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Recent years have witnessed major advances that have improved outcome of adults with acute lymphoblastic leukemia (ALL). The emergence of the concept of measurable residual disease has fine-tuned our prognostic models and guided our treatment decisions. The treatment paradigms of ALL have been revolutionized with the advent of tyrosine kinase inhibitors targeting BCR-ABL1, monoclonal antibodies targeting CD20 (rituximab), antibody-drug conjugates targeting CD22 (inotuzumab ozogamicin), bispecific antibodies (blinatumomab), and CD19 chimeric antigen receptor T cell therapy (tisagenlecleucel). These highly effective new agents are allowing for novel approaches that reduce reliance on intensive cytotoxic chemotherapy and hematopoietic stem cell transplantation in first remission. This comprehensive review will focus on the recent advances and future directions in novel therapeutic strategies in adult ALL.

Significant advances have been made in recent years in the field of Philadelphia-negative acute lymphoblastic leukaemia (ALL). New insights into the biology and genetics of ALL as well as novel clinical observations and new drugs are changing the way we diagnose, risk-stratify and treat adult patients with ALL. New genetic subtypes and alterations refine risk stratification and uncover new actionable therapeutic targets. The incorporation of more intensive, paediatric and paediatric-inspired approaches for young adults seem to have a positive impact on survival in this population. Minimal residual disease at different time points can assist in tailoring risk-adapted interventions for patients based on individual response. Finally, novel targeted approaches with monoclonal antibodies, immunotherapies and small molecules are moving through clinical development and entering the clinic. The aim of this review is to consolidate the abundance of emerging data and to review and revisit the concepts of risk-stratification, choice of induction and post-remission strategies as well as to discuss and update the approach to specific populations with ALL, such as young adult, elderly/unfit and relapsed/refractory patients with ALL., (© 2017 John Wiley & Sons Ltd.)

In the last 2 decades an increasing number of patients reported with extramedullary involvement among relapsed acute promyelocytic leukemia (APL) patients. Several investigators related this phenomenon to the relatively new treatment of all-trans-retinoic-acid (ATRA). In this review article we will examine what has been reported in the medical literature on extramedullary disease in APL: the common sites to be involved, the clinical risk factors to its development, the role of ATRA and arsenic tri-oxide and the recommended treatment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The dose intensity of daunorubicin (DNR) delivered during the induction period represented the major prognostic factor for the outcome of adult acute lymphoblastic leukemia (ALL). The aim of this study was to determine the survival or toxicity of escalated doses of DNR in induction treatment of adult patients with acute lymphoblastic leukemia who are at least 15 years of age. For induction chemotherapy, all patients were given 90 mg/m(2)/day of DNR by continuous intravenous (IV) infusion over 24 h daily on days 1-3, 2 mg of vincristine IV push on days 1 and 8, and 60 mg/m(2)/day of prednisolone per oral (PO) on days 1-14 in conjunction with 4,000 units/m(2)/day of L-asparaginase intramuscular or subcutaneous on days 17-28. The median patient age was 32 years (range, 15-69). Complete remission (CR) was achieved in 169 (88.5 %) patients, while 4 died before CR was reached. Additionally, 11 patients died from leukemia progression, 4 had refractory disease, and 3 had follow-up loss. The median follow-up time was 697 days (range, 12-2,270). The 3-year cumulative incidence of relapse was 49.3 %. The probabilities of disease-free survival and overall survival at 3 years were 46.1 and 43.1 %, respectively. The dose of DNR was 100 % of the target dose, and there were no additional specific toxicities. The results show that escalated doses of DNR in induction chemotherapy are similar with the standard dose in response and toxicities. Our study indicates that a more effective regimen or better chemotherapy agents are needed to improve the CR rate and prolong survival in Philadelphia-negative adult ALL.

As a member of the B7 family, inducible co-stimulator ligand (ICOSLG) expressed on tumor cell has been reported to have an important role in tumor immunity. In this study, we sought to determine whether the expression of ICOSLG in mouse hematological malignancy cells influences GVL reaction after mouse allogeneic BMT. In our study, we analyzed the expression of ICOSLG in six mice hematological malignancy cell lines for the first time, and found that FBL3, A20 and P388 cells expressed high levels of ICOSLG. Then, we chose A20 cells as targets to construct a GVL model and study the effects on the GVL reaction by silencing the ICOSLG gene. The survival was analyzed. We found that in GVL model, mortality of interference groups was significantly delayed compared with the control group (P=0.0005). Our results indicate that knockdown of ICOSLG of mouse leukemic cells may significantly enhance GVL effect after allogeneic BMT.

B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.

