Adjuvant immune stimulation with Corynebacterium parvum during maintenance chemotherapy of acute myeloid leukemia

Of 93 consecutively treated patients with acute myeloid leukemia 36 (39%) achieved complete remission (CR). Thirty-five patients were randomized to receive either maintenance chemotherapy alone (C) or a combination of active nonspecific immunotherapy with Corynebacterium parvum and chemotherapy (C + I). Maintenance therapy was given monthly for 1 year or until relapse. The median survival time was 21 months for patients treated with chemotherapy alone, compared with 30 months for patients treated with chemotherapy and immunotherapy. The median remission duration was 15 months for patients treated with chemotherapy, compared with 18 months for chemotherapy and immunotherapy group. While no statistically significant difference in remission duration or survival time could be attributed to the use of immune stimulation, a plateau of 40% long-term time survivors was defined in the chemotherapy and immunotherapy group. Age and sex were found to be the major prognostic factors for achievement of CR. No difference was found in remission duration or survival between the two different induction schedules. Neither did the morphological subtype of AML (FAB classification) or the leukocyte count at diagnosis correlate with remission rate or survival.     

Acute leukemia in adults: assessment of remission induction with combination chemotherapy by clinical and cell-culture criteria.

Remission induction was assessed by clinical and cell-culture criteria for 65 patients with acute myelogenous leukemia (AML), 11 patients with chronic myelogenous leukemia (CML) in blast crisis and 19 patients with acute lymphoblastic leukemia (ALL). Cyclophosphamide, cytosine arabinoside and vincristine (CAV) therapy resulted in complete remission in 23 of 50 previously untreated patients with AML and in 3 of the 11 patients with CML. Fourteen patients with ALL responded to vincristine-prednisone induction therapy and two to induction therapy with CAV. The median duration of survival of the responding patients was 2.2 years, compared with 4 months for the patients who did not respond to treatment. Granulopoietic colony formation, assessed by assay of colony-forming units dependent on colony-stimulating activity in culture (CFU-C), was abnormal in 37 of 42 bone marrow aspirates from patients with AML before treatement. CFU-C concentration increased when leukocyte-conditioned medium (LCM) was added to the cultures; 13 cultures had normal or elevated CFU-C concentration with LCM. Marrow cells of patients with ALL or CML in blast crisis demonstrated a similar pattern. Serial studies of marrow CFU-C concentration of 31 patients with AML demonstrated a change to a normal pattern with successful remission induction. Results of this study suggest that administration of purified LCM to leukemic patients might increase granulocyte production from potential but unstimulated granulopoietic precursors. This therapy would lessen the probability of death from infection during remission induction.     

Adjuvant immune stimulation with Corynebacterium parvum during maintenance chemotherapy of acute myeloid leukemia

Summary Of 93 consecutively treated patients with acute myeloid leukemia 36 (39%) achieved complete remission (CR). Thirty-five patients were randomized to receive either maintenance chemotherapy alone (C) or a combination of active nonspecific immunotherapy with Corynebacterium parvum and chemotherapy (C + I). Maintenance therapy was given monthly for 1 year or until relapse. The median survival time was 21 months for patients treated with chemotherapy alone, compared with 30 months for patients treated with chemotherapy and immunotherapy. The median remission duration was 15 months for patients treated with chemotherapy, compared with 18 months for chemotherapy and immunotherapy group. While no statistically significant difference in remission duration or survival time could be attributed to the use of immune stimulation, a plateau of 40% long-term time survivors was defined in the chemotherapy and immunotherapy group. Age and sex were found to be the major prognostic factors for achivement of CR. No difference was found in remission duration or survival between the two different induction schedules. Neither did the morphological subtype of AML (FAB classification) or the leukocyte count at diagnosis correlate with remission rate or survival.     

