Central nervous system (CNS) involvement occurred in 45 of 222 (20.3%) leukemic adults achieving bone marrow (BM) complete remission (CR), including 12 of 23 (52%) acute undifferentiated leukemia (AUL), 12 of 32 (39%) lymphoma leukemia, 5 of 26 (19%) acute lymphoblastic leukemia, and 16 of 142 (11%) acute myelogenous leukemia. Risk factors for CNS disease were lactic dehydrogenase (LDH) greater than or equal to 25,000/mm3. AUL morphology, age less than 20 years, and extramedullary involvement were most significant. Pattern of CNS involvement varied with morphology. Survival after CNS relapse depended most on BM status and symptoms. Duration of CNS CR was longest for asymptomatic patients with low CSF cell counts. Also important were duration of first BM CR, ease of achievement of initial BM CR, and leukocyte count (original and at most closely antecedent BM involvement), reflecting the common origin of BM and CNS leukemic cells. Central nervous system relapse generally did not shorten BM CR or survival, although early primary CNS relapse was associated with early BM relapse.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819810101%2947%3A1%3C184%3A%3AAID-CNCR2820470130%3E3.0.CO%3B2-M

Natural history of central nervous system acute leukemia in adults.

There is general agreement that most chemotherapy agents achieve only relatively low concentrations in the normal central nervous system, that the blood-brain barrier is variably disrupted in malignant brain tumors, and that the concentration of chemotherapy drugs in the brain adjacent to tumor is intermediate between concentrations achieved in brain tumors vs normal brain. However, there is substantial controversy regarding the role of the blood-brain barrier in resistance to chemotherapy of intracerebral tumors. Many chemotherapy agents achieve concentrations in brain tumors that are comparable to those in extracerebral tumors, and drugs that cross the intact blood-brain barrier only poorly may be active against intracerebral tumors. Furthermore, the hypothesis that the brain is a pharmacological sanctuary where metastases may grow while tumor is responding in other parts of the body may be flawed: there are only 2 or 3 types of malignancies (out of all those that are sensitive to chemotherapy) in which the risk of isolated central nervous system relapse is moderately high, and even in these 2 or 3, effective central nervous system prophylaxis has minimal or no impact on overall survival. Furthermore, drugs that cross the BBB do not appear to be more effective than other drugs at reducing the risk of brain metastases, and brain metastases at the time of diagnosis do not necessarily convey a worse prognosis than metastases to various other sites. While average drug concentrations in brain adjacent to tumor are lower than those within brain tumors, very small numbers of tumor cells may be capable of inducing local leakiness in blood vessels, and there is little information on drug concentrations achieved in individual tumor cells within the brain adjacent to tumor. Furthermore, any limitation of uptake of drugs into brain tumors could be at least partially due to increased tissue pressure within tumors rather than being due to blood-brain barrier phenomena. This distinction could be important, since strategies that one might use to increase drug delivery to brain tumors might differ depending on whether the reduced delivery were due to barrier phenomena vs blood flow phenomena. The role of the blood-brain barrier in resistance of intracerebral tumors to chemotherapy remains unclear: while it may well play some role (and perhaps even a major one), self-fulfilling prophecies and unintentional bias in data selection and interpretation may have previously made it appear more important than it actually is. The feeling by many investigators that the blood-brain barrier is a major factor in brain tumor resistance to chemotherapy may at times have unnecessarily delayed and limited the exploration of new chemotherapy drugs and strategies in the treatment of human brain tumors. While antineoplastic drug pharmacology is important in the treatment of all malignant tumors, intrinsic drug cytotoxicity may well be a much more important factor in treatment outcome than is any limitation of drug uptake by the blood-brain barrier.

A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors

Treatment of the central nervous system (CNS) is an essential therapy component for childhood acute lymphoblastic leukemia (ALL). Individual patient data from 47 trials addressing 16 CNS treatment comparisons were analyzed. Event-free survival (EFS) was similar for radiotherapy versus intrathecal (IT), and radiotherapy plus IT versus IV methotrexate (IV MTX) plus IT. Triple intrathecal therapy (TIT) gave similar EFS but poorer survival than intrathecal methotrexate (IT MTX), but additional IV MTX improved both outcomes. One trial resulted in similar EFS and survival with IV MTX plus IT MTX versus TIT alone. Radiotherapy can generally be replaced by IT therapy. TIT should be used with effective systemic therapy such as IV MTX.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/pbc.24228

Systematic review and meta-analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia†

Controversies in the therapy of acute myelogenous leukemia

Modern therapy for acute 1 ymphocytic leukaemia (ALL) induces remission and prevents evident central nervous system (CNS) leukaemia in over 90% of children (Simone, 1974). The quality and duration of remission has so improved that therapy may be stopped safely in a significant proportion of patients (Aur et al , 1974). Despite these advances, the current treatment of ALL leaves much to be desired. Modern therapy is complex, costly and largely empirical; it has side effects ranging from merely annoying to life-threatening ; it is potentially carcinogenic and may have latent functional effects on organs such as the gonads, liver, nervous system and heart. The most serious immediate problem facing modern therapy, however, is its inability to prevent haematological relapse in one-third to two-thirds of patients. When haematological relapse occurs in patients receiving chemotherapy at the time, the chance for survival is virtually eliminated. Although the ideal therapy for preventing or delaying haematological relapse is unknown, useful guidelines have been developed. Studies have clearly established the necessity of continuing therapy during remission (Freireich et al, 1964), the superiority of intermittent over daily methotrexate administration (Acute Leukemia Group B, 1965) and the value of giving maximum-tolerated doses of chemotherapy (Pinkel et al , 1971). While methotrexate and mercaptopurine have been the most effective agents for prolonging haematological remission, controlled studies failed to establish the substantial superiority of simultaneous, sequential or cyclic combinations (Frei et al , 1961; Australian Study Group, 1968; Krivit et al , 1968). The addition of other chemotherapeutic agents prolonged remission in some studies (Holland & Glidewell, 1972; Leikin et al , 1969; Pinkel, 1971; Haghbin et al, 1974) and not in others (Aur et a l , 1972; Sackman Muriel et al , 1974; Simone et al , 197~a, b). However, since no regimen has emerged with sufficient efficacy to become standard, the composition of therapy during remission requires periodic re-examination (Simone, I 974). This annotation presents new data from an analysis of factors influencing haematological remission duration in four consecutive ‘total therapy’ studies of ALL at this hospital and attempts to explain the inferior results in one study. As shown in Table I, all studies employed multiple-agent therapy and, after Study V (Aur et a/, 1971a), a series of modifications was tested by randomization in Studies VI (Aur et al, 1972), VII (Aur et a!, 1973) and VIII (S’ imone, 1974; Simone et al, 1975a, b). All patients who attained haematological remission are included in the comparisons between studies except the 20 patients in study VIII randomized to receive methotrexate alone; excessive neurotoxicity required early termination of this limb (Simone et al, 197sa). To quantify the haematological relapse rate for each study and subgroup, the regression coefficient was derived by the least squares method from the proportion of patients remaining in haematological remission at 6 month intervals. Analysis is limited to 24 months in Studies V-VII because most relapses occur during this time and the slopes subsequently become

Factors that influence haematological remission duration in acute lymphocytic leukaemia.

A total of 146 previously untreated acute lymphoblastic leukemia patients—126 children and 20 adults—has been studied prospectively in order to evaluate the relative efficacy and toxicity of: A) two induction of remission treatments (Group A: Daunorubicin‐vincristine‐prednisone vs. Group B: Adriamycin‐vincristine‐prednisone) and the use of the same drugs as reinforcement courses every 90 days during the 1st year of complete remission and every 180 days thereafter; B) the use of a short course of L‐asparaginase early in remission as intensification treatment (to half of Group A only (Group Aa); Groups Ab and B did not receive this treatment); and C) the use of 2400 rads cobalt‐60 irradiation to cranium coupled with five doses of intrathecal methotrexate as prophylactic CNS treatment. Complete remission was achieved in 85.7% of 112 cases of Group A and in 79.4% of 34 cases of Group B. The median duration of hematologic remission was 23, 21, and 22 months for Groups Aa, Ab, and B respectively. Toxicity was about the same for all regimens. The median duration of complete remission was 24 months, and of hematologic remission 27 months in the CNS prophylactically treated group, against 9 and 18 months, respectively, for the non‐treated group. We have concluded that: A) Adriamycin did not seem to be any better than Daunorubicin in inducing or prolonging complete remission when used in combination with vincristine and prednisone, either as induction treatment or in reinforcement courses; B) we did not demonstrate any significant difference in duration of remission, incidence, or site of relapse between L‐asparaginase‐treated and non‐treated patients; and C) the CNS prophylactic treatment employed in this trial is very effective in preventing CNS relapse, although it does not seem to prevent hematologic relapse.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197408%2934%3A2%3C418%3A%3AAID-CNCR2820340227%3E3.0.CO%3B2-X

Evaluation of induction of remission, intensification, and central nervous system prophylactic treatment in acute lymphoblastic leukemia.

A total of 114 previously untreated patients with myeloblastic leukemia was included in a sequential therapy protocol. Daunorubicin, vincristine, and prednisone were employed for the first 3 weeks, followed by two or more 5-day courses of cytosine arabinoside and 6-mercaptopurine; there was a 5-day rest between courses. Maintenance therapy was as follows: the continuing 6-mercaptopurine and methotrexate treatment was interrupted every 30 days for sequential reinforcement courses consisting of one dose of daunorubicin and vincristine and 7 days of prednisone, or by a 5-day course of cytosine arabinoside plus 6-mercaptopurine. Of the 114 patients, 48 obtained complete remission, 14 had partial remission, 16 failed to respond, and 36 died during the course of treatment. The remission rate in children (under 16) was 57%; in adults (16-45) 54%; and in those over 45, 19%. The difference in the incidence of complete remission in patients under 45 and those over 45 was statistically significant (p less than 0.01). The median duration of complete remission was 8 months: 12 months in children and 5 months in adults. The over-all survival rate was 4 months: 13 months for patients with complete remission, 4 months for those with partial remission, and 1 month for patients who did not respond to therapy. The difference in survival of those with complete remission and all the others was significant (p less than 0.01).

Sequential therapy for induction and maintenance of remission in acute myeloblastic leukemia

The purpose of this study is to see if immunotherapy with C. parvum and prevention of central nervous system relapse with intrathecal methotrexate can prolong duration of complete remission and survival as well as avoid central nervous system relapse. For induction, three weekly I.V. injections of vincristine and Daunorubicin were given with daily prednisone orally, followed by 5-day courses of Cytosine Arabinoside and 6-mercaptopurine. The patients were randomized to chemotherapy or chemoimmunotherapy. Maintenance consisted of vincristine, Daunorubicin, and prednisone one week every odd month, and a 5-day course of Cytosine Arabinoside and 6-mercaptopurine every even month. Every week, the chemoimmunotherapy group also received, without chemotherapy, one injection of C. parvum 4 mg, subcutaneously. All patients received five weekly injections of intrathecal methotrexate 13 mg/m2 right after complete remission was achieved. Out of 181 evaluable cases, 80 (44%) achieved complete remission, 45 were randomized to chemotherapy, and 35 to chemoimmunotherapy. In the chemoimmunotherapy group 32/35 relapsed, and in the chemotherapy group 36/45. Median duration of complete remission and survival were: for group chemotherapy, 8 and 15 months; for group chemoimmunotherapy, 5 and 10 months. This difference is not significant. Intrathecal methotrexate was given to all patients. Six patients (7%) had central nervous system leukemia at the time of the first injection. None had central nervous system relapse after prevention with intrathecal methotrexate. This method seems useful in preventing central nervous system relapse in patients with acute myeloblastic leukemia, but does not seem to prolong complete remission.

Chemoimmunotherapy with Corynebacterium parvum in acute myelocytic leukemia.

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Evaluation of induction of remission, intensification, and central nervous system prophylactic treatment in acute lymphoblastic leukemia.

Sequential therapy for induction and maintenance of remission in acute myeloblastic leukemia

Chemoimmunotherapy with Corynebacterium parvum in acute myelocytic leukemia.