Methods for evaluating response to treatment in adult acute leukemia

The criteria for evaluating response to treatment for patients with adult acute leukemia are objective, quantitative, and effective. The first objective of treatment is to achieve a complete clinical and hematological remission, since in the absence of such response the disease has a rapidly progressive and inevitably fatal outcome. Logistic regression analysis and the generation of models for predicting the probability of response for each patient have proven to be extremely useful techniques for evaluating new candidates for front-line treatment in acute leukemia. In prospective tests, such modeling procedures have proven to predict accurately for response. It is evident that this methodology will be highly effective for selecting treatment for individual patients and for detecting improved treatments for patients who respond poorly to conventional treatment. For patients who achieve complete remission, the duration of that remission can also be evaluated by logistic regression analysis. Variables which predict for duration of remission have proven to be different from those variables which predict for probability of response. In addition, variables which predict for prolonged remission--that is, beyond 2 and 3 years--have proven to be different from variables which predict for relapse in the first year of remission. Therefore, the models which estimate risk of relapse per unit of time at risk should prove most valuable for evaluating not only the choice of treatments to be used during remission, but the duration of treatment and the strategy of treatment, that is, whether intensive treatment or low-dose intermittent treatment should be chosen. Finally, the demonstration that a significant fraction of the patients in complete remission will have long term disease-free and treatment-free survival makes the identification of such patients even more important. Evaluation of innovative higher-risk strategies for treatment of the patient in remission should be offered primarily to patients who have a low probability of having already been cured with conventional treatment. Thus, the rapid evolution of effective treatment for adult acute leukemia over the last 15 years has necessitated the development of more precise and more effective methods for evaluating the effects of those treatments on patients with this disease.     

Strategy for antithyroid drug therapy in Graves' disease

A critical review of the literature concerning the treatment of patients with Graves' disease discusses the multitude of protocols used. Prospective studies of patients treated with carbimazole alone for a predetermined duration reveal that the remission rate after 6 years' follow-up is between 40 and 50%. The incidence of treatment duration on remission rates is discussed: the authors think that long-term treatments give better results than short-term treatments. Nevertheless, no standard duration for treatment can be indicated and the most appropriate attitude is an adaptation to each individual case. Various criteria which could modify the prognosis are discussed: small goiter size and normalization of early iodine uptake improve the prognosis. While better results were obtained after high doses of carbimazole in a preliminary work, further study is necessary to clarify this point.     

Intermittent treatment of duodenal ulcer with cimetidine.

Intermittent treatment with short courses of cimetidine given only when symptoms recurred was assessed in patients with duodenal ulcer as an alternative to maintenance treatment. Their progress was followed up for up to 22 months. Gastroscopy was carried out in most attacks to confirm recurrence of the ulcer and subsequent healing. Out of 125 patients treated, 83 relapsed, of whom 21 defaulted. After retreatment 36 patients relapsed again. The pattern of relapse and remission for the group as a whole was similar after both courses of treatment, indicating an unchanged natural history. Nevertheless, wide variation occurred in individual patients, so that the pattern of relapse could not be predicted by the duration of the initial remission. Most patients had one or two or rarely three symptomatic relapses a year, which were rapidly treated successfully with cimetidine. Therefore, unless the necessity for long-term maintenance treatment is established, intermittent treatment provides an adequate alternative in most patients with duodenal ulcer.     

Prophylactic effect of cimetidine in duodenal ulcer disease.

Fifty-seven symptom-free patients with duodenal ulcer entered a double-blind trial to assess the prophylactic effect of cimetidine. Patients were randomly allocated to receive cimetidine 400 mg twice daily (29 patients) or placebo (28 patients). The trial was designed to imitate daily clinical practice, so duodenal ulcer disease was diagnosed by means of x-ray examination. Three patients from each group withdrew from the trial. All remaining patients continued to receive treatment for 12 months or until symptoms recurred. Three out of 26 patients suffered relapses during cimetidine treatment, compared with 20 out of 25 receiving placebo. No side effects were attributable to cimetidine. Long-term cimetidine treatment had no curative effect as relapses occurred soon after treatment was stopped. The estimated chance (cumulative remission rate +/- 2 SE) of remaining symptom-free 13 weeks after one year''s cimetidine treatment had been completed was 47 +/- 21%. Maintenance treatment with cimetidine is a suitable alternative to elective in surgery in patients with duodenal ulcer subjects frequent relapses. Further study is needed to establish the optimal duration and safety of prolonged cimetidine treatment.     