A randomized trial of chemoimmunotherapy of acute nonlymphocytic leukemia in adults using a protein-bound polysaccharide preparation

Summary The effect of immunotherapy with a protein-bound polysaccharide preparation termed PSK on remission duration and survival of adults with acute nonlymphocytic leukemia (ANLL) was studied in a prospective randomized cooperative trial. After having achieved complete remission and receiving a consolidation therapy, 73 patients were randomized either to maintenance chemotherapy or to maintenance chemotherapy plus immunotherapy with PSK. Ultimately 36 patients in the chemotherapy group and 31 in the chemoimmunotherapy group were evaluable. Six months after the last entry, immunotherapy with PSK showed a borderline beneficial effect on remission duration (P=0.089) and on duration of survival (P=0.062). When the data were analyzed 12, 18, and 24 months after the last entry there were no significant differences in duration of remission and survival between the two groups. However, analysis of the data of patients who had maintained complete remission for more than 270 days revealed that immunotherapy had a suggestive beneficial effect (P=0.105), prolonging the 50% remission period by 418 days (885 vs 467 days). Thus, immunotherapy with PSK seems to be active in the treatment of adult ANLL when used for maintenance therapy in combination with chemotherapy, especially in patients with a good prognosis.     

Complete remission in a patient with acute myelogenous leukemia treated with leukocyte α-interferon and cimetidine

Summary A 76-year-old woman with acute myelogenous leukemia with approximately 65% myeloblasts on bone marrow examination was treated daily with a combination of 4 megaU of leukocyte interferon IM and 1,000 mg cimetidine PO. During therapy there was a gradual decrease of bone marrow myeloblasts down to 9% and a normalization of peripheral white blood cells. The treatment was discontinued after 6 weeks because of increasing fatigue and anorexia. The general condition improved greatly during the following weeks and the patient entered complete remission, which has continued for 6 months so far. In the course of therapy there was a gradual appearance of antibodies showing a selective binding capacity to autochthonous leukemic cells with no tendency to increased binding to remission cells. The aim of this report is to stimulate a further evaluation of this form of therapy in additional AML patients whenever this might be justified as an alternative to conventional chemotherapy.     

Immunotherapy of breast cancer,malignant melanoma,and acute leukemia with BCG: Prolongation of disease free interval and survival

Summary Results of immunotherapy with BCG in patients with malignant melanoma, breast cancer, and acute leukemia are described. The first study demonstrated that high doses of living BCG organisms (6×10⁸ viable units) delivered by scarification in the upper arms and legs prolonged the disease-free interval and survival of 52 malignant melanoma patients with regional lymph node metastases compared to 218 comparable surgical control patients. Patients with trunk and extremity, but not head and neck melanoma, benefited from BCG, suggesting the importance of the delivery of BCG into the tumor-involved lymphatics.The second study evaluated the therapeutic efficacy of living BCG organisms by scarification in a group of adult acute leukemia patients after the cessation of chemotherapy. Thirty-seven patients had been in remission on intermittent chemotherapy for 12–24 months. Following late intensive consolidation chemotherapy, 7 consecutive patients received no further therapy and then 30 consecutive patients received BCG. Patients maintained on BCG have had a prolonged disease-free interval compared to those given on no further therapy (P=0.07) or compared to a group of similar patients maintained on chemotherapy alone (P=0.001). Similarly, the survival has been improved for patients maintained on BCG compared to those left unmaintained (P=0.009), or those maintained on chemotherapy (P=0.001).The principles of intermittent chemotherapy combined with BCG immunotherapy, first developed in patients with disseminated melanoma and acute myelogenous leukemia, have been confirmed in a series of patients with disseminated breast cancer. Forty-five patients treated with a combination of 5-FU, adriamycin, and cyclophosphamide (FAC) plus BCG by scarification showed prolongation of remission as well as survival compared to a comparable group of 44 patients treated with FAC chemotherapy without immunotherapy. Thus, 23/44 patients treated with FAC have died (median=14 months) compared to only 5/45 patients on FAC-BCG (median=12⁺ months), P=0.005. The limitations of BCG immunotherapy as well as speculations for future developments of immunotherapy are discussed.This work was supported by Contract No1-CB 33888 from the National Institutes of Health, Public Health Service, Bethesda, Maryland 20014. Drs. Gutterman and Mavligit are the recipients of Career Development Awards (Ca 71007-02 and CA 00130-01, respectively) from the National Institutes of Health, Education, and Welfare, Bethesda, Maryland 20014.     

