therapy was 33 months and was 21 months for previously treated patients. Survival after progression of disease was also strongly correlated with the degree of prior therapy. No successful salvage regimen after initial fludarabine therapy was shown for patients refractory to alkylating agents, although fludarabine achieved further remissions in patients who had received fludarabine as their initial treatment or were not refractory to alkylating agents. The morbidity of patients in unmaintained remission on discontinuation of fludarabine was low, with less than one episode of infection per patient-year at risk. The morbidity during this time was correlated with clinical response and whether the patients had received prior therapy. Although fludarabine is a very effective cytoreductive regimen, most patients, including those who achieved true complete remissions, will have recurrent disease. Longer follow-up and comparative trials are required before the effect of fludarabine on survival is shown.

Evidence suggests that prognosis in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) depends more on karyotype than on formal classification as either MDS or AML according to the French-American-British (FAB) system. We provide further evidence of overlap between these two entities, reporting 4 patients who presented with either inv(16) (p13q22), del(16) (q22), or t(8;21) despite an FAB diagnosis of MDS rather than the diagnosis of AML with which these abnormalities are generally associated. In 3 patients, disease was relatively long-standing (3-10 months) prior to diagnosis, suggesting that the association between MDS and these cytogenetic abnormalities may not merely reflect a transient phenomenon. Two patients with inv(16) and the MDS subtype refractory anemia with excess blasts in transformation (RAEB-t) received AML-type chemotherapy as did a patient with t(8;21) and RAEB-t. All entered CR paralleling the high CR rate seen in patients with AML and these abnormalities. Our data support the concept that MDS and AML may be different manifestations of the same disease.

Seven adult patients with untreated acute lymphocytic leukemia (ALL) who manifested 5% to 40% myeloperoxidase (MPO)-positive blasts by electron microscopy (EM) are reported. Six patients had an L2 morphology, and one had an L1 morphology by the French-American-British (FAB) classification. The immunophenotype was T cell in four patients. Molecular analysis showed rearrangement of the immunoglobulin JH in four patients, three of them also having rearrangement of the T-cell receptor beta or gamma. Induction chemotherapy with vincristine-doxorubicin-dexamethasone (VAD) produced a complete remission in five of six patients (83%). Our findings suggest the existence of a previously undescribed subtype of mixed-lineage leukemia, which by morphology and immunophenotype often appears as T-cell ALL but exhibits MPO-positive blasts by EM.

Twenty-five adult patients with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2 intravenously over 1 hour daily for 5 days and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. Overall, nine patients (36%) achieved complete remission, eight (32%) died during induction, and eight (32%) had resistant disease. No significant associations were found between pretreatment patient characteristics and remission. Remission durations toxic effects were related to myelosuppression. Febrile episodes requiring hospitalization occurred in 23 patients (92%), including five episodes of fever of unknown origin (20%) and 18 episodes of documented infections (72%). The authors conclude that the combination of mitoxantrone and high-dose cytosine arabinoside has significant activity in adults with refractory acute lymphocytic leukemia. The addition of colony-stimulating growth factors to the intensive chemotherapy, and the use of the combination regimen as part of front-line maintenance intensification therapy may further improve the prognosis in these patients.

The prognostic importance of patient pretreatment clinical and laboratory features was investigated in a group of 303 patients with Philadelphia chromosome-positive benign-phase chronic myelogenous leukemia. Intensive chemotherapy was given to 97 patients, and 78 underwent an early elective splenectomy. The overall median survival time, dated from hospital admission, was 39 months. Patient characteristics associated with shortened survival were age 60 years or older, black race, the presence of hepatomegaly, splenomegaly, symptoms, weight loss, and poor performance status. Adverse blood and bone marrow parameters were anemia, thrombocytosis or thrombocytopenia, a high proportion of peripheral blasts plus promyelocytes or of basophils, a high proportion of marrow blasts or basophils, decreased marrow megakaryocytes, and cytogenetic abnormalities in addition to the Philadelphia chromosome. Several of these factors were interrelated. A multivariate regression analysis demonstrated that the combination blood basophilia, race, additional cytogenetic abnormalities, age and marrow basophilia had the strongest predictive relationship to survival time. This resulted in a model segregating patients into low-, intermediate-, and high-risk groups, with median survivals of 53, 39, and 25 months, respectively. Another model was derived that did not include the marrow features and identified splenomegaly and platelet counts as adding to the prognosis prediction by blood basophilia, race, and age. Evaluation of the effect of therapy, after adjusting for differences in prognostic characteristics, showed that intensive chemotherapy was associated with survival prolongation among patients at intermediate and high risk of death. We conclude that a combination of pretreatment factors identifies different risk subcategories in patients with chronic myelogenous leukemia and is helpful in assessing overall prognosis and treatment effect.