Bone marrow transplantation in childhood leukaemia--experience and strategies in the Federal Republic of Germany

BMT has gained its place in the treatment of childhood leukaemia. Nevertheless, there are still many questions open. In acute lymphoblastic leukaemia children should normally be grafted in 2nd remission (CR). Some high risk cases, however, should probably be grafted in 1st CR. It is not clear whether children with late relapses benefit more from BMT than from renewed chemotherapy. Children with a relapse during maintenance therapy, however, have a better survival rate with BMT. In acute nonlymphoblastic leukaemia certain high risk patients should be grafted in 1st CR but it has still to be shown that BMT is superior to chemotherapy in such cases. It is not clear whether children with a relapse following intensive chemotherapy (such as the BFM-protocols) will benefit from BMT at all. In chronic myelocytic leukaemia, BMT in chronic phase should be performed. Thus, for the first time cure has become possible for this disease. Waiting for acceleration or even the occurrence of a blast crisis decreases the chance of survival after BMT dramatically. Since complications of BMT such as graft-versus-host reaction or severe infections are less frequent in children, relapses remain the main problem after BMT in childhood leukaemia.     

Medical cost of curing childhood acute lymphoblastic leukaemia

Between 1970 and 1979 acute lymphoblastic leukaemia was diagnosed in 378 children at this hospital. The outcome for the 181 survivors was examined six or more years after diagnosis to assess morbidity in an unselected group of long term survivors. One hundred and thirty seven of the survivors were in first remission and probably cured (group I). Forty four (group II) had had one or more relapses, some of whom, who had isolated extramedullary relapses, also have a good chance of cure.In group I 136 patients had prophylactic cranial or craniospinal irradiation, while patients in group II, in addition to having that treatment, received local testicular (17) or craniospinal radiation (seven) for testicular or central nervous system relapse. Eight had additional prophylactic cranial radiotherapy after bone marrow relapse, and six had total body irradiation before bone marrow transplantation. The incidence of clinically important growth and endocrine morbidity was 20% in group I and 68% in group II. The morbidity in patients in group I was mainly attributable to early pubertal maturation. In group II 30 patients had growth failure, of whom 19 had gonadal failure from testicular or total body irradiation, 14 had growth hormone deficiency after doses of cranial irradiation of over 2400 cGy, and 10 had spinal growth impairment after craniospinal irradiation. Two also had early pubertal maturation. Five out of six patients who received total body irradiation had multiple endocrine deficiency. Neuropsychological sequelae of treatment were seen in 40 (42%) of 96 schoolchildren in group I and in 12 (38%) of 32 schoolchildren in group II. Postinfective sequelae of treatment were found in patients in both groups.These results show that the survivors who were in their first remission had a 42% residual morbidity related to treatment compared with an 82% morbidity in the survivors of one or more relapses who had multiple treatments.     

Restoration of the immune balance by autologous bone marrow transplantation in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is one of the most frequent autoimmune diseases in childhood and is characterized by chronic inflammation of the synovial fluid in joints. Several drugs are available for the treatment of JIA, including various biological agents that interfere with critical cytokine pathways. Though very effective in suppressing disease activity, none of these drugs can cure the disease and induce a lasting medication free remission. A small proportion of JIA patients will become or are unresponsive to any form of medical treatment. For these severely ill patients autologous bone marrow transplantation (aBMT) is a last resort treatment. aBMT is remarkably effective in suppressing disease activity, with beneficial outcome reported in around 70% of these previously refractory patients. Moreover aBMT is the only treatment that can induce a lasting medication-free-disease remission in these patients. In the very long term (after 7 years of remission) however, some disease relapses are observed, with the disease returning in a less severe form compared to prior aBMT. The exact mechanism of how aBMT is inducing this lasting disease remission is still largely unknown, but data from both animal models and humans suggest a prominent role for regulatory T cells. In this review we reviewed the current views of the cellular mechanisms that lay beneath disease induction of JIA and the disease remission caused by aBMT therapy.     

Treatment with interferon alpha prior to discontinuation of imatinib in patients with chronic myeloid leukemia

Imatinib (IM) is the current first line treatment for chronic myeloid leukemia (CML). However, the disease will progress in the majority of patients pausing IM. IFN-α may intensify the response and increase the percentage of patients maintaining remission after IM cessation. Eleven patients with stable (≥ 2 years) complete cytogenetic responses (CCyR) on IM therapy were recruited to the study. They were administered Peg-IFN-α for 9 months before and for 3 months following IM discontinuation. During the 12 months of Peg-IFN-α therapy the remission status improved in five (45%) of the patients. Six (55%) of the patients experienced cytogenetic relapses at a median period of 8 months (range 2-33) after IM withdrawal. All six patients regained CCyR following IM restart. With a median follow up of 47 months (range 35-50), five (45%) out of the 11 studied patients maintain cytogenetic response off IM therapy. The role of Peg-IFN-α in patients pausing IM is to be further evaluated.     