Various uses of BCG and allogeneic acute leukemia cells to treat patients with acute myelogenous leukemia

Summary Ninety-six remission patients with acute myelogenous leukemia have been treated with various forms of immunotherapy and chemotherapy in three distinct studies and the clinical outcome of these patients has been reported. In the first study 22 patients were maintained on chemotherapy alone and 28 patients were given the same chemotherapy and additional immunotherapy consisting of BCG and irradiated allogeneic AML cells given at separate sites weekly. It was found that there was a significant increase in survival time of the patients who received immunotherapy (median 510 days) compared with the chemotherapy alone patients (270 days). The p value for this was 0.03. The reason for this prolongation of survival was mainly due to a markedly increased survival time of immunotherapy patients after they relapsed when compared with the chemotherapy patients (165 days compared with 75 days median, p equal to 0.0005). In the second sequential study 24 patients were given immunotherapy alone consisting of irradiated allogeneic AML cells and BCG given at separate sites, and this was compared with unirradiated allogeneic cells and BCG given to 22 patients. There was no difference in the remission length or survival between these two groups. In the third study 13 patients received irradiated cells and BCG as in Study 1 and a further 11 patients received the same immunotherapy but also received a mixture of cells and BCG given during the first three months. There was no difference in the remission and survival of these two groups. The significance of these results is discussed.     

预激方案HAG及CAG治疗老年初治急性髓性白血病的对比研究

目的:评价含粒细胞集落刺激因子(granulocyte colony-stimulating-factor,G-CSF)的预激HAG及CAG方案治疗老年初治急性髓性白血病(AML)的疗效及不良反应,并对两个方案的疗效及不良反应进行比较。方法:65例老年初治AML分为HAG预激治疗组及CAG预激方案治疗组,31例患者予以HAG预激方案治疗,34例患者予以预激方案CAG方案治疗,所有患者在第1疗程后间歇14d左右进行第2个疗程。结果:HAG预激方案治疗组的完全缓解率为74.2%,总有效率为83.8%;CAG预激治疗组完全缓解(CR)率为67.6%,总有效率达为82.4%。两治疗组的血液系统不良反应及非血液系统毒性不良反应比较无显著性差异。结论:HAG预激方案化疗强度温和、敏感性好、CR率及有效率高、毒副作用小;与CAG预激治疗比较,HAG预激方案可以取的相似的疗效及较少的不良反应,在老年初治AML患者值得推荐应用。     

Management of Adult Acute Myelogenous Leukaemia

Consecutive adult patients admitted to St. Bartholomew''s Hospital with acute myelogenous leukaemia have been treated with a remission induction drug schedule consisting of daunorubicin and cytosine arabinoside. Intermittent five-day courses were used in 72 patients, and a complete remission was obtained in 39 patients (54%). An alternative drug schedule in 22 patients resulted in fewer remissions but this may have been due to age differences in the two groups. Age and initial platelet count were found to be important factors in determining the success of remission induction therapy; the older patients and those with low platelet counts responded less well.A series of 23 patients who achieved remissions was divided into two groups; one received intermittent combination chemotherapy as the only form of maintenance, and the other was given weekly immunotherapy in addition to the chemotherapy. The immunotherapy consisted of irradiated allogeneic leukaemic cells and B.C.G. Eight of the 10 patients on chemotherapy alone have already relapsed compared with five out of 13 patients in the immunotherapy group. It is hoped that these promising initial results with this form of maintenance will be confirmed as more patients enter the maintenance trials.     