We administered a combination of rubidazone, cytosine arabinoside, vincristine, and prednisone (ROAP) to 91 patients with acute myelogenous leukemia who were 50 yr of age or older. These patients had been identified in previous studies to be a group with a relatively poor prognosis. One-third of the patients had an antecedent hematologic disorder prior to treatment. Forty patients (48%) obtained a complete hematologic and clinical remission. A history of an antecedent hematologic disorder, male sex, and absence of Auer rods were adverse factors for achieving remission in this older population. More than half of the patients achieved remission in one course. The major cause of failure to obtain a remission was death due to infection, 40% of which were caused by fungi. Resistance to chemotherapy, although uncommon, was noted more frequently in patients with an antecedent hematologic disorder. Univariate and multivariate prognostic factor analysis was used to compare these patients with a historical control group treated with a program in which adriamycin was used instead of rubidazone (AdOAP). No significant difference in remission rate was detected. Cyclocytidine was used as a maintenance agent in this study, and while the median remission duration was only 37 wk, 30% of patients are expected to be in remission for 2 yr. Chemotherapy programs combining an anthracycline with cytosine arabinoside, given to older patients in similar fasion to younger patients will achieve remissions in one-half of a group of older patients. These remissions are of comparable quality to those of younger patients. Mathematical models derived from analysis of prognostic factors are of use in identifying patients likely to fail these programs who are in need of innovative approaches to treatment.

The continuous flow centrifuge extracorporeal circulating system presently used for the collection of large quantities of leukocytes from patients with leukemia has been modified to increase operating efficiency. A feedback loop was designed and incorporated into the system, which has increased the efficiency of collecting leukocytes from 31 to 47 per cent. This improvement has reduced the treatment time required for a given patient.

Combination chemotherapy with an anthracycline, Adriamycin or rubidazone, cytosine arabinoside, vincristine and prednisone resulted in a complete remission rate of 62% in 325 consecutive unselected adults with acute leukemia. The results by morphologic categories were 58% for acute myelogenous leukemia (AML), 70% for acute undifferentiated leukemia (AUL), and 77% for acute lymphoblastic leukemia (ALL). The median survival was 43 weeks. Ten percent of all patients are projected to be alive and in remission at five years. The median remission duration for the whole group was 51 weeks, durations being significantly longer for AML (60 wks) than ALL (30 wks) and AUL (21 wks). Central nervous system involvement was uncommon in AML (4%), but much more common in patients with AUL (37%) and ALL (32%). One in five complete responders with AML is projected to be in their first remission at five years off all chemotherapy. Age, sex, morphology, cytogenetic pattern, temperature of presentation, and presence of a documented preceding hematologic abnormality are found to be significant variables for response and survival.

A phase I clinical study of aziridinylbenzoquinone (AZQ) was conducted in 33 patients with various types of advanced solid tumors to evaluate its toxicity and efficacy. The initial dose of 0.5 mg/m2/day X 5 days repeated at 3-week intervals was progressively increased to a maximum dose of 12.0 mg/m2/day. Thrombocytopenia was the dose-limiting toxic effect; it was delayed, cumulative, and occurred more often in patients with extensive prior chemotherapy and radiotherapy. Anemia was common and severe at higher doses, while nausea and vomiting were observed only in some patients and usually were mild. Objective tumor regressions were observed in 3 of 17 patients who received biologically active doses of AZQ, i.e., 6 mg/m2/day or higher. Minor responses were seen in two of three patients with malignant melanoma and in a patient with adenocarcinoma of unknown primary. The recommended starting dose of AZQ for good-risk patients is 8.0 mg/m2/day X 5 days for phase II studies.

Prognostic factors were examined in 31 patients with hairy cell leukemia seen at M. D. Anderson Hospital. Long survival from presentation was significantly associated with ease of aspiration of iliac crest bone marrow, absence of major infection, hemoglobin greater than 10 g/dl, and absence of a prior history of pneumonia. Long survival from splenectomy was associated most closely with absence of a prediagnosis history of pneumonia, suggesting that a long-standing host defense abnormality may exist that is not corrected by splenectomy. Generally, patients with sustained improvement in hematologic parameters postsplenectomy lived longest from splenectomy, although the results were not statistically significant.