Experiences with the Ommaya reservoir for prophylaxis and treatment of the central nervous system in adult acute myelocytic leukemia

Intraventricular chemotherapy was administered to adult AML patients via an Ommaya reservoir. Twenty-eight patients received central nervous system (CNS) prophylaxis and seven patients were treated for meningeal leukemia (ML). A treatment course lasted at least 6 months. Asymptomatic ML developed in two patients (7%) of the prophylaxis group concomitantly with bone marrow relapse. One of these patients had not completed the standard course. CNS remission could be obtained in all evaluable patients with ML. The easy entrance to the cerebrospinal fluid (CSF) offers the advantage of frequent investigations of the CSF, early diagnosis and treatment of CNS relapses without radiotherapy, and caused little patient discomfort. CNS prophylaxis in this small study seemed to prolong first remission duration slightly. In M4 and M5 subtypes CNS prophylaxis can be valuable.     

Management of Ontario children with acute lymphoblastic leukemia by the Dana-Farber Cancer Institute protocols.

There is ample evidence of the value of intensive therapeutic strategies in the management of acute lymphoblastic leukemia (ALL), the commonest form of malignant disease in children. Such a program, devised at the Dana-Farber Cancer Institute (DFCI), Boston, and incorporating high-dose L-asparaginase, was adopted in 1984 by the Children''s Hospital at Chedoke-McMaster, Hamilton, Ont., and the Children''s Hospital of Western Ontario, London. We describe the experience of these institutions in the treatment of 82 children with ALL, 19 of whom were switched to the DFCI protocols while in continuing first remission with other treatment programs to complete a minimum of 2 years of maintenance therapy; the remaining 63 children, who had recently diagnosed disease, were consecutively enrolled in the DFCI protocols. Each child was assigned at diagnosis to a category of risk for relapse and treated accordingly. There were no remission induction failures or deaths due to induction therapy among the patients with newly diagnosed disease. There were no differences in total or event-free survival rates between the patients in Hamilton and those in London or between those whose protocols were switched and those who were treated from the beginning with the DFCI protocols. With a median follow-up interval of 144 weeks the total survival rate was 95% and the event-free survival rate 88%. For patients at standard risk of relapse the event-free survival rate was 100%, for those at high risk the rate was 82%, and for those at very high risk the rate was 67%. If infants (all of whom suffered a relapse) are excluded from the last category the rate was 89%. These results were achieved with moderate toxic effects (except for two deaths, one of which was due to a therapeutic misadventure) and suggest that the prospect for cure in children with ALL. may now approximate 80%, a degree of success that demands that consideration be given to reducing total therapy, at least for children with standard-risk disease. Further follow-up will determine whether these high event-free survival rates will stabilize and meet the criteria for cure.     

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.     

Commentary: assessing the effects of environmental pollution when people know that they have been exposed.

OBJECTIVE: To examine the effectiveness of routine clinic review in detecting relapse after treatment for Hodgkin''s disease. DESIGN: Review of hospital records. SETTING: Regional centre for cancer treatment and research. SUBJECTS: 210 patients with Hodgkin''s disease recruited to a chemotherapy trial protocol between 1984 and the end of 1990 who had achieved a complete or partial remission after treatment. MAIN OUTCOME MEASURES: The number of clinic visits made by patients over the period of observation, the number of relapses occurring during that time, and the route by which relapse was detected. RESULTS: The 210 patients generated 2512 outpatient reviews, and 37 relapses were detected. Thirty relapses (81%) were diagnosed in patients who described symptoms, which in 15 cases had resulted in an earlier appointment being arranged. In only four cases (11%; 95% confidence interval 4% to 25%) was relapse detected as a result of routine physical examination on investigation of a patient who did not have symptoms. CONCLUSIONS: Relapse of Hodgkin''s disease after treatment is usually detected as a result of the investigation of symptoms rather than by routine screening of asymptomatic patients. It is therefore proposed that the frequency of routine follow up visits should be reduced and greater emphasis placed on patient education. This should underline the importance of symptoms and encourage patients to arrange an earlier appointment if these develop.     