Conflicting conclusions can be drawn from the available data concerning antileukemic efficacy and risks of intrathecal (i.t.) chemoprophylaxis to children after hematopoietic SCT (HSCT). To address this, we enrolled six transplantation centers with similar treatment and patient material. Of the 397 children included, 136 patients had received post-HSCT i.t. treatment (i.t. group) and 261 had not (non-i.t. group). The two groups were, apart from the i.t. therapy given or not given, at equal risk of post-HSCT central nervous system (CNS) relapse, which was the primary endpoint studied. Isolated CNS relapses were observed in 2 (1.5%) patients from the i.t. group and 2 (1%) from the non-i.t. group. Combined relapses, including CNS, involved 4 (3%) patients from the i.t. group and 6 (2%) from the non-i.t. group. Overall survival and the occurrence of neurological side effects did not differ significantly between the groups. There was no statistically significant difference in the incidence of isolated or mixed CNS relapses between the two groups, suggesting little or no benefit from i.t. therapy post-HSCT in children.

The overall survival of childhood leukaemia has increased dramatically over recent decades. With the increasing number of survivors, chemotherapy protocols are designed not only to improve cure rates but also to minimise long-term sequelae. Central-nervous-system-directed therapy given as intrathecal chemotherapy and/or cranial irradiation plays a crucial part in acute leukaemia treatment but can also result in adverse effects on the developing brain. The elimination of cranial irradiation from current treatment protocols has improved the neurocognitive outcome without compromising survival rates. Although neurodevelopmental long-term sequelae after chemotherapy-only central-nervous-system-directed therapies may be more subtle, survivors of childhood leukaemia will continue to require methodical follow-up and appropriate rehabilitation.

Central nervous system (CNS) recurrence continues to be a significant complication in the treatment of adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence has been a therapeutic challenge and has not been addressed critically in many clinical trials. Adult studies modeled on childhood ALL studies have used multiple treatment modalities, including radiation therapy, systemic therapy, intrathecal therapy, and combinations thereof. Cranial irradiation is effective but is offset by substantial toxicity, including neurologic sequelae. Systemic chemotherapy, especially with cytarabine (AraC) and methotrexate, has demonstrated promise in decreasing CNS recurrence, but therapeutic levels of drugs in the cerebrospinal fluid (CSF) are not maintained. Intrathecal chemotherapy with or without high-dose systemic therapy is the most common approach to CNS prophylaxis. Liposomal AraC recently has become available and confers prolonged levels of free AraC in the CSF, a critical requirement for CNS prophylactic therapy. This review discusses the various modalities used for CNS prophylaxis in patients with ALL and the emerging trends, with specific emphasis on the outcome in terms of event-free survival and toxicity., ((c) 2010 American Cancer Society.)

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders - medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1-18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin-Frankfurt-Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 +/- 5.9% and the INS 98 (n = 43), 83.7 +/- 5.6% (P = 0.12); the cumulative incidence (CI) of any CNS relapse was 5.0 +/- 2.8% and 2.3 +/- 2.3% (P = 0.50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) >or=100 x 10(9)/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61.9 +/- 5.3% in INS 89 and 72.9 +/- 5.8% in INS 98, (P = 0.21); the CI of any CNS relapse was 7.1 +/- 2.8% and 1.7 +/- 1.7% (P = 0.142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.

To evaluate the impact of contemporary therapy on the clinical outcome of children with pre-B acute lymphoblastic leukemia (ALL) and the t(1;19)/TCF3/PBX1, we analyzed 735 patients with B-cell precursor ALL treated in four successive protocols at St Jude Children's Research Hospital. The 41 patients with the t(1;19) had a comparable event-free survival to that of the 694 patients with other B-cell precursor ALL (P=0.63; 84.2+/-7.1% (s.e.) vs 84.0+/-1.8% at 5 years). However, patients with the t(1;19) had a lower cumulative incidence of any hematological relapse (P=0.06; 0 vs 8.3+/-1.2% at 5 years) but a significantly higher incidence of central nervous system (CNS) relapse (P<0.001; 9.0+/-5.1% vs 1.0+/-0.4% at 5 years). In a multivariate analysis, the t(1;19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t(1;19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse.

The tyrosine kinase inhibitor (TKI) imatinib has become an integral part of front-line therapy for Ph(+) ALL, with remission rates exceeding 90% irrespective of whether imatinib is given alone or combined with chemotherapy. Treatment outcome with imatinib-based regimens has improved compared with historic controls, but most patients who do not undergo allogeneic stem cell transplantation (SCT) eventually relapse. Acquired resistance on TKI treatment is associated with mutations in the bcr-abl tyrosine kinase domain in the majority of patients, and may be detected at low frequency prior to TKI treatment in a subset of patients. Second generation TKIs, eg, dasatinib and nilotinib, show activity against most of the bcr-abl tyrosine kinase domain (TKD) mutations involved in acquired imatinib resistance, but clinical benefit is generally short-lived. Accordingly, SCT in first complete remission (CR) is considered to be the best curative option. Molecular monitoring of minimal residual disease levels appears to have prognostic relevance and should be used to guide treatment. International standardization and quality control efforts are ongoing to ensure comparability of results. Mutation analysis during treatment relies increasingly on highly sensitive PCR techniques or denaturing HPLC and may assist in treatment decisions, eg, in case of molecular relapse. Results from current studies of second-generation TKI as front-line treatment for Ph(+) ALL are promising and show high molecular response rates, but follow-up is still too short to determine their impact on remission duration and long-term survival. Strategies to improve outcome after SCT include the pre-emptive use of imatinib, which appears to reduce the relapse rate. In patients ineligible for transplantation, novel concepts for maintenance therapy are needed. These could involve novel immunotherapeutic interventions and combinations of TKI.