One hundred thirty-eight adults with advanced cancers were treated with Baker's Antifol. The complete response + partial response rate was only 10%. Best responses were obtained in 31 patients with lung adenocarcinoma (complete response + partial response, 13%), in 25 patients with colorectal carcinoma (partial response, 16%), and in 6 patients with renal cell carcinoma (partial response, 50%). Two partial responses occurred in 15 patients with squamous cancer. No significant responses were seen in 27 patients with other adenocarcinomas, 13 with sarcomas, 14 with melanomas, and 8 with miscellaneous tumors. The most frequent toxicities were dermatitis, stomatitis, gastrointestinal symptoms, and mild myelosuppression. The incidence of dermatitis was significantly decreased by shortening the schedule of Baker's Antifol administration from 5 to 3 days. Baker's Antifol has some degree of antitumor activity, and studies of combination of this agent with other effective chemotherapeutic agents are indicated.

Chronic lithium administration to 22 patients with oligoleukemia did not alleviate cytopenia or stimulate bone marrow proliferative activity. The authors identified, however, pretreatment characteristics discriminating two evolutionary endpoints of oligoleukemia (marrow failure, 10 patients; overt acute leukemia, 12 patients): higher marrow leukemic infiltrate, normal myeloid precursor proportion, platelet count, and female sex all favored eventual transition to overt leukemia which, in comparison with marrow failure, was associated with a significantly longer survival duration from symptoms. For patients developing overt leukemia, survival from diagnosis was inversely correlated with the degree of marrow leukemic infiltrate. The lack of lithium responsiveness in oligoleukemia is consistent with the concept of differentiated leukemia with abnormalities either at the level of a lithium-responsive adherent cell elaborating colony stimulating activity (CSA) or at the level of CSA-responsive CFUs.

Although collagen myelofibrosis indicates poor prognosis in late stages of chronic myelogenous leukemia, the significance of reticulin stain-measured fibrosis in newly diagnosed patients is unknown. One hundred and thirty-eight patients with untreated or minimally treated chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia had reticulin stain studies made on their bone marrows at diagnosis. Reticulin fibrosis was graded on a scale of 1 to 4. Significant (Grade 3 or 4) fibrosis was noted in 65 patients (47%). Compared with patients with mild (Grade 1 to 2) reticulin fibrosis, those with significant fibrosis had a higher incidence of splenomegaly greater than or equal to 10 cm (29% versus 49%; P = 0.02), hemoglobin less than 10 g/dl (19% versus 49%; P less than 0.01), weight loss greater than or equal to 6.75 kg (10% versus 30%; P = 0.11), marrow blasts greater than or equal to 5% (7% versus 28%; P less than 0.01), peripheral blasts greater than or equal to 3% (30% versus 46%; P = 0.09), and additional karyotypic abnormalities (1% versus 17%; P less than 0.01). The incidence of thrombocytosis was similar in the two groups. Prognostically, median survival was significantly shorter for the 26 patients with Grade 4, compared with the 39 patients with Grade 3, and the 73 patients with Grade 1 or 2 reticulin fibrosis (32 versus 49 versus 57 months; P = 0.03). Reticulin fibrosis is a useful biologic and prognostic index in newly diagnosed patients with chronic phase chronic myelogenous leukemia.

Twenty-six patients with inv(16)(p13q22) or del(16)(q22) in association with acute myelomonocytic leukemia (AMML-M4, FAB classification), and abnormal marrow eosinophils have been treated at this institute. Initial bone marrow eosinophilia (greater than or equal to 4%) was observed in 22 of 26 patients (85%), and abnormal eosinophil morphology, characterized by immature cells with some interspersed basophilic granules, was evident in 26 of 26 (100%). Giemsa-banded chromosome analysis performed in all patients revealed 16 cases with inv(16)(p13q22) alone, and ten cases with additional chromosome changes. Twenty-five patients received combination induction chemotherapy, and 23 (92%) achieved complete remission (CR). The median duration of remission was 18 months (range, six to 72 + months), and the median duration of survival was 34 months (range, 0.5 to 133 months). Nine patients (35%) relapsed in the CNS at a median time of 19 months (range, six to 133 months) from first marrow CR. All patients had leptomeningeal disease, and in addition, six of nine (66%) demonstrated two or more enhancing lesions on computed tomography brain scan, consistent with intracerebral myeloblastomas. Review of 384 Giemsa-banded patients with acute myeloid leukemia revealed no other morphologic or cytogenetic subgroup with either an equivalent incidence of CNS leukemia or documented intracerebral myeloblastomas. This series of inv(16)(p13q22)/del(16)(q22) AMML reports a favorable prognosis for such patients and associates a specific clonal cytogenetic subgroup of acute leukemia with a distinct propensity for CNS relapse, manifesting as leptomeningeal disease and intracerebral myeloblastomas.

