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Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a cancer and leukemia group B study.

Patients with acute nonlymphocytic leukemia were randomized to receive remission induction therapy consisting of seven days of cytosine arabinoside and three days of daunorubicin ("7 + 3") or to receive the same regimen intensified by either the addition of 6-thioguanine or by extension of the administration of cytosine arabinoside to ten days. Additionally, all patients were randomized to receive or not to receive cotrimoxazole antibacterial prophylaxis during the remission induction phase. Neither an increase in intensity of chemotherapy nor the antibacterial prophylaxis increased the remission rate above the 53% for patients treated with the standard "7 + 3" regimen. The second part of this study addressed the issue of the utility of long-term maintenance chemotherapy. To this end, patients were randomized to discontinue all treatment after 8 months of maintenance chemotherapy or to continue maintenance therapy for a total of 3 years. Although there was a transient increase in the relapse rate for patients who discontinued therapy, the proportion of long-term remitters was identical in the two patient groups. Additionally, there is a suggestion of a survival advantage for patients randomized to discontinue all therapy at 8 months.

Acute Disease↗

Nutrition and acute leukemia in adults: relation between nutritional status and infectious complications during remission induction.

BACKGROUND: The purpose of this study was to determine whether nutritional state was related to infectious complications in adult patients with acute leukemia. METHODS: During first-remission induction therapy (mean, 71 days), the duration of neutropenia, various infections, and fevers were related to changes in body weight and serum albumin concentrations as well as total parenteral nutrition (TPN) in 52 patients receiving standardized anti-infectious treatment. RESULTS: Severe neutropenia prevailed for 27% and fever for 28% of the induction period. A mean weight loss of 5.1 kg, corresponding to a reduction of body mass index from 23.5 to 21.7, was correlated with the number of days that patients had fever (P = 0.026). Despite a normal serum albumin value at the time of admission, patients had severe hypoalbuminemia (<25 g/L) during 16% of the induction period. The drop in serum albumin was independently related to the weight loss (r = 0.37, P = 0.03). Moreover, the incidence and duration of hypoalbuminemia were significantly correlated with duration of fever (P < 0.0001), diarrhea (P = 0.03), and TPN administration (P = 0.00002). CONCLUSIONS: Weight loss and severe hypoalbuminemia were common during remission induction for these adult patients with acute leukemia and were closely related to the patients' infections.

Adolescent↗

Sequential combination chemotherapy and surgery for disseminated testicular cancer: cis-dichlorodiammineplatinum(II), vinblastine, and bleomycin remission-induction therapy followed by cyclophosphamide and adriamycin.

A multimodality treatment program for disseminated testicular cancer using vinblastine/bleomycin/cis-dichlorodiammineplatinum(II) remission-induction therapy followed by surgery and cyclophosphamide/Adriamycin maintenance therapy has been used in 25 patients. The overall complete and partial response rate was 100%. Six of six patients (100%) with stage II (advanced abdominal) disease have remained in complete remission for a median followup period of 8 months. Seventeen of 19 patients (89%) with stage III metastatic disease have been in complete remission for a median duration of 20 months. No relapses have occurred in any patients who achieved a complete remission. Two of 19 patients (11%) with stage III disease achieved a partial response; one died at 4 months and the other died at 14 months. The toxicity was severe, especially during remission induction. However, there were no drug- or surgically related deaths.

Antineoplastic Agents↗

A characteristic pattern of leukemic cell differentiation without cytoreduction during remission induction in acute promyelocytic leukemia.

While differentiation of leukemic cells in vitro is well established, the role of differentiation in vivo is not defined and is generally attributed to differentiation inducers. In five patients with acute promyelocytic leukemia (APL) an unusual pattern of a slow and progressive decrease of immature blasts with a concomitant increase in mature cellular elements was observed following intensive combination chemotherapy. All patients eventually achieved complete remission, four of them without an intermediate phase of marrow hypoplasia. This morphologic pattern of response suggests that leukemic cellular differentiation rather than cytotoxicity was one mechanism involved in remission induction. Cytogenetic studies of remission revealed disappearance of the cytogenetic marker, the balanced translocation between the long arms of chromosomes 15 and 17. This remission induction process appears to be due to the cellular biologic characteristic rather than the therapy used as it occurs in a substantial proportion of patients with APL. It should be considered for optimal diagnostic and therapeutic decisions.