Extramedullary Relapse of the AML Transformed from MDS Following Auto-HSCT: A Case Report

The treatment for AML (Acute myeloid/myelogenous leukemia) transformed from MDS (myelodysplastic syndrome) is difficult and controversial clinically, especially in elder patients. In this case report, we diagnosed a 59-year-old female patient with AML-M2a transformed form MDS which might be caused by her chemotherapy for mastocarcinoma. After achieving complete remission (CR) through combined chemotherapy, autologous peripheral blood stem cell transplantation (auto-PBSCT) was attempted. Following auto-HSCT, marrow showed continuous CR but the patient later developed extramedullary bone-infiltration relapse. Then local radiotherapy has been applied, and the patient now has prolonged survival. This is the first (or a successful) case report of auto-HSCT in an elderly patient with AML transformed from MDS.     

Late marrow recurrences in childhood acute lymphoblastic leukaemia.

Thirty children with acute lymphoblastic leukemia had a recurrence in the bone marrow after treatment was stopped electively. A second haematological remission was achieved in 27 (90%), and the median duration of remission was shortest (six months) in those relapsing within six months of stopping treatment. Four of six children relapsing over one year after stopping treatment remained in second haematological remission. Leukaemic infiltration of the central nervous system developed in four patients remaining in marrow remission. It is concluded that conventional chemotherapy is unlikely to be effective in children with acute lymphoblastic leukaemia who relapse soon after stopping treatment, that "reprophylaxis" of the central nervous system probably with long-term intrathecal chemotherapy is essential, and that some patients relapsing after prolonged unmaintained remission may achieve long-term leukaemia-free survival.     

An abnormal CD34+ myeloid/CD34+ lymphoid ratio at the end of chemotherapy predicts relapse in patients with acute myeloid leukemia.

During conventional follow-up of patients with acute myeloid leukemia (AML), the emergence of cytopenias is considered to be a sign of impending relapse, and it represents an example of how leukemic hematopoiesis affects normal hemopoietic differentiation. In the present study, we have explored the possible value of the analysis of the distribution of CD34+ myeloid and CD34+ lymphoid progenitor cells in follow-up complete remission bone marrow samples from de novo AML patients as a prognostic parameter for predicting relapse. A total of 213 bone marrow samples from 36 AML patients in morphological complete remission, obtained at the end of induction, consolidation, and intensification therapy and every six months thereafter were analyzed. The normal CD34+ myeloid/CD34+ lymphoid ratio ranged between 2.4 and 8.9. In contrast, in most AML cases an abnormally high ratio (> or =10) was observed at the end of induction and consolidation therapy: 96% and 75% of cases, respectively. On the other hand, at the end of intensification, 70% of the patients displayed a normal CD34+ ratio. Patients with a myeloid/lymphoid CD34+ ratio higher than 10 at the end of intensification showed a significantly lower overall survival (median survival of 19 months versus median not reached, P = 0.05), as well as a lower disease-free survival (median of 7 months versus 30 months, P = 0.0001). Regarding sequential studies, 67% of the relapses were preceded by the re-appearance of an abnormal CD34 ratio, whereas relapse was not predicted in four patient with leukemia classified as M3 undergoing maintenance therapy. From the remaining 18 patients who are still in continuous complete remission, all except 3 cases (17%) displayed a normal CD34 myeloid/lymphoid ratio. In summary, the present study shows that the persistence at the end of chemotherapy of an abnormally high (> or =10) ratio between CD34+ myeloid and CD34+ lymphoid progenitors in the bone marrow of AML patients is associated with high risk of relapse and a shorter overall survival.     

Immunoreactive calcitonin: a tumor marker for myelogenous leukemias

In a series of 59 patients with chronic or acute myelogenous leukemia (CML, AML) we investigated whether circulating immunoreactive human calcitonin (i-hCT) levels correlate with diagnosis, response to therapy and clinical course. I-hCT was detectable in plasma samples of 88% of patients with CML in the chronic phase and in 100% of patients with CML in blastic transformation. In the AML patients, a significant relation was observed between the cytological subtype and i-hCT levels at diagnosis. In sequentially studied patients the i-hCT plasma concentration was related to the overall mass of leukemic cells, being lower when complete remission was achieved than at diagnosis and increasing at time of recurrence. These data suggest that circulating i-hCT levels can serve as a "tumor marker" in human myelogenous leukemias.     