Background: To evaluate the treatment results of central nervous system preventive therapy (CNSP) with triple intrathecal therapy (TIT) alone in children with acute lymphoblastic leukemia (ALL)., Methods: We retrospectively studied a cohort of 59 patients with median follow-up time 50.6 months (range: 27-80 months) at a single institution in Taiwan. Patients with ALL were classified in risk groups at diagnosis. TPOG-ALL-93 protocols and TPOG-ALL-2002 protocols were used. Both protocols were for multicenter studies in Taiwan and contained protocols for standard-risk (SR), high-risk (HR), and very-high-risk (VHR) patients. In this study, we used TIT alone for CNSP. In all ALL patients, methotrexate, hydrocortisone, and cytarabine were given at age-dependent doses., Results: As of October 2006, patients had a 3-year event-free survival and an overall survival 89.4 +/- 4.1% (S.E.) and 93.1 +/- 3.3%, respectively. Under TIT no patients had complications such as seizure, encephalitis, or infection, and no morbidities like those caused by cranial irradiation. In this study, we used TIT alone for CNSP and had no CNS relapse., Conclusions: In the context of effective systemic therapy, TIT alone appears to be effective CNSP for most patients with ALL., ((c) 2007 Wiley-Liss, Inc.)

The current treatment programs for adult patients with acute lymphoblastic leukemia are modeled on pediatric regimens. The result has been complete remission rates comparable to those seen in children, but a significant proportion of adult patients relapse. Salvage therapy for patients with acute lymphoblastic leukemia continues to have limited success. Advances in molecular biology have discovered new targets for therapeutic intervention, and the introduction of some targeted agents, such as the new tyrosine kinase inhibitors and monoclonal antibodies, has led to improvements in response and survival in some subsets. The development of techniques for identification and monitoring of minimal residual leukemia has provided possible ways to predict relapse and consider early intervention. It is likely that we will further refine therapeutic approaches and improve patient outcome through the translation of biologic and molecular discoveries into effective and risk-adapted strategies.

Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and cytarabine on alternating courses. Liposomal cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal cytarabine. Toxicities usually manifested after the MTX and cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and cytarabine can result in significant neurotoxicity.

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biologic and prognostic subgroups. The treatment of adults with ALL has evolved largely from the therapy developed for childhood ALL and, despite differences across regimens, can be broadly classified as including induction, consolidation, maintenance, and central nervous system prophylaxis. Although there has been marked improvement in the outcomes for pediatric patients with ALL, the same success has not yet been realized for adult patients. Some of this difference can be attributed to a greater incidence of unfavorable cytogenetic subtypes in adults than in children. In addition, the ability to tolerate intensive regimens likely plays a role. This article reviews the classification, prognostic features, current treatment programs, and new advances as applied to adult patients with newly diagnosed ALL.

Expression of E- and P-selectin ligands is required for T cell entry into skin. Sialyl Lewis X moieties are critical for ligand activity and are elevated on malignant skin-homing T cells. We hypothesize that these glycosylations are selectable targets for treating the dermal tropism associated with cutaneous lymphomas. In this study, we analyzed the efficacy of a novel 4-fluorinated analog of N-acetylglucosamine (GlcNAc) on E- and P-selectin ligands expressed by malignant skin-homing T cells. We also examined the specificity of 4-F-GlcNAc (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose) action by contrasting the effects on sialyl Lewis X expression displayed by P-selectin glycoprotein ligand-1 (PSGL-1) with sialylated O-glycans expressed by CD43. Using parallel-plate flow analysis, we found that 4-F-GlcNAc elicited 5-fold more potent inhibition on P-selectin ligand activity than on E-selectin ligand activity. To determine whether glycosylations conferring E- and P-selectin ligand activities were inhibited, we analyzed the expression of sialyl Lewis X and sialyl-fucosylated core 2 O-glycan (CHO-131 antigen), respectively. We found that 4-F-GlcNAc treatment resulted in dose-dependent ablation of sialyl Lewis X and CHO-131 antigen expression on PSGL-1, whereas sialylated O-glycans on CD43 were minimally affected. These results indicate that 4-F-GlcNAc treatment can selectively downregulate the P-selectin ligand activity and potentially prevent dermal dissemination of cutaneous lymphomas.