Acute Disease↗

Remission induction of acute promyelocytic leukemia by all-trans-retinoic acid: molecular evidence of restoration of normal hematopoiesis after differentiation and subsequent extinction of leukemic clone.

Sequential molecular and cellular changes during remission induction were investigated in a case of acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA). By means of clonality analysis, the assessment of the retinoic acid receptor alpha gene alterations, as well as conventional cytologic studies, it was demonstrated that remission induction of APL by ATRA proceeds in two steps: first, the differentiation of the leukemic clone to mature granulocytes and its subsequent extinction; second, proliferation/differentiation of the residual normal clones to restore polyclonal hematopoiesis.

Adult↗

Long-term follow-up of hemostatic molecular markers during remission induction therapy with all-trans retinoic acid for acute promyelocytic leukemia. Keio Hematology-Oncology Cooperative Study Group (KHOCS).

Hemostatic molecular markers were serially monitored in a prospective fashion during remission induction therapy with all-trans retinoic acid (ATRA) in sixteen patients with acute promyelocytic leukemia (APL). One patient with leukocytosis before treatment and three patients who later developed hyperleukocytosis also received chemotherapy with behenoyl Ara-C and daunorubicin. Plasma levels of E-fragment of fibrin and fibrinogen degradation product (FDP-E), FDP-D dimer (D-D), thrombin-antithrombin complex (TAT), and plasmin-alpha 2 plasmin inhibitor complex (PIC) were markedly elevated in all but one patient before treatment, and these parameters decreased to normal or near normal ranges in most patients within the first 7 days of treatment. Interestingly, we have found that these parameters were again elevated during the later course of ATRA therapy (after day +7) in eleven patients for various reasons including cytotoxic chemotherapy (3 cases), fever (5 cases; 2 cases with apparent infection, 3 cases without known etiology), Caesarean section (1 case), and no apparent etiology (2 cases). Three patients showed bleeding complications during re-elevation of molecular markers, but none developed thrombosis. Plasma elastase-alpha 1 proteinase inhibitor complex (E-alpha 1 PI) was markedly elevated in all patients at diagnosis and did not decrease significantly during ATRA therapy. Plasma tissue factor antigen was mildly elevated in one out of four patients studied, and thrombomodulin was elevated in two out of ten patients tested. These results confirmed the rapid normalization of coagulopathy during the early phase of remission induction therapy with ATRA but suggest that re-elevation of molecular markers occurs frequently during the later course of ATRA therapy.

Adolescent↗

Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia.

We determined the prognostic importance of morphologically identifiable persistent disease at day 15 and days 22 to 25 of remission induction in childhood acute lymphoblastic leukemia (ALL). Among 546 patients entered on 2 consecutive protocols, 397 patients had evaluable bone marrow (BM) examinations on day 15 (+/- 1 day) and 218 on days 22 to 25 (+/- 1 day). Fifty-seven patients (14%) had persistent lymphoblasts (> or = 1%) in the BM on day 15 and 27 patients (5.5%) had persistent lymphoblasts on days 22 to 25. The 5-year event-free survival (EFS) was significantly worse for patients with lymphoblasts on day 15 (40% +/- 6%) or on days 22 to 25 (4% +/- 3%) as compared to those without lymphoblasts on these dates (78% +/- 2% and 76% +/- 2%, respectively, P <.001 for both comparisons). A worse prognosis was observed even for patients with a low percentage of lymphoblasts (ie, 1%-4%) at either day 15 (5-year EFS = 56% +/- 8%) or days 22 to 25 (5-year EFS = 0%) compared to those without morphologically identifiable persistent lymphoblasts at these times (P <.001 for both comparisons). The prognostic impact of persistent lymphoblasts on both dates remained significant after adjusting for other known risk factors, including treatment protocol, age, white blood cell count, DNA index, cell lineage, and central nervous system status, and National Cancer Institute/Rome criteria simultaneously. Hence, persistence of lymphoblasts (even 1%-4%) on day 15 of remission induction was associated with a poor prognosis and on days 22 to 25 signified a particularly dismal outcome; these very high-risk patients require novel or more intensive therapy to improve outcome.

Blast Crisis↗

Chemoimmunotherapy versus chemotherapy for remission induction in patients with non-Hodgkin's lymphoma: progress report of a Southwest Oncology Group study.