Sixty-four adult patients with refractory acute lymphocytic leukemia (ALL) received salvage therapy with the vincristine, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and dexamethasone (VAD) regimen consisting of induction chemotherapy with the three agents followed by multiple-agent maintenance therapy for 2 years. Overall, 25 patients (39%) achieved complete remission. The median remission duration was 28 weeks with 20% of these patients remaining disease-free at 2 years. The median overall survival was 23 weeks. Prognostic factors associated with differences in remission rates included patient performance status, hemoglobin and platelet levels, and degree of peripheral and marrow blastosis. Factors related to differences in survival were patient age and performance status, hemoglobin and platelet levels, percentage of peripheral blasts, and albumin and bilirubin levels. The toxicity of the regimen was minimal, with 33% of patients requiring hospitalization because of febrile episodes of unknown origin (17%) or documented infections (16%). Therapy-related mortality occurred in four patients (6%). We conclude that the VAD program has significant antileukemic efficacy and acceptable toxicity in adult salvage ALL.

The effect of maintenance chemotherapy on remission duration was analyzed in 39 of 70 patients (56%) with acute promyelocytic leukemia (APL) who achieved complete remission on induction chemotherapy. Overall, the median remission duration was 26 months, with a 3-year remission rate of 42%. The 3-year remission rate was significantly higher in patients who received 6-mercaptopurine and methotrexate (POMP) during maintenance, compared with those who did not (56% versus 30%; P less than 0.01), and in patients who received long-term maintenance therapy (P less than 0.01). A multivariate regression analysis selected maintenance therapy with POMP to be the only statistically significant factor associated with long-term remission duration. The type of maintenance chemotherapy is important in overall prognosis of patients with APL, and should be investigated further.

High-dose chemotherapy using drugs with predominant marrow toxicity and autologous bone marrow support has been investigated in a number of tumor types. High response rates are uniform and complete responses are also high; but long-term disease-free survival is occasional. This review discusses those tumor types where patients treated with this approach have survived disease free for several years. Also discussed is what other tumor types and prognostic subgroups of those tumors might benefit therapeutically from high-dose cytotoxic intensification with autologous bone marrow support or at least have this approach considered as the first alternative for initial relapse.

Thirty patients with clinical stage I-II malignant lymphoma of aggressive histologic types (histiocytic, undifferentiated, and mixed) were treated with chemotherapy alone. Of 25 patients with measurable disease, 22 (88%) achieved a complete remission. The remaining five patients had been rendered disease-free at the time of excisional biopsy; for this reason, they are considered evaluable only for duration of disease-free survival. Of the 27 patients who achieved disease-free status, 23 (85%) remain free of any evidence of disease. All eight patients with stage I disease and 15 of the 19 patients with stage II disease remain free of disease. The use of clinical instead of surgical staging, followed promptly by systemic treatment with combination chemotherapy, results in a substantial cure rate and avoids the undesirable morbidity and treatment delay associated with laparotomy. The results of this approach compare favorably with those obtained by radiotherapy alone or with combined radiation and chemotherapy for surgically staged patients.

A phase I clinical study of bruceantin was conducted in 66 patients with various types of advanced solid tumors to evaluate its toxicity and efficacy. The initial dose of 0.2 mg/m2/day x 5 days repeated at 2-week intervals was progressively increased to a maximum dose of 4.5 mg/m2/day. Hypotension was the dose-limiting toxic effect; it was delayed, cumulative, and occurred more often in patients with abnormal pretreatment liver function. Nausea, vomiting, and fever were common at higher doses, and diarrhea, stomatitis, alopecia, paresthesia, and rash were observed in some patients. The hematologic toxicity of bruceantin was moderate at high doses and was manifested mainly as thrombocytopenia; it was more severe in patients with abnormal hepatic and renal functions. No objective tumor regressions were observed. The recommended dose of bruceantin is 3.5 mg/m2/day x 5 days for phase II studies.