Acute lymphoblastic leukemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. The mechanism for selective homing of ALL cells to preferential sites has long been unclear. Recent reports indicate that the chemokine receptor CXCR4 is found on ALL cells and its ligand is highly expressed at sites associated with ALL-induced organ infiltration. This results in chemotaxis, or directed migration of leukemic cells from the bone marrow via the circulation to preferential sites of extramedullary organ infiltration. Because overexpression of CXCR4 on ALL cells is associated with high extramedullary organ infiltration and shorter disease-free survival, numerous pharmacological agents affecting CXCR4 have currently been investigated. The most promising data are available for histone deacetylase inhibitors (HDAIs), which have been shown to be safe and well tolerated in phase I clinical trials. In vitro, HDAIs extensively down-regulate CXCR4 protein and mRNA levels. As a result, the ability of CXCR4 ligand to induce cellular migration is impaired. Wider recognition of the role of CXCR4 in ALL and manipulation of this important mechanism may lead to novel approaches in the treatment and outcome of this disease.

Corticosteroids are an essential component of treatment for acute lymphoblastic leukaemia (ALL). Prednisolone is the most commonly used steroid, particularly in the maintenance phase of therapy. There is increasing evidence that, even in equipotent dosage for glucocorticoid effect, dexamethasone has enhanced lymphoblast cytotoxicity and penetration of the central nervous system (CNS) compared with prednisolone. Substitution of dexamethasone for prednisolone in the treatment of ALL might, therefore, result in improved event-free and overall survival. Children with newly diagnosed ALL were randomly assigned to receive either dexamethasone or prednisolone in the induction, consolidation (all received dexamethasone in intensification) and continuation phases of treatment. Among 1603 eligible randomized patients, those receiving dexamethasone had half the risk of isolated CNS relapse (P = 0.0007). Event-free survival was significantly improved with dexamethasone (84.2% vs. 75.6% at 5 years; P = 0.01), with no evidence of differing effects in any subgroup of patients. The use of 6.5 mg/m(2) dexamethasone throughout treatment for ALL led to a significant decrease in the risk of relapse for all risk-groups of patients and, despite the increased toxicity, should now be regarded as part of standard therapy for childhood ALL.

'Aleukaemic leukaemia cutis' or acute leukaemia confined to the skin is extremely rare, although skin involvement with underlying leukaemia is well recognized, and is associated with a poor prognosis. We report a case of isolated acute myeloid leukaemia (AML) in the skin. A literature review shows this to be commonly misdiagnosed. Its recognition is important, because early diagnosis should lead to more appropriate chemotherapy, and a better prognosis. These patients probably require therapy directed specifically to the skin, as well as to other extramedullary sites, such as the central nervous system, to prevent early relapse.

The treatment of adults with acute lymphoblastic leukemia (ALL) has been modeled on therapy developed for childhood ALL. The similarity between childhood and adult forms of this disease allows for inferences to be drawn from experience in the pediatric population. However, adults with ALL have far poorer outcome when compared to children. Some of this difference can be attributed in ability to tolerate intensive therapy coupled with an increased incidence of unfavorable cytogenetic subgroups and a decreased incidence of favorable cytogenetic subgroups. Treatment of adult ALL is typically divided into four broad categories: induction, consolidation, maintenance, and central nervous system prophylaxis. Despite three decades of clinical investigation for devising improved treatment programs for adults with ALL, no single program has emerged as the standard. Here we review classification, prognostic features, current treatment programs, and new advances as applied to adult patients with newly diagnosed ALL.

In recent years, synthetic tyrosine kinase inhibitors have made a rapid transition from basic research to therapeutic application. These compounds represent a major clinical advance in the approach to cancer in their relative specificity of action and decreased toxicity. We report here the effects of a novel tyrosine kinase inhibitor CR4 that interferes with growth-promoting pathways to markedly inhibit the growth and survival of both Philadelphia-positive and -negative acute lymphoblastic leukemia (ALL) as well as acute myeloid leukemia (AML). While efficiently ablating leukemic cell growth, normal cell growth and differentiation remain unaffected by CR4. CR4 demonstrates an ability to inhibit the function of multiple growth-critical kinases and yet exhibits a low level of cytotoxicity. These findings suggest that CR4 may prove to be highly effective as a therapeutic agent.

Chronic myelogenous leukemia (CML) is a hematopoietic malignant disease associated with expression of a chimeric BCR-ABL gene. We recently succeeded in designing a novel allosterically controllable ribozyme, the maxizyme (Tanabe et al. Biomacromolecules 2000, 1, 108-117; Kuwabara et al. Biomacromolecules 2001, 2, 788-799), that not only specifically cleaves BCR-ABL mRNA and induces apoptosis in cultured CML cells but also shows significant inhibition against the growth of an established BV173 cell line in a mouse model (Tanabe et al. Nature 2000, 406, 473-474). As an extension of our studies, we tested the maxizyme against primary CML cells in the same mouse model. The maxizyme under the control of a tRNA(Val) promoter showed significant inhibition against the growth of the primary bone marrow cells from a Japanese patient with CML. Specifically, to examine the applicability of the maxizyme in the treatment of CML, we assessed the antitumor effect of the maxizyme in murine models of CML. Fourteen weeks after the injection of primary CML cells into a NOD-SCID mouse, the bone marrow of the mouse was filled with primary CML cells as a result of diffuse leukemia. In marked contrast, when maxizyme-expressing primary CML cells were injected, the mouse remained disease-free. These results further strengthen our earlier suggestion that the maxizyme technology might provide a useful approach to the treatment of CML.