The Southwestern Oncology Group is conducting a controlled clinical trial for patients with all types of advanced non-Hodgkin's lymphoma in which chemoimmunotherapy (CHOP + BCG) is being compared with chemotherapy alone (CHOP + bleomycin or COP + bleomycin) for remission induction. Patients achieving a complete remission confirmed by systematic restaging are then randomly assigned to maintenance BCG or to no further therapy. As of April, 1977, 669 patients had been registered on this trial and 420 were fully evaluable. No significant differences in response rates between the three remission induction regimens are apparent. After restaging, early relapses have occurred with equal frequency in the BCG and no-further-therapy groups. Longer follow-up and further analysis will be required to fully evaluate the potential effects of BCG on remission duration or survival in this study.

Antineoplastic Agents↗

Nephrotoxicity of cis-diamminedichloride platinum (CDDP) during remission-induction and maintenance chemotherapy of testicular carcinoma.

We studied renal function in nine patients with disseminated testicular carcinoma before and after remission-induction and maintenance therapy with a drug combination containing cis-platinum. The median glomerular filtration rate (GFR) decreased during remission-induction therapy from 146 to 118 ml/min. No effect of cumulative toxicity on the median GFR was found during maintenance therapy, nor did the median GFR improve. The median effective renal plasma flow (ERPF) decreased during the total period from 705 to 514 ml/min. No significant changes in median filtration fraction (FF) and serum creatinine were observed. It is suggested that intrarenal hemodynamic effects are important in the nephrotoxicity of cis-diamminedichloride platinum (CDDP).

Adult↗

Causes of initial remission induction failure in patients with acute myeloid leukemia and myelodysplastic syndromes.

We analyzed 144 of 475 previously untreated patients with acute myeloid leukemia (AML, n = 87) and 'high-risk' myelodysplastic syndromes (MDS, n = 57) who failed to achieve a complete remission with fludarabine- and high-dose cytarabine-containing regimens between 1991 and 1994. The AML and MDS groups were comparable with regard to age, major prognostic indicators, supportive care received, type of antileukemia response and causes of death and were considered together. The causes of death of 118 evaluable patients were compared to a series of 123 AML initial remission induction failures previously reported from our institution. The induction failure rate was significantly lower (30 vs 43% P <0.001). We found a significant decrease in fatal infections (autopsied patients, P = 0.001) and a reduction in bacterial (autopsied and non-autopsied patients, P <0.005) but not fungal (non-autopsied patients, P = 0.93; autopsied patients P = 0.15) infections as causes of induction death. Pulmonary hemorrhage was twice as common in the present report (P < 0.005, with pulmonary hemorrhage almost three times as common as fatal cerebral hemorrhage. A comparison restricted to the AML patients in the present study yielded similar results. We conclude that the mortality profile in AML remission induction has undergone substantial changes at our institution since our last report, probably as a consequence of the introduction of new chemotherapy regimens and supportive care modalities.

Acute Disease↗

Infectious complications during remission induction therapy in 577 patients with acute myeloid leukemia in the Japan Adult Leukemia Study Group studies between 1987 and 1991.

The Japan Adult Leukemia Study Group analyzed infectious episodes in 577 patients with acute myeloid leukemia during remission induction therapy between 1987 and 1991. 542 patients (93.9%) experienced at least one infectious episode, 121 (21.0%) had microbiologically documented infection; there was clinically documented infection in 184 (31.9%) and unexplained fever in 237 (41.1%). Among 121 microbiologically documented infections, bacteremia/fungemia was observed in 68, pneumonia in 33, and other types of infections in 20. Among the bacteremia/fungemia, gram-negative bacteria accounted for 41.2% (Pseudomonas aeruginosa was the most common), gram-positive bacteria for 39.7%, fungi for 16.2% (Candida spp. being most frequent), and polymicrobial for 2.9%. The most frequent isolates among pneumonia were Pseudomonas aeruginosa and Aspergillus. A total of 70 patients (12.1%) died during remission induction. Mortality of 68 patients with bacteremia/fungemia was 26.5%; in these patients, mortality with concomitant pneumonia increased to 41.4%; without pneumonia, mortality was 15.4% (P < 0.05). Mortality according to the isolated microbes was 17.2% for gram-negative bacteria, 25% for gram-positive bacteria, and 54.5% for fungi. Mortality of 113 patients with pneumonia (33 microbiologically documented and 80 clinically documented), 20 with other microbiologically documented infections, 104 with other clinically documented infections, and 237 with unexplained fever was 25.7%, 5.0%, 5.8%, and 5.1%, respectively.

