Timothy Gee

Treatment of acute leukemia in adults

Improvement in the management of acute leukemia in adults has not progressed nearly so rapidly as has the treatment of childhood leukemia. One important difference is that most adults have myeloblastic or related forms of the disease (AML), whereas the majority of children have lymphoblastic leukemia (ALL). However, even adults with ALL fail to respond as well to a similar regimen as do children with the same type of leukemia. In a recent series of patients with ALL who were treated with the complex multiple drug “L‐2” protocol, the incidence of complete remission in adults was 78% vs. 99% in children, and the median duration of remission was only 24 months in the adults, whereas it has not yet been reached in the children and is projected to be over 4 years. In AML and the related nonlymphoblastic forms of acute leukemia, therapy is still unsatisfactory in both adults and children. With the best current drug treatment schedules, the incidence of complete remission is now better than 50%, but it is often difficult to compare the exact remission rates in different series because of differences in reporting results. In adults treated with the multiple drug “L‐6” protocol, the incidence of remission in previously untreated patients was 56% and the median duration of remission was 10 months. The median survival of all patients (responders and non‐responders) was 1 year whereas that of responders only was 2 years. It is encouraging that a significant proportion of those patients with AML who have complete remissions now remain in remission for extended periods; about 45% of patients responding to the “L‐6” protocol remained in remission over 1 year, and 18% have been in continuous remission for 2 to over 4 years. Even after discontinuing treatment, some patients with AML stay in remission for long periods, and it is possible that some of them may have been cured. If this proves to be true, it becomes of great importance to determine what is different about the patients who do exceptionally well as compared to the majority who continue to die within a year. However, no consistent nor distinctive favorable prognostic features have yet been identified.

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.

Prognostic significance of serum lactate dehydrogenase in malignant lymphoma

The pretreatment serum lactate dehydrogenase level (LDH) was the single most important prognostic variable in 30 patients with diffuse histiocytic lymphoma treated between January 1973 and January 1977 with a poly‐drug chemotherapy program called the cyclophosphamide L2 protocol at the Memorial Sloan‐Kettering Cancer Center. A highly significant difference was found between the survival patterns of patients with LDH levels of 500 U or less and those with LDH levels greater than 500 U. (Two‐year survival rates were 67% and 13%, respectively.) A similar trend was observed for 25 patients with diffuse, poorly differentiated lymphocytic lymphoma treated with the same protocol, although this difference was not statistically significant. (Corresponding two‐year survival rates were 74% and 33%, respectively.) The association of LDH level with survival was evident even after adjustment for other factors of potential prognostic significance. Pretreatment serum LDH determinations may provide a useful means of stratifying patient populations when comparing treatment programs for advanced stage non‐Hodgkins lymphoma. Cancer 46:139–143, 1980.

Acute lymphoblastic leukemia in adults and children. Differences in response with similar therapeutic regimens.

Twenty‐three adult patients (ages greater than 15 years) and 75 children with acute lymphoblastic leukemia were treated with similar intensive, sequential cytotoxic protocols (L‐2). The adult patients have a lower remission rate (78%) than the children (98%). The duration of remission and the length of survival are also shorter in adults. The incidence of central nervous system (CNS) relapse in adults (27.7%) is higher than in children (7.1%) suggesting that prolonged prophylactic intrathecal methotrexate as given to the children is more effective than the schedule used for adults where intrathecal methotrexate was given only in the first 2 months of therapy. The low incidence of CNS involvement in children on the L‐2 protocol compares favorably with other series reported using a combination of cranial irradiation and intrathecal methotrexate. In both adults and children there seemed to be a higher incidence of CNS involvement in patients with initial white blood cell counts greater than 25,000 cells/mm3.

Lymphoblastic lymphoma in adults.