Objective: Focus on long-term side-effects after cancer therapy in childhood has become of the utmost importance. The hypothalamic-pituitary thyroid (HPT) axis is exposed to irradiation when some children are treated for acute lymphoblastic leukaemia (ALL) with prophylactic cranial irradiation (CIR). Whether this treatment causes hypofunction of the HPT axis remains controversial., Design: We measured plasma levels of total T3 (T3), total T4 (T4) and TSH before stimulation with TRH and plasma levels of TSH, 30 and 150 minutes after stimulation with TRH in 95 patients in first continuous remission of childhood ALL., Patients: Patients diagnosed with ALL before the age of 15 years between 1970 and 1991 and who were in first continuous remission and off treatment for at least one year were studied. The children were aged between 0.5 and 14.8 years (median: 3.9) at diagnosis of ALL. Thyroid function was assessed between 1.2 and 18.3 years (median: 7.6) after completion of therapy., Measurements: We measured T4 levels before, and compared TSH levels before and after, stimulation with TRH in patients who were treated with prophylactic CIR (15-24 Gy) (n = 38) (CIR group) with patients who were treated with chemotherapy only (n = 57) (non-CIR group)., Results: We found that T3 and T4 levels were normal in all individuals (excluding the women who were on oral contraceptives). The median time from end of treatment to time at follow-up was 9.1 years in the non-CIR group vs. 4.2 years in the CIR group (P < 0.001), and the effect on follow-up time was significant (P = 0.04). It was estimated that just after irradiation, the TSH levels before and 30 and 150 minutes after TRH stimulation was 49% lower in the CIR group; however, after 4.0 years, TSH levels were not significantly different between the two groups. Although within normal limits, the T4 levels were significantly higher in the CIR group compared to the non-CIR group (P = 0.003). It was estimated that, just after the end of treatment, T4 was 19.9% higher in the CIR group. However, in the CIR group, the T4 level decreased significantly over time with -1.5% per year (P = 0.025), while the difference in the non-CIR group was not significant. There was no correlation between T4 and TSH levels and sex, age at diagnosis, age at the end of treatment or age at follow-up., Conclusions: We conclude that, in our cohort of survivors of childhood ALL, prophylactic cranial irradiation of the central nervous system did not have an adverse effect on hypothalamo-pituitary-thyroid function within a median follow-up time of 8 years.

Purpose: The European Organization for Research and Treatment of Cancer 58881 study was designed to test in a prospective multicentric randomized trial the value of high-dose (HD) intravenous (IV) cytarabine (Ara-C) added to HD IV methotrexate (MTX) to reduce the incidence of CNS and systemic relapses in children with increased-risk acute lymphoblastic leukemia (ALL) or stage III and IV lymphoblastic lymphoma treated with a Berlin-Frankfurt-Munster (BFM)-based regimen., Patients and Methods: After completion of induction-consolidation phase, children with increased-risk (risk factor > 0.8 or T-lineage) ALL or stage III and IV lymphoblastic lymphoma were randomized to receive four courses of HD MTX (5 g/m(2) over 24 hours every 2 weeks) and four intrathecal administrations of MTX (Arm A) or the same treatment schedule with additional HD IV Ara-C (1 g/m(2) in bolus injection 12 and 24 hours after the start of each MTX infusion) (Arm B)., Results: Between January 1990 and January 1996, 653 patients with ALL (593 patients) or lymphoblastic lymphoma (60 patients) were randomized: 323 were assigned to Arm A (without Ara-C) and 330 to Arm B (with Ara-C). A total of 190 events (177 relapses and 13 deaths without relapse) were reported, and the median follow up was 6.5 years (range, 2 to 10 years). The incidence rates of CNS relapse were similar in both arms whether isolated (5.6% and 3.3%, respectively) or combined (5.3% and 4.6%, respectively). The estimated 6-year disease-free survival (DFS) rate was similar (log-rank P =.67) in the two treatment groups: 70.4% (SE = 2.6%) in Arm A and 71.0% (SE = 2.5%) in Arm B. The 6-year DFS rate was similar for ALL and LL patients: 70.2% (SE = 1.9%) versus 76.3% (SE = 5.6%)., Conclusion: Prevention of CNS relapse was satisfactorily achieved with HD IV MTX and intrathecal injections of MTX in children with increased-risk ALL or stage III and IV lymphoblastic lymphoma treated with our BFM-based treatment protocol in which cranial irradiation was omitted. Disappointingly, with the dose schedule used in this protocol, HD Ara-C added to HD MTX, although well tolerated, failed to further decrease the incidence of CNS relapse or to improve the overall DFS.