Acute Disease↗

Cooperative randomized studies on the treatment of adult acute leukemia in Poland. A comparison of two remission induction regimes and two maintenance regimes for AML.

In a prospective study 100 AML cases were randomized in two groups and underwent remission induction treatment in 4 departments with "Ara-C c. inf. from the first to the eight day plus Adr. from the first to the third day" or "Ara-C + 6-TG + Adr., 6 + 6 + 2 days". The CR patients were divided into two subgroups. Subgroup A obtained maintenance therapy with 5 day course of Ara-C s.c. in addition to 6-TG, Vincristine plus Prednisone and Adriamycin sequentially, with each cycle repeated at 6 week intervals. Subgroup B obtained the calf thymus extract (TFX-Polfa) between the cycles additionally. The current results of remission induction treatment are similar to "8 + 3" and "6 + 6" regimens as measured by the CR rate (45% and 44%), survival curves (survival after 24 months - 23% and 28% respectively) and relapse rates (3.5%/pt.mo.obs. and 5.3%/pt.mo.obs.). It is still too early to evaluate the efficacy of this maintenance treatment, because the programme is still open to patient entries. At present 13 patients received maintenance regimen A and 12 patients received maintenance regimen B, with an average survival being equal to 14 and 13.5 months respectively.

Adult↗

Quantitative expression of proliferating cell nuclear antigen by western blot (PCNAWB) in peripheral blasts correlates with remission induction in patients with acute myelogenous leukemia.

Proliferating cell nuclear antigen (PCNA) is a 36-kD nuclear protein that functions as a cofactor of delta DNA polymerase which is regulated in a cell cycle-dependent fashion. PCNA expression also increases when cells are actively engaged in DNA repair. We used Western blotting (WB) to measure the level of expression of PCNA in peripheral blasts of 36 adult acute myelogenous leukemia (AML) patients treated with Ara-C based induction regimens. PCNA levels correlated positively with the percentage of cells in S+G2M of the cell cycle. Logistic regression analysis revealed PCNA (beta = 4.5162; p = 0.0260) together with age (beta = 0.1777; p = 0.0364) as independent variables for remission induction: high PCNA levels were associated with poor response to induction therapy. PCNA expression was not, however, a predictor of survival in this subset of patients. We conclude that PCNA levels in this disease may be important for predicting response to Ara-C based remission induction chemotherapy.

Adult↗

Fludarabine, arabinosyl cytosine and idarubicin (FLAI) for remission induction in poor-risk acute myeloid leukemia.

Progress in treatment of acute myeloid leukemia (AML) is slow and treatment intensification alone has limited effects, particularly in poor-risk cases. Poor-risk cases, that are identified mainly by prior history, leukemic cell mass and cytogenetic abnormalities, share multiple mechanisms of drug resistance that are responsible for treatment failure. Since Pgp-mediated resistance to anthracycline can be reduced with Idarubicin (IDA) and resistance to arabinosyl cytosine (AC) can be reduced with Fludarabine (FLUDA), we tested a combination of high dose AC (2000 mg/sqm, 5 doses), FLUDA (30 mg/sqm, 5 doses) and IDA (12 mg/sqm, 3 doses) for remission induction and consolidation in 45 consecutive cases of poor-risk AML. The complete remission (CR) rate was 71% after the first course and 82% overall, with a projected 2-year survival and relapse-free survival of 44% and 50% respectively. Non-hematologic toxicity was very mild, that is very important in elderly patients, but hemopoietic toxicity was substantial, with a time to hematologic recovery of 3 to 4 weeks and two cases of death in CR. Peripheral blood stem cells (PBSC) could be mobilized and collected successfully only in 11 cases. This three-drug combination is effective and has a limited non-hematologic toxicity, but FLUDA may increase the difficulty of obtaining PBSC early after remission induction.

Acute Disease↗

Monitoring the remission induction therapy of acute nonlymphoblastic leukemia by bone marrow cell culture criteria.