1975 current results of the first 100 cytologically typed acute lymphoid leukemia submitted to BCG active immunotherapy

Summary The first 100 acute lymphoid (and undifferentiated) leukemias, (of which the smears at the first presentation of the disease are still available for typing), treated successively with remission induction chemotherapy, complementary cell-reducing chemoradiotherapy and then active immunotherapy with irradiated pooled allogeneic leukemic cells and fresh Pasteur Institute BCG applied on scarifications, have been reviewed, especially in connection with BCG application.Tolerance of BCG has been good. Its application had to be stopped due to a side effect (choroiditis) in only one patient. This toxic cost is negligible compared to that of so-called maintenance chemotherapy.No subject of our first control trial started in 1963 has relapsed between 3 and 13 years.In the overall group of the 100 patients studied, no relapse has been observed after 48 months, which is quite different to the observations of frequent relapses after that time in patients submitted to maintenance chemotherapy.Moreover, second remissions are obtained in 94% of the patients who relapsed early under immunotherapy, and their life expectancy after a second remission is as high as it is after the first remission.The median of survival is longer than 5 years.The action of active immunotherapy on the immune machinery has been followed by several assays, of which the increase of null cells (which include K-cells) may be the most interesting.Several prognostic factors have been demonstrated among which are sex, the volume of the neoplasia, meningeal localizations, and the cytological types. Age has no prognostic value in immunotherapy patients, contrary to maintenance chemotherapy patients. Also the cytological types behave differently under immunotherapy and under maintenance chemotherapy. The disease-free survival of more than 85% of the microlymphoblastic patients submitted to immunotherapy is not observed in J. Bernard's patients submitted to maintenance chemotherapy, which suggests that this high cure rate is due to active immunotherapy. Hence, these prognostic factors are probably factors of sensitivity to active immunotherapy. A statistical computerized study has shown that there is a link between the cytological types and other prognostic factors and that they all depend on the cytological type.Hence, our present protocol is adapted to this immunotherapy sensitivity factor. It comprises a nonrisk preimmunotherapy chemotherapy for the microlymphoblastic type, and a longer and more intensive chemotherapy for less immunotherapy sensitive types.     

Bone-marrow relapse in acute lymphoblastic leukaemia in childhood.

The outcome after bone-marrow relapse was assessed in 53 children with acute lymphoblastic leukaemia (ALL). Twenty-five out of 37 children (67%) whose first remission ended in relapse during treatment (group A) achieved a second remission, as did 15 out of 16 (94%) who relapsed after treatment had been stopped (group B). Nevertheless, the median duration of second remission was only 12 weeks in group A and 35 weeks in group B. The median survival from time of relapse was 32 weeks in group A and 75 weeks in group B. It is concluded that marrow relapse is equally serious whether it occurs during treatment or after treatment has been stopped, and that most children with ALL have a single chance of cure at the time of diagnosis.     

Factores pronósticos de remisión a largo plazo tras cirugía transesfenoidal en la enfermedad de Cushing

There is no consensus on the remission criteria for Cushing's disease or on the definition of disease recurrence after transsphenoidal surgery, and comparison of the different published series is therefore difficult. A long-term recurrence rate of Cushing's disease ranging from 2%-25% has been reported. Predictors of long-term remission reported include: 1) adenoma–related factors (aggressiveness, size, preoperative identification in MRI), 2) surgery-related factors, mainly neurosurgeon experience, 3) clinical factors, of which dependence on and duration of glucocorticoid treatment are most important, and 4) biochemical factors. Among the latter, low postoperative cortisol levels, less than 2 mcg/dL predict for disease remission. However, even when undetectable plasma cortisol levels are present, long-term recurrence may still occur and lifetime follow-up is required. We report the preliminary results of the first 20 patients with Cushing's disease operated on at our hospital using nadir cortisol levels less than 2 mcg/dl as remission criterion.     

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.     

Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid

5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZA (100?mg/m(2), 5?days) plus valproate (VPA; continuous dosing, trough serum level 80-110?μg/ml). According to WHO classification, 5 patients had MDS, 2 had MDS/MPD, and 17 had acute myeloid leukemia (AML). Seven patients (29%) had previously received intensive chemotherapy, and five had previous HDAC inhibitor treatment. The overall response rate was 37% in the entire cohort but significantly higher (57%) in previously untreated patients, especially those with MDS (64%). Seven (29%) patients achieved CR (29%) and two PR (8%), respectively. Hematological CR was accompanied by complete cytogenetic remission according to conventional cytogenetics in all evaluable cases. Some patients also showed complete remission according to FISH on bone marrow mononuclear cells and CD34(+) peripheral blood cells, as well as by follow-up of somatic mitochondrial DNA mutations. Four additional patients achieved at least marrow remissions. Factors influencing response were AML (vs. MDS), marrow blast count, pretreatment, transfusion dependency, concomitant medication with hydroxyurea, and valproic acid (VPA) serum level. This trial is the first to assess the combination of AZA plus VPA without additional ATRA. A comparatively good CR rate, relatively short time to response, and the influence of VPA serum levels on response suggest that VPA provided substantial additional benefit. However, the importance of HDAC inhibitors in epigenetic combination therapy can only be proven by randomized trials.     