Therapy for acute myeloid leukemia in 119 adults: a comparison of two treatment protocols

Of 119 patients with acute myeloid leukemia, 69 were treated with Adriamycin, Vincristine and Cytosine Arabinoside (Therapy 1) and 50 with Daunorubicin, Cytosine Arabinoside and 6-Thioguanine (Therapy 2) as well as a consolidation therapy. The maintenance therapy with Cytosine Arabinoside and 6-Thioguanine was the same for both groups. The complete remission rate was 44% for Therapy 1 and 68% for Therapy 2 (p less than 0.05). - The median values for remission duration were 7 and 13 months respectively (p = 0.10); for survival time the median values were 18 and 19 months. These figures show in retrospect that high remission rates can be attained through intensive induction therapy and that longer remission duration is correlated with more aggressive induction therapy. A mild form of maintenance therapy seems to have little effect on the duration of complete remission.     

Quantitative cytology in leukemia research

A study was undertaken to determine the usefulness of flow cytometric analysis of bone marrow cells as an objective means for diagnosis, classification and prognosis in patients with leukemia. Abnormal DNA content as a marker of neoplastic disease was found in only 15% of 264 adult patients with acute leukemia (13% in AML, 26% in ALL/AUL). Alternative means of tumor cell detection in heterogeneous marrow samples include determination of nucleolar antigen density and double-stranded RNA content. Phenotypic characterization of leukemia subtypes can be afforded by RNA content analysis of acridine orange-stained cells, demonstrating significantly higher mean RNA content values in AML, compared to ALL/AUL. Cytokinetic parameters amenable to flow cytometric analysis include measurements of cell cycle compartment distribution by DNA content, of cycle traverse rate by BUdR-induced modification of fluorescence intensity of DNA specific dyes and of growth fraction employing the method of in situ DNA denaturation and subsequent acridine orange staining. Determination of cell cycle distribution and RNA content pretreatment and serially during remission induction in 82 patients demonstrated a significantly lower pretreatment biopsy S phase proportion in responding patients with AML compared to individuals failing treatment whereas an opposite trend was noted in patients with ALL/AUL. While of no prognostic impact pretreatment, serial determinations of the RNA content during the first chemotherapy induction course revealed significant differences between responding and failing patients with AML. Also, patients attaining remission demonstrated a rise in marrow biopsy S phase compartment size by day 10 to 14 of treatment, thus, predicting remission during marrow hypoplasia. We conclude that quantitative cytologic examination of marrow cells from patients with acute leukemia provides useful diagnostic and prognostic information that should aid in the stratification of patients with poor prognosis to receive new agents.     

Serial immunologic assessment during a randomized trial of chemoimmunotherapy in acute myelogenous leukemia

Summary Thirty-one adults who had acute myelogenous leukemia and in whom remission had been induced and consolidated with chemotherapy were randomized to receive one of three maintenance schedules: (A) BCG + chemotherapy [1, 3-bis-(2-chlorethyl)-1-nitrosourea (BCNU) and cytosine arabinoside]; (B) splenectomy, followed 1 week later with BCG and chemotherapy; or (C) allogeneic leukemic cells, BCG, and chemotherapy. Serial immunologic assessments were performed at the onset of maintenance and every 3 months.No differences were found in duration of remission (median 209 days) or survival (median 454 days) among the three schedules. Six patients remain in remission after from 2–4 + years. Skin test responses, mitogen responses, mixed lymphocyte culture responses, antibody responses, and T and B lymphocyte numbers were depressed at the onset of maintenance therapy. Therapy clearly improved the state of anergy as defined by recall antigen responsiveness, and induced in vivo and in vitro PPD reactivity. However, immunotherapy resulted in a reduction of the number of T or B cells and of the in vitro lymphocyte response to mitogens and allogeneic cells. Serum obtained at diagnosis and during remission inhibited in vitro blastogenic responses in more than half the patients. These data indicate that chemoimmunotherapy given as described tended to be more immunosuppressive than stimulatory.     