In 31 cases of acute nonlymphoblastic leukemia, bone marrow cells were serially cultured in semi-solid agar during the remission induction therapy. A normal in vitro cell growth pattern returned in 15 out of 22 patients up to 77 days before a complete remission was established by clinical and hematological criteria. In 6 cases the return of normal colonies coincided with clinical and hematological evidence of a complete remission. Nine patients failed to attain a remission and died from complications of bone marrow aplasia. Only one had a normal number of colonies and a normal cluster/colony ratio in cultures prepared 11 days after the completion of the first course of chemotherapy. At this time, his platelet count increased to normal level, possibly indicating a developing remission. Bone marrow cell culture criteria are useful in monitoring the remission induction therapy in patients with acute nonlymphoblastic leukemia. An early return of normal in vitro cell growth pattern suggests an approaching remission, which may be achieved several weeks later.

Acute Disease↗

[Superior sagittal sinus thrombosis during remission induction therapy for acute lymphoblastic leukemia].

Superior sagittal sinus thrombosis (SSST) has been reported to be caused by coagulopathy following oral contraceptive therapy, DIC, infection around the sinus, compression from a tumor, infiltration of tumor, and an inherited deficiency of proteins C and S, but SSST associated with hematological malignancies and L-asparaginase (L-Asp) therapy is rare. We report a case of an adult patient with acute lymphoblastic leukemia (ALL) who developed SSST during the remission induction therapy. A 25-year-old man was admitted with left facial nerve palsy and, following bone marrow aspiration and lumbar puncture, he was diagnosed as having T-ALL with CNS involvement. He received a 1-AdVP regimen as remission induction therapy and intrathecal administration of methotrexate and cytarabine. On day 29, he had a generalized convulsion and SSST was demonstrated by imaging tests. Lymphoid malignancy (ALL in particular), the use of L-Asp, CNS involvement, and intrathecal chemotherapy might be risk factors for the occurrence SSST. When a patient with those factors develops any neurological symptoms, we should pay attention to the occurrence of SSST, as well as stroke or CNS involvement, though SSST is rare.

Adult↗

Thrombotic events are not exclusive to the remission induction period in patients with acute lymphoblastic leukemia: a report of two cases of cerebral sinus thrombosis.

It is well established that in acute lymphoblastic leukemia (ALL) patients L-asparaginase (L-Ase) provokes thrombotic events reducing coagulation inhibitors in both adults and children. A tight correlation between thrombotic and hemorrhagic complications and ALL has also been hypothesized because of the high incidence of disseminated intravascular coagulation (DIC) found during the early period of chemotherapeutic treatment apart from L-Ase. All the authors reporting on this subject, however, consider the remission induction phase of treatment the most risky, if not exclusive, for the development of a thrombotic event, in particular if it includes the administration of L-Ase. We report here two cases of ALL patients who experienced a cerebral sinus thrombosis in a later phase of treatment, demonstrating that the thrombotic risk is surely exacerbated by chemotherapy but is not exclusive to the remission induction period.

Adult↗

[Efficacy of combination with granisetron and methylprednisolone for nausea, vomiting and appetite loss in remission induction chemotherapy of acute myeloid leukemia--a randomized comparative trial between granisetron alone and granisetron plus methylprednisolone].

The prevention of nausea, vomiting and appetite loss induced by remission induction chemotherapy for acute myeloid leukemia was compared by randomization between granisetron alone and combination with granisetron plus methylprednisolone. Granisetron was administered at 40 micrograms/kg during chemotherapy, and methylprednisolone was administered concomitantly at 125 mg/body for 3 days or more in the combination group. The single and combination groups comprised 14 and 13 patients, respectively, and there was no significant difference between the background of both groups. To evaluate the effect they were scored according to 4 grades, and evaluated every 24 hours from the start of chemotherapy to 5 days after its completion. The complete inhibition rate of vomiting was as high as 71.4% and 92.3% in the single and combination groups, respectively, showing no significant difference. The grade of vomiting was mild in both groups. Nausea was noted in 71.4% and 46.2%, respectively, and the inhibitory effect tended to be higher in the combination group. Appetite loss developed in 92.9% and 41.7%, respectively, and the prevention effect was clearly higher in the combination group. The prevention effects on nausea 7, 8 and 10 days after the start of chemotherapy, on appetite loss 2-10 days after it, and 2-5 days after its completion, were higher in the combination group. Granisetron revealed an excellent inhibitory effect on vomiting induced by remission induction chemotherapy for acute myeloid leukemia, but combination with granisetron and methylprednisolone was considered useful for nausea in the latter half of the treatment period and for appetite loss during the whole period.

Acute Disease↗