Minimal residual disease in hematopoietic malignancy: Technical approaches and clinical significance

New technology continues to provide methods to refine the definition of complete remission in patients with hematopoietic malignancy. Recent evidence indicates that quantitation of residual tumor burden over time may identify gradual increases indicative of potential relapse. It is the general hope that this increased sensitivity for identification of patients with residual tumor burden will allow for a more effective selection of therapeutic alternatives for these patients.In order to accurately assess whether lowering the threshold for definition of remission improves the clinical outcome of patients with MRD, future studies must include several important parameters. Effective clinical studies will require large groups of patients meeting carefully designed diagnostic criteria with strictly controlled, homogenous treatment protocols. In addition, they must utilize a multidisciplinary technical approach for the detection of MRD in order to properly assess the ability of each technology to measure clinically significant parameters. The choice of the most effective technologies and when to test the patient will be identified only through these carefully planned clinical trials. Additional considerations of cost and availability must then enter into utilization decisions as important financial considerations to be weighed against clinical significance.     

High dose rate endobronchial brachytherapy in the management of advanced lung cancer – comparison of different doses – preliminary assessment

PurposeBrachytherapy is one of the most efficient methods of overcoming endobronchial obstruction in palliative treatment of lung cancer. In single cases, brachytherapy is performed as radical treatment, however in most of cases, due to advanced clinical stage it has a palliative aim. In the absence of clear consensus regarding the value of doses used in brachytherapy different fraction doses are used in clinical treatment. The aim of this work is to compare results of palliative high dose rate brachytherapy using various treatment protocols with the view to analysing differences in survival and diminishing breathing difficulties.Material and methodsBetween May 1999 and February 2000 at the Greatpoland Cancer Center, 69 patients with advanced lung cancer were treated by high dose rate brachytherapy. They were disqualified from radical treatment due to advanced clinical stage. The age of the patients ranged from 39 to 76 years (average 53,2 years). Fifty-one patients received a total dose of 22,5 Gy in 3 fractions once a week, 18 patients received one single fraction of 10 Gy. All the patients were divided into two groups according to their clinical stage and the Karnofsky score – those with the Karnofsky score lower than 50 were qualified for a single fraction treatment. They were under clinical and endobronchial observation as regards survival rates, local remission and subsiding dyspnoea, breathing, cough and haemoptysis in the first, third, sixth and twelveth month of observation.ResultsFour weeks after the end of treatment subjective improvement (subsidence of all symptoms) was ascertained in 61/69 (88,4%) patients. In 12 cases (17,4%) complete remission (CR), in 49 cases (71,0%) – partial remission (PR) of the tumor were found. During one year of observation 45 (65,2%) patients died, in 10 cases (14,5%) improvement of in dyspnoea was observed and in 14 cases (20,3%) recurrence and progression of the disease were noted. There was no statistical difference in the survival rates between the two groups of patients treated with different fractions protocols.Conclusions

• 1.Brachytherapy in advanced lung cancer is an efficient method that led in most of patients to subcidence of symptoms and to improvement of the quality their lives.
• 2.The two treatment protocols showed similar efficiency in overcoming difficulties in breathing.
• 3.Survival rates were similar in both group of patients treated with different treatment protocols.

     

The reactogenicity and efficacy of a dried cell-free staphylococcal vaccine in treating chronic bronchitis]

The data obtained in the controlled trial of the immunotherapy of chronic bronchitis (CB) patients with lyophilized acellular staphylococcal vaccine developed at the Mechnikov Research Institute for Vaccines and Sera (USSR Acad. Med. Sci.), Moscow, are presented. The patients were divided at random into two groups; of these, one group received the vaccine and the other, placebo (0.9% sodium chloride solution). The preparations were injected subcutaneously simultaneously with traditional treatment. The vaccine was well tolerated by the patients. In the blood of the patients receiving the vaccine, in contrast to those receiving placebo, a significant increase in the level of specific antibodies determined in the passive hemagglutination test and IgG was noted. When following the remote consequences of the disease for a year after the course of immunotherapy, a significant decrease in the occurrence of aggravations, an increase in the duration of remission and a decrease in the duration of sick leaves were registered. These data indicate that the immunotherapy of CB with lyophilized acellular staphylococcal vaccine is a promising method of preventing relapses.