The pretreatment characteristics of 325 adults with acute leukemia who were treated at the M. D. Anderson Hospital between 1973 and 1977 have been evaluated to assess their value as prognostic indicators. The patient population includes all patients treated with an anthracycline (Adriamycin or rubidazone), cytosine arabinoside, vincristine, and prednisone during the time period. Most patients had one of the variants of acute myelogenous leukemia (75%), and the remaining patients had acute lymphoblastic leukemia (16%) or undifferentiated leukemia (8%). Twenty-one factors were found to be significantly associated with probability of obtaining a complete response. In addition to characteristics previously known to provide prognostic information such as age, temperature status at the start of treatment, morphology, the presence of Auer rods, sex, and hemoglobin level, we identified the presence of a documented antecedent hematologic disorder and the finding of insufficient metaphases on cytogenetic analysis using the squash technique as being major prognostic variables. In addition, the pretreatment biochemical characteristics of hypoalbuminemia and elevated blood urea nitrogen and creatinine were found to adversely influence prognosis. The prognostic significance of factors such as the leukocyte count and platelet count, identified in earlier studies, was not confirmed in this group of patients. From this natural-history analysis predictive models for response have been developed using multivariate logistic regression techniques. One of these models has been used to evaluate the effect of morphology, treatment, and cytogenetic pattern on response to the combination of drugs used.

Twenty-seven patients in the blastic phase of chronic myelogenous leukemia received combination chemotherapy with mitoxantrone 5 mg/m2 intravenously daily for 5 days, and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. The patients' median age was 42 years (range, 19-61 years), and 26 of them had Philadelphia chromosome-positive disease. Overall, seven patients (26%) achieved complete remission, and one (4%) had a partial remission for an overall response rate of 30%. Eight patients died during remission induction, and 11 had resistant disease. The median survival was 14 weeks for the total population, and 24 weeks for patients achieving a complete remission. The nonmyelosuppressive toxicity of the combination was acceptable; serious neurologic and pulmonary toxicities were uncommon. Significant marrow hypoplasia was observed resulting in a high incidence of febrile episodes (85% of patients). The combination of mitoxantrone and high-dose cytosine arabinoside did not significantly improve overall prognosis. Since chemotherapy continues to produce disappointing results, other innovative approaches need to be explored.

Nine patients with hematological malignancies were treated with difluoromethylornithine and methylglyoxal bis(guanylhydrazone). The number of circulating blast cells decreased in all of the patients treated with DFMO and MGBG for longer than 1 wk. Morphological evidence of myeloid maturation was evident in four patients with leukemia and the circulating M Protein decreased in one patient with multiple myeloma. The polyamine content of the mononuclear cells in both the peripheral blood and bone marrow was transiently increased after the initial MGBG dose. During administration of DFMO decreases were achieved in the peripheral blood mononuclear cell putrescine levels in 7 patients, spermidine levels in 5 patients, and spermine levels in 4 patients. Alterations in bone marrow mononuclear cell polyamine levels were similar to those which occurred in the peripheral cells. An average of 9 days of DFMO treatment was required to lower mononuclear cell polyamine levels. Three of the 4 evaluable patients receiving multiple MGBG doses had an increased mononuclear cell content of MGBG after DFMO pretreatment. Enhancement of cellular MGBG levels was not directly correlated to the degree of cellular polyamine depletion.

Sixty-one patients with advanced disseminated cancer were given progressively increasing doses of pyrazofurin to evaluate toxicity patterns and to establish the dosage that produces maximum therapeutic effect with clinically tolerable toxicity. The drug was given by intravenous injection over 5-day courses repeated every 2--3 weeks. Toxic reactions included stomatitis, myelosuppression, skin rash, erythema, proctitis, and occasional nausea and vomiting. Stomatitis was the dose-limiting toxicity and it occurred in 32 patients. Myelosuppression was mild to moderate. Of 75 evaluable courses for marrow toxicity, leukopenia occurred in 14 and thrombocytopenia in 28. Thrombocytopenia was apparently dose-independet. Marrow recovery was complete by day 21 of therapy. Twelve patients developed mild or severe cutaneous toxicity depending on dose. When mild, the skin changes consisted of self-limited erythema or rash, and when severe, bullous lesions and skin ulcers were also observed. Proctitis occurred in six patients and was associated with severe stomatitis. Nausea and vomiting were occasional and mild. There was no evidence of liver or renal toxicity. All toxic manifestations other than marrow toxicity were dose-related. No responses were observed. A reasonable dose schedule is 45 mg/m2/day X 5 repeated every 3 weeks. We recommend that Phase II studies be pursued particularly in diseases that have been shown to be sensitive to the drug.