Fifty-one patients with lymphoblastic lymphoma (LBL) treated with one of five successive intensive chemotherapy protocols for acute lymphoblastic leukemia (ALL) since 1971 were reviewed. The patients were divided into leukemic and nonleukemic groups, and their clinical and laboratory parameters compared. The projected 5-year survival rate for all patients treated with the L10/17 protocols was 45% for both leukemic and nonleukemic LBL. The response to treatment was compared with that of 111 patients with ALL and was nearly identical. Poor prognostic factors were age beyond 30, WBC greater than 50,000/microL, failure to achieve a complete response (CR), and a late CR during induction. Leukemia at presentation, T cell surface markers, and the presence of a mediastinal mass did not adversely affect survival. The use of intensive chemotherapy protocols has proven to be a significant advance in the treatment of LBL.

Infection with Human T-Cell Leukemia Virus Type I in Patients with Leukemia

Among 211 adults with leukemia who received multiple transfusions, 6 were found to be seropositive for human T-cell leukemia virus Type I (HTLV-I). Before the positive serum specimens were obtained, these patients received a mean of 14 units of red cells and 78 units of platelets. Seroconversion could be documented in three patients. None of the 6 patients seropositive for HTLV-I had a T-cell leukemia, other illnesses attributable to HTLV-I infection, or risk factors for HTLV-I infection other than transfusion: none were seropositive for human immunodeficiency virus. Patients with leukemia who receive multiple transfusions appear to be at risk for HTLV-I infection.

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

Homoharringtonine (HHT) is a new plant alkaloid originally isolated in the Peoples 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.

Cytarabine with high-dose mitoxantrone induces rapid complete remissions in adult acute lymphoblastic leukemia without the use of vincristine or prednisone.

PURPOSE To evaluate the efficacy and safety of a new induction regimen for adult acute lymphoblastic leukemia (ALL) that does not contain vincristine or corticosteroids. PATIENTS AND METHODS Thirty-seven adult patients with newly diagnosed ALL and lymphoblastic lymphoma were treated with a dose-intense induction regimen. This regimen was designed to increase the fraction of patients achieving an early complete remission (CR) in an attempt to increase long-term disease-free survival. The induction regimen was cytarabine (Ara-C) 3 g/m2/d for 5 days and mitoxantrone 80 mg/m2 as a single dose on day 3. Granulocyte colony-stimulating factor (G-CSF) 200 micrograms/ m2/d beginning on day 7 was used to promote early myeloid recovery. RESULTS There were 31 CRs (84%). Median time to CR was 34 days, median hospital stay was 28 days, and the median number of days with a neutrophil count less than 500/microL was 18. There were three patients with resistant disease who experienced treatment failure and three early deaths from sepsis. Four patients with Philadelphia chromosome-positive (Ph+) ALL achieved hematologic and cytogenetic CRs. CONCLUSION This dose-intense induction regimen produced a high incidence of CRs with acceptable toxicity without the use of vincristine or corticosteroids. Comparisons with our prior vincristine/prednisone-based induction regimen (the L-20 protocol) suggest that patients treated on the current study were more likely to achieve a CR and that they achieved this remission earlier than patients treated with a traditional four-drug (vincristine, prednisone, doxorubicin, and cyclophosphamide) induction regimen.

Acute nonlymphoblastic leukemia. Prognostic factors in adults with long-term follow-up

Seventy‐nine adult patients with acute nonlymphoblastic leukemia (ANLL) were treated on the L‐6 protocol at Memorial Sloan‐Kettering Cancer Center between May 1970 and January 1974. Forty‐two patients achieved a complete remission (CR) and nine of these are still disease free, with a minimum of seven years of follow‐up. An extensive statistical analysis has been carried out on a large number of pretreatment and treatment characteristics to identify factors related to CR and remission duration. Multivariate regression techniques yielded as favorable characteristics associated with CR, in order of importance: young age at diagnosis, the presence of Auer rods at diagnosis, and treatment with Pseudomonas vaccine. A regression model for remission duration identified as favorable prognostic factors for long‐term remission: at most two courses of induction therapy, an intermediate age range, and a low platelet count at diagnosis.