Stem cell transplantation in pediatric leukemia and myelodysplasia: state of the art and current challenges

The role of stem cell transplantation in the treatment of leukemia and myelodysplasia (MDS) in children has changed over the past decade. In pediatric acute lymphoblastic leukemia (ALL), the overall cure-rate is high with conventional chemotherapy. However, selected patients with a high-risk of relapse are often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission (CR1). Patients with a bone-marrow relapse who attain a second remission frequently receive HSCT. High minimal residual disease (MRD) levels directly prior to HSCT determines the relapse risk. Therefore, MRD positive patients are eligible for more experimental approaches such as intensified or experimental chemotherapy pre-HSCT, as well as immune modulation post-HSCT. In pediatric acute myeloid leukemia (AML) the role of allo-HSCT in CR1 is declining, due to better outcome with modern multi-agent chemotherapy. In relapsed AML patients, allo-HSCT still seems indispensable. Targeted therapy may change the role of HSCT, in particular in chronic myeloid leukemia, where the role of allografting is changing in the imatinib era. In MDS, patients are usually transplanted immediately without prior cytoreduction. New developments in HSCT, such as the role of alternative conditioning regimens, and innovative stem cell sources such as peripheral blood and cord blood, will also be addressed.     

The Management of Acute Leukemia

The therapy of acute leukemia has improved rapidly in the last two decades. Using available therapeutic agents, complete clinical and hematological remission can be achieved regularly in children with acute lymphocytic leukemia. The choice of chemotherapeutic agent, management of complications of hemorrhage and infection, and recognition of prognostic factors are important for the induction of a hematological remission. While patients in complete hematological remission are free of evidence of disease they still have residual leukemic cells, but in our present state of knowledge and with available techniques, we are unable to detect these. For this reason it is important to treat patients while in remission. The importance of dosage schedule for remission maintenance chemotherapy is stressed.In patients studied to date, regardless of the treatment used, the disease has recurred eventually. Available therapeutic agents are highly effective and highly selective, but they still fall short of providing ideal control of the disease. The continuing search for new chemotherapeutic agents is aided by the knowledge gained and techniques developed with current agents.     

Bacille Calmette-Guérin as maintenance therapy for non-Hodgkin's lymphoma.

Following complete remission of non-Hodgkin''s lymphoma by chemotherapy, irradiation or both, 44 patients were studied to assess the value of bacille Calmette-Guérin (BCG) as maintenance therapy. Patients with stage LI, EI or EII disease were allocated at random to receive BCG or no further maintenance therapy, and those with stage LII, LIII, EIII or IV disease received BCG therapy or orally administered cyclophosphamide. BCG had no effect on the duration of remission or the overall survival from the time of randomization. However, after the first recurrence there was a significant improvement in survival in the patients who had received BCG maintenance therapy.     

Adjuvant immunotherapy in acute nonlymphocytic leukemia

Summary Of 112 patients (maximum age 70 years) with acute nonlymphocytic leukemia, 62 (55%) went into remission on an induction therapy of cytosine arabinoside and daunorubicin. 20 patients were randomized for maintenance treatment consisting of chemotherapy only and 22 patients for combined chemo-immunotherapy. The chemotherapy consisted in 5-day courses of daunorubicin and cytosine arabinoside and of thioguanine and cytosine arabinoside, alternating every month. The chemo-immunotherapy group also received weekly intracutaneous injections of 10⁹ allogeneic nonirradiated leukemic myeloblasts and 10⁶ BCG organisms (Glaxo) by Heaf gun.The median duration of the first remission was 164 days for the chemotherapy group and 464 days for the chemo-immunotherapy group. The corresponding median times of survival were 344 days for the first group and 734 days for the second group. The difference concerning median duration of survival is statistically significant. Thus immunotherapy seems to prolong survival.