Between 1965 and 1982, 105 patients with a diagnosis of Philadelphia chromosome-negative chronic myelogenous leukemia were referred to our institution with minimal or no prior therapy. The median age was 63 years and 64% were males. The overall median survival from time of referral was 14 months; 53% of patients survived 1 year and only 10% survived beyond 5 years. At the time of analysis, 92 patients (88%) were dead, 56% of deaths being preceded by a blastic crisis. Compared with Philadelphia chromosome-positive disease, patients with Philadelphia chromosome-negative chronic myelogenous leukemia were older and had a significantly higher incidence of anemia, thrombocytopenia, monocytosis, marrow blasts, decreased marrow megakaryocytes and a lower incidence of basophilia and thrombocytosis. Chromosomal abnormalities occurred in 33% of patients and consisted most frequently of trisomy 8, or an additional chromosome C, loss of the Y chromosome, or abnormalities in chromosomes #5 and #7. Of nine pretreatment characteristics significantly associated with poor survival, a multivariate analysis identified four to have independent additive prognostic significance: severe thrombocytopenia, hemoglobin levels less than 10 g/dl, increasing peripheral blasts and promyelocytes, and age 60 years or older. Monocytosis was not of prognostic significance. The derived prognostic model divided patients into three risk groups, low, intermediate, and high, with median survivals of 36, 16, and 3 months, respectively. The authors conclude that Philadelphia chromosome-negative chronic myelogenous leukemia is a distinct entity among the myeloproliferative syndromes with characteristic clinical and laboratory features and a poor prognosis. Prognostic factors and related risk categories were demonstrated within this disease entity.

Previous classification in vitro of adult acute leukemia incorporating morphology has been complex and difficult to understand. We have devised a simplified classification based solely on leuekemic proliferation in vitro. Seventy-six patients with adult acute leukemia previously untreated were included in this study and received identical chemotherapy. Three groups were recognized. The complete remission rate was 76% in the 21 patients with no leukemic growth in vitro (Group 1), 75% in 36 patients with leukemic cell growth but aggregates of 20 cells or less (Group 2), and only 21% in the 15 patients with aggregates of greater than 20 (Group 3). There was a highly significant difference in complete remission rates between Group 3 and the other two groups (p less than 0.001). Linear logistic regression analysis demonstrated the independence of the growth in vitro from other prognostic variables. A predictive model utilizing the in vitro result more accurately predicted for remission, both retrospectively and prospectively, than a model constructed with presently known prognostic parameters. The cause of death in failures suggested that this system detects resistance to the chemotherapy.

Sixty patients with acute promyelocytic leukemia were treated between 1973 and 1984. The overall median survival was 16 months with a five-year survival rate of 31 percent. The complete remission rate was 53 percent and was similar whether they received amsacrine- or anthracycline-based regimens (60 percent versus 51 percent). The median remission duration was 29 months. At five years, 43 percent of patients with responses to treatment had continuous remission and 57 percent were alive. Salvage therapy produced remissions in 53 percent of patients during first relapse, with two long-term survivors after further consolidation with bone marrow transplantation. Early fatal hemorrhage associated with disseminated intravascular coagulopathy during induction therapy occurred in 16 patients (26 percent). Multivariate analysis of the pretreatment patient characteristics significantly associated with an increased risk of fatal hemorrhage identified four that have primary prognostic importance: thrombocytopenia, elevated absolute blast and promyelocyte counts, old age, and anemia. Patients having up to two unfavorable features had a low risk of fatal hemorrhage compared with those who had more than two (5 percent versus 58 percent; p less than 0.0001). Overall, patients who received heparin had a lower incidence of fatal hemorrhage than those who did not (19 percent versus 32 percent). Heparin therapy was not beneficial to those at low risk but was associated with a trend towards decreased hemorrhagic deaths among high-risk patients (45 percent versus 67 percent). Cytogenetic studies demonstrated the characteristic 15;17 translocation in 73 percent of patients with analyzable metaphases, whereas 12 percent had other karyotypic abnormalities. Remission induction was often associated with a gradual atypical morphologic evolution into remission without intermediate hypoplasia with the interim marrows showing a high proportion of blasts. It is concluded that acute promyelocytic leukemia is a unique disease with a high potential for cure. Knowledge of its prognosis using present frontline and salvage therapy, of the factors related to fatal hemorrhage, and of the unusual patient marrow profiles during remission induction may improve the therapeutic approach.