An unforeseen consequence of improved disease-free survival in many hematologic and solid tumor malignancies has been an increase in the incidence of disease recurrence in the leptomeninges. The recognition of the central nervous system (CNS) as a unique 'sanctuary' site has resulted in the development of therapeutic strategies specifically directed at the leptomeninges. Although therapeutic strategies have been successful in the prevention and treatment of CNS leukemia, there are still a paucity of therapeutic options for patients with neoplastic meningitis due to solid tumors or recurrent CNS leukemia. This article provides an overview of the pharmacology and toxicity of intrathecal agents that are commonly employed in the treatment and prevention of leptomeningeal disease, and describes new agents that are in the early stages of clinical development.

With effective CNS prophylaxis, most adults with ALL may remain free of CNS leukemia. Several combinations of IT chemotherapy, high-dose systemic chemotherapy, and cranial irradiation have been used with varying results. Excellent prophylaxis can be achieved without cranial irradiation, and in view of the potential acute and long-term toxicity of radiation, these methods may be preferable. A prophylactic approach tailored to the risk of CNS leukemia was shown to be valuable in childhood ALL and in at least one adult study. Further studies should focus on defining risk groups for CNS leukemia and designing effective prophylaxis for each group. More research is needed to define the intensity and duration of treatment and the role of cranial irradiation in the treatment of isolated CNS relapses.

Contemporary chemotherapy has significantly improved event-free survival among patients with T cell-lineage acute lymphoblastic leukemia (T-ALL). Unlike B-precursor ALL, most investigators are still using cranial radiation (CRT) and are hesitant to rely solely on intrathecal therapy for T-ALL. In this study we assessed the effects of CRT upon event-free survival and central nervous system (CNS) relapses in a cohort of children with high risk features of T cell leukemia. In a series of six consecutive studies (1987-1995) patients were non-randomly assigned their CNS prophylaxis per individual protocol. These protocols were based on POG 8704 which relied on rotating drug combinations (cytarabine/cyclophosphamide, teniposide/Ara-C, and vincristine/doxorubicin/6-MP/prednisone) postinduction. Modifications such as high-dose cytarabine, intermediate-dose methotrexate, and the addition of G-CSF, were designed to give higher CNS drug levels (decreasing the need for CRT), to eliminate epidophyllotoxin (decreasing the risk of secondary leukemia), and to reduce therapy-related neutropenia (pilot studies POG 9086, 9295, 9296, 9297, 9398). All patients included in this analysis qualified for POG high risk criteria, WBC >50000/mm3 and/or CNS leukemia. Patients without CNS involvement received 16 doses of age-adjusted triple intra-thecal therapy (TIT = hydrocortisone, MTX, and cytarabine) whereas patients with CNS disease received three more doses of TIT during induction and consolidation. Patients who received CRT were treated with 2400 cGy (POG 8704) or 1800 cGy (POG 9086 and 9295). CNS therapy included CRT in 144 patients while the remaining 78 patients received no radiation by original protocol design. There were 155 males and 57 females with a median age of 8.2 years. The median WBC for the CRT+ and CRT- patients were 186000/mm3 and 200000/mm3, respectively. CNS involvement at diagnosis was seen in 16% of the CRT+ and 23% of the CRT- groups. The complete continuous remission rate (CCR) was not significantly different for the irradiated vs. non-irradiated groups (P = 0.46). The 3-year event-free survival was 65% (s.e. 6%) and 63% (s.e. 4%) for the non-irradiated vs. the radiated group. However, the 3-year CNS relapse rate was significantly higher amongst patients who did not receive CRT; 18% (s.e. 5%) vs. 7% (s.e. 3%) in the irradiated group (P = 0.012). Our analysis in a non-randomized setting, suggests that CRT did not significantly correlate with event-free survival but omitting it had an adverse effect on the CNS involvement at the time of relapse.

Background: Infants diagnosed with acute lymphoblastic leukemia (ALL) are considered the patient subgroup at the highest risk for central nervous system (CNS) disease, both at presentation and as an isolated extramedullary relapse. In addition, they are highly vulnerable to adverse developmental sequelae from CNS-directed therapy., Methods: Thirty patients younger than 12 months at diagnosis (12 males, 18 females) in first hematologic remission were evaluated after completion of ALL therapy (mean age = 62.1 months; standard deviation = 17.2 months; range = 38-102 months). CNS-directed treatment included very high dose infusions of methotrexate (MTX) and intrathecal cytarabine and MTX. Three patients had meningeal leukemia that required additional therapy. Children were administered the McCarthy Scales of Children's Abilities, and parents completed a sociodemographic questionnaire to obtain information about occupation and education., Results: Mean scores on all 6 cognitive and motor indices of the McCarthy Scales were in the average range (Verbal = 52.0; Perceptual = 53.6; Quantitative = 49.6; General Cognitive Index [GCI] = 102.1; Memory = 49.2; Motor = 51.0). Score distributions for each neurodevelopmental index were comparable to age-based population standards. One patient obtained a GCI that exceeded 2 standard deviations above the mean; none scored more than 2 standard deviations below. There was no report of developmental disabilities or neurologic disorders for any of the patients. Risk factors, including age at diagnosis, gender, additional CNS-directed treatment, and family socioeconomic status, were not associated with developmental outcome., Conclusions: Test findings indicated a generally positive neurodevelopmental outcome for ALL patients diagnosed in infancy who were treated with very high dose MTX as CNS-directed therapy. Combined with the reduction in the isolated CNS relapse rate achieved by the Children's Cancer Group (CCG) clinical trial CCG-107, the results of this study represent a substantial improvement in neurodevelopmental outcome for very young patients compared with infants treated for ALL in the past.