Seventy-four adult patients with acute leukemia in relapse were studied. They received high-dose intravenous boluses of cytosine arabinoside (Ara-C) according to the following schedules: 3 g/m2 over 2 hours, every 12 hours for 4 to 12 consecutive doses, or a continuous infusion over 5 days at 200, 400, or 800 mg/m2/day. The patients' ages ranged from 16 to 68 years (median, 35). Subacute pulmonary failure attributable to Ara-C was observed in 16 of 72 evaluable patients (22%) and appeared 2 to 21 days (median, 6) after the first dose. None of the 28 patients who received up to six doses experienced any toxicity. With repeated courses or more than six doses in the first course there was a sharp increase in the incidence of toxicity. Thus, subacute pulmonary failure developed in 6 of 24 patients who received 9 doses and 6 of 19 patients who received 12 doses. The increase in toxicity with increasing number of doses is significant (P = 0.03). This suggests that the high-dose Ara-C regimen should be used with awareness of possible drug-induced pulmonary toxicity.

The records of 109 patients with non-Hodgkin's lymphoma of nodular pattern were reviewed to determine which factors were associated with a favorable response to therapy and prolonged survival. A logistic regression model was utilized to identify the pertinent variables. Prognostic factors associated with a favorable response were, in order of decreasing importance: treatment with an Adriamycin combination regimen, absence of bulky tumor, and no exposure to prior chemotherapy. Thos associated with prolonged survival were: normal hemoglobin level, treatment with an Adriamycin combination regimen, female sex, and no prior exposure to therapy. Achievement of complete remission in these disorders resulted in a statistically longer duration of survival compared to partial responses or failures. Patients whose complete remission was induced with an Adriamycin-containing regimen and maintained with BCG immunotherapy had a significantly longer complete remission than those who did not receive BCG. Knowledge of these factors can be important in planning and analyzing future therapeutic trials.

One-hundred-two patients with malignant melanoma who had distant metastases surgically resected and were judged to be clinically free of disease (M. D. Anderson Stage IVA melanoma) were studied. The median survival for all the patients from time of diagnosis of stage IVA disease was 18 months. The site of the resected metastases did not appear to influence survival, being approximately the same for the brain (15 months), lung (16 months), intraabdominal (18 months), and skin and/or lymph nodes (23 months). The site of the resected metastases also did not influence the median disease-free interval. Patients who had metastases resected from several organs at the same time had a median survival of 15 months, which was similar to that of patients with one resected site. Patients who were rendered Stage IVA on several occasions by surgical excisions had a median survival of 36 months. Thirty-five patients received surgery only and 67 patients received adjuvant chemotherapy, immunotherapy, or combined chemoimmunotherapy after surgery. For the group treated with surgery only, the median disease-free interval and survival from diagnosis of stage IVA disease were 6 months and 16 months, respectively, and for the adjuvant group 6 months and 21 months, respectively. Specifically, by the type of adjuvant therapy, the median disease-free interval and survival from stage IVA for 23 patients receiving Corynebacterium parvum were 6.9 and 19 months; for 39 patients receiving BCG, eight months and 26 months; for 24 patients receiving BCG + DTIC, eight and 17.4 months; and for all 51 DTIC treated patients 6.3 and 17.8 months, respectively. Patients receiving BCG had a median survival superior to the surgery only group (P = 0.02). An increase in survival was seen predominantly in patients who achieved IVA status more than once and received BCG. Patients with recurrent soft-tissue metastases appeared to benefit most from BCG in prolonging the disease-free interval. Only 1/10 treated by surgery alone had a disease-free interval longer than 1 year, compared with 9/16 who received BCG (P = 0.01). Stage IVA melanoma appears to be distinctly different in prognosis from Stage IVB melanoma and should be classified separately. Patients with recurrent soft-tissue disease may benefit significantly from treatment with BCG.

Fifty patients with inoperable squamous carcinoma of the lung. 38 with extensive, and 12 with limited disease, were treated with BACON. Tumor regression greater than 50% was observed in 17 patients (45%) with extensive, and four patients (33%) with limited disease. Stabilization of disease for greater than or equal to 8 weeks was seen in four extensive and eight limited patients, and had the same prognostic importance with regard to survival as response: in extensive disease, responding and stable patients had median survival (MST) of 26 weeks from start of therapy, while MST for non-responders was 9 weeks. MST in limited disease (all patients responding or stable) was 32 weeks. Analysis of survival in extensive disease by performance status showed improvement in each category over historical control results for supportive care alone. BACON was better tolerated and probably more effective when CCNU was given every 8 weeks, rather than every 4 weeks.

Long-term second remissions were seen in 5/66 patients with all. Relapse was extramedullary in 2/5. Persistent, progressive marrow lymphocytosis preceded relapse in 4/5 patients and persistent marrow eosinophilia in 1/5. All 5 patients had had an unmaintained remission of at least 6 months prior to relapse, and responded the second time to drugs which were essentially the same as those used initially. We conclude that long-term second remissions may occur in all. Patients who relapse after 6 months or more of unmaintained remission should be treated with the drugs used in current initial induction regimens in hope of cure.

A broad phase II study of vindesine was conducted in 79 adults with advanced malignancies. Most patients had solid tumors, particularly adenocarcinomas (59%), and 67 patients had received prior chemotherapy which included vincristine in 24 patients and vinblastine in one. Depending on tolerance to previous therapy, patients received vindesine at doses of 3-4 mg/m2 administered iv at 2-week intervals. Objective tumor regressions were seen in eight of 36 patients (one complete response, one partial response [PR], and six minor responses) with colorectal cancer, one of four patients (PR) with squamous cell cancer of the esophagus, one of four patients (PR) with malignant melanoma, and one of two patients (PR) with lymphoma. Five of 11 responding patients had received vincristine previously. Toxic effects were manageable. The results of this study justify in-depth, disease-oriented phase II evaluations of vindesine, regardless of prior therapy with other vinca alkaloids.

Mitoxantrone was administered to 41 adults with refractory acute leukemia. The initial dose employed was 4 mg/m2/day X 5 days. Eventually a starting dose of 10 mg/m2/day X 5 days was used, with some patients receiving a subsequent course at 12 mg/m2/day X 5 days. Three patients had a complete response, one a partial response, and one hematologic improvement. Although antileukemia effect was more frequent at the higher doses, so was death following treatment.

We have treated 37 adults with acute lymphoblastic leukemia (ALL), who have relapsed on previous intensive chemotherapy, with a combination of L-asparaginase and methotrexate (MTX) +/- ifosfamide. The initial study included 26 patients who received the two-drug combination of L-asparaginase and MTX given sequentially. Of the 26 patients, 15 (58%) achieved complete remission (CR), while 3 patients had a partial remission (PR), resulting in an overall response rate of 69%. The median duration of CR was 17.5 weeks. The median survival of complete responders was 39 weeks compared with 10 weeks for failures (P=0.001). The regimen was generally well tolerated and it was possible to give MTX doses of up to 400 mg/m2 with minimal myelosuppression, and severe stomatitis was infrequent. A further study involved the use of this regimen combined with ifosfamide in 11 patients. In this continuing study, there were six CR's (55%) and two PR's, with an overall response rate of 73%. The median duration of CR was 14+ weeks, and the median survival was 40+ weeks. Combination chemotherapy with asparaginase and MTX is effective in inducing remission in adults with ALL in relapse. It should now be considered for inclusion as part of induction therapy of previously untreated adults with ALL.

Thirty-five patients with advanced malignancies were treated with doxorubicin-DNA complex in a phase I clinical trial. The patients ranged in age from 30 to 77 years (median, 51) and received doxorubicin-DNA in doses that ranged from 20 to 135 mg/m2. Of the doses administered, 73% were 60-90 mg/m2 (median, 60). Nonhematologic toxic effects included nausea and vomiting in 32% of the patients, fever and chills in 24% mucositis in 18%, and decreases in ECG QRS voltage of greater than 30% in 18%. Fever of unknown origin was seen in 26% of the patients, with documented infection in 9%; 6% had drug-related deaths. All patients experienced alopecia. Hematologic toxic effects (median day, Day 14) included median granulocyte count nadirs of 0.8 X 10(3)/microliter at a 60-mg/m2 dose and 0.3 X 10(3)/microliter at 75 mg/m2. Thrombocytopenia was less severe, with median nadir counts of 131,000 cells/microliter at a 60-mg/m2 dose on median day. Day 13. Treatment courses could be repeated every 3 weeks. Clinical responses (complete plus partial) were seen in 12% of the patients, with an additional 48% showing stable disease. No patients entered in the study were known to be doxorubicin-resistant. Based on these data, we recommend a starting dose of 60 mg/m2 in patients with adequate bone marrow reserve and 50 mg/m2 in those with compromised bone marrows. Doxorubicin-DNA exhibits major clinical toxic effects on the gastrointestinal and hematopoietic systems, with dose-limiting granulocytopenia.