Objective: Examine cognitive and academic late effects among children and adolescents who had received central nervous system (CNS) prophylactic chemotherapy alone for acute lymphocytic leukemia (ALL); none had received whole brain radiation therapy (RT)., Method: Subjects included 47 children and adolescents from 5 to 22 years of age who were treated on the same protocol and had been off treatment from 2 to 7 years at the time of assessment., Results: As a group the survivors displayed generally average performance on measures of cognitive and academic abilities, although they differed from normative means on tests of nonverbal skills. Girls performed more poorly than the normative sample on nonverbal tasks, while no differences were found for boys. Age at diagnosis and time off treatment were not significantly associated with cognitive and academic functioning for survivors of this particular chemotherapy-only protocol., Conclusions: Data were interpreted to support generally modest potential late effects in specific areas for children and adolescents surviving ALL. These findings suggest a need for monitoring nonverbal cognitive skills for childhood survivors of ALL, particularly for girls.

Central nervous system (CNS) relapse has been an obstacle to uniformly successful treatment of childhood acute lymphoblastic leukemia (ALL) for many years. We therefore intensified intrathecal chemotherapy (simultaneously administered methotrexate, hydrocortisone, and cytarabine) for 165 consecutive children with newly diagnosed ALL enrolled in Total Therapy Study XIIIA from December 1991 to August 1994. The 64 patients (39%) who had 1 or more blast cells in cytocentrifuged preparations of cerebrospinal fluid at diagnosis, with or without associated higher-risk features, received additional doses of intrathecal chemotherapy during remission induction and the first year of continuation treatment. Patients with higher-risk leukemia, regardless of cerebrospinal fluid findings, also received additional doses of intrathecal chemotherapy during the first year of continuation treatment. Cranial irradiation was reserved for patients with higher-risk leukemia (22% of the total). The 5-year cumulative risk of an isolated CNS relapse among all 165 patients was 1.2% (95% confidence interval, 0% to 2.9%), whereas that of any CNS relapse was 3.2% (0. 4% to 6.0%). The probability of surviving for 5 years without an adverse event of any type was 80.2% +/- 9.2% (SE). Our results suggest that early intensification of intrathecal chemotherapy will reduce the risk of CNS relapse to a very low level in children with ALL, securing a higher event-free survival rate overall.

The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.

The development of successful therapy for most children with acute lymphoblastic leukemia can be attributed to sequential clinical studies that show the importance of combination chemotherapy, sanctuary-specific treatment, and supportive care measures. The relative resistance of acute myelogenous leukemia to chemotherapy led to strategies that include dose-intensified chemotherapy and bone marrow transplantation. The improvement in long-term survival for children with acute leukemia has been gratifying but also has been associated with late effects that underscore the need for careful follow-up and for designing risk-adapted therapies.

Objectives: To assess the incidence of isolated central nervous system (CNS) relapses in patients of acute lymphoblastic leukemia (ALL) treated with a protocol containing cranial irradiation and intrathecal methotrexate as CNS directed therapy., Design: Prospective non randomized study., Setting: Department of Medical Oncology, Tata Memorial Hospital., Subjects: 623 children of ALL on MCP 841., Methods: CNS relapse was diagnosed, if upon examination of the CSF, more than 50 cells/microliter were observed, or a count of 5 cells which were unequivocally lymphoblasts., Results: The incidence of isolated CNS relapse was 1.75% with the use of this treatment. Age, sex, white blood cell count, platelet count, lactic dehydrogenase and immunophenotyping were not significantly related to isolated CNS relapse., Conclusion: A low incidence of isolated CNS relapse demonstrates the adequacy of the presymptomatic CNS therapy.

Cognitive outcome, as measured by verbal and performance IQs, was compared in 35 girls and 47 boys who were in first remission for acute lymphoblastic leukaemia. All children had received presymptomatic cranial radiotherapy and intrathecal methotrexate. The mean age at diagnosis was 4.2 years and the mean elapsed time from initial diagnosis to intellectual assessment was 7.1 years. Results showed that children irradiated before the age of 4 years were impaired in certain aspects of non-verbal ability, as well as in measures of short term memory and attention, calculated by factor scores derived from selected subtests of the IQ test. Subtests requiring verbal and non-verbal reasoning showed the greatest impairment after early diagnosis and treatment. In addition girls were selectively impaired in verbal IQ and other aspects of verbal ability, with the degree of impairment exacerbated by early treatment. No relationship was found between degree of impairment and either time since treatment or number of methotrexate injections. It is concluded that early age at irradiation increases the risk of impaired intellectual outcome, particularly in girls.

The prevention of meningeal leukemia has long been a keystone in its cure. The need was recognized when it became apparent in the 1950s and 1960s that meningeal relapse heralded hematologic relapse and a fatal course and that its incidence increased as systemic chemotherapy became more effective in controlling hematologic and visceral leukemia. Evasion of a biologic safety net, the blood-CSF barrier, is required to prevent meningeal leukemia. Three methods are used: meningeal radiotherapy, intrathecal administration of antileukemia drugs, and high-dosage intravenous antileukemia drugs. Recent and current clinical studies reflect a continuing dialogue about which methods are preferable and under what circumstances. For prevention of meningeal leukemia, extended intrathecal therapy and intensive systemic chemotherapy appear to be as effective as radiotherapy for most patients. For treatment of overt meningeal leukemia, meningeal radiotherapy may be necessary. However, its administration compromises subsequent systemic chemotherapy so that delay may be advisable to allow intensive systemic chemotherapy for control of concurrent hematologic and visceral leukemia, whether clinically evident or not. For patients with meningeal leukemia at diagnosis, cranial irradiation may be delayed or possibly omitted if evidence of disease is minimal and intrathecal and systemic chemotherapy are intensive. For those who develop meningeal leukemia while on therapy or after its completion, cranial or craniospinal irradiation is probably required as well as intensive intrathecal and systemic chemotherapy. Hopefully, current and future studies will dispel the uncertainties and better quantitate risks and benefits of alternative methods. Whatever method is used, careful attention to technical details is required to assure optimal efficacy at the least possible expense in immediate toxicity and late sequelae.

In acute lymphoblastic leukaemia (ALL) substantial progress has been achieved within the last few years. Complete remission rates up to 95% can now be achieved in children and 70-85% in adults; disease free survival rates are 70 and 30% respectively. To improve results further high dose treatment has been included, particularly to overcome drug resistance and to reach cytostatic levels in the sanctuary sites, such as the central nervous system. High dose cytarabine in combination with other cytostatic drugs, preferentially anthracyclines, seems to be of benefit for high risk adult ALL patients. High dose methotrexate, mostly explored in childhood ALL, is now also included in a variety of combinations in the treatment of adult ALL, but its effectiveness remains to be established. Substantial progress has been achieved in adult T-ALL and B-ALL with survival rates of 40-50%. The optimal form and duration of maintenance therapy in adult ALL is not yet clear but general omission of maintenance leaves patients with an inferior outcome. Which subgroups of adult ALL require maintenance and in what form still requires investigation. In recent adult ALL trials with intensive chemotherapy similar prognostic factors for disease free survival have emerged. Of adverse influence are delayed time to reach CR (more than 4/5 weeks), a high initial white blood cell count, higher age (above 50 or 60 years), and probably the immunological subtypes pre-T-ALL, pre-B-ALL, My(+)-ALL; of very adverse influence in elderly patients is the karyotype t(9;22) or the corresponding BCR/ABL gene rearrangement. High risk adult ALL patients with one or more of these adverse factors are candidates for allogeneic or autologous bone marrow transplantation in first remission. Whether all adult ALL patients are candidates for BMT in first CR is currently being explored in large prospective randomized trials.

The majority of therapeutic gains for patients with ALL have come from prospectively planned clinical trials. Beginning in the 1970s, series of well-designed protocols have produced valuable information that has permitted the development of curative therapy for more than two-thirds of patients. This success emphasizes the importance of controlled, carefully analysed therapeutic studies, which pay dividends for many years by providing a sound basis for future developments. Experienced biostatisticians should be involved early in the development of clinical trials to ensure that research questions can be reliably answered in terms of the size and composition of the patient sample and in terms of accrual time. Despite extensive pre-planning, a protocol may require early termination due to unexpected results that compromise the integrity of the initial design (Rivera et al, 1985). Thus, periodic treatment assessment of the trial is crucial to a successful outcome. Extended follow-up of patients is a requirement in every leukaemia study since relapses may occur many years after diagnosis, especially if patients have a lower risk of treatment failure (Rivera et al, 1979). The quality of long-term survival must also be well documented because all protocols include toxic therapy (Ochs and Mulhern 1988). Every physician treating children with ALL would like to select therapy that is both effective and well tolerated. Unfortunately, this is not always possible when patients have high-risk features. Secondary AML, deaths in remission and fatal organ toxicity (Steinherz, 1991c) are equally devastating complications of current chemotherapy for ALL, and no single protocol can be recommended over any other. Patients with ALL may be equally well served by any of several different protocols. The practice of administering 6MP + MTX alone and usually orally as continuation treatment has been virtually abandoned. Today, most children receive intensified chemotherapy in one schedule or another, including good-risk patients on POG protocols who, although treated largely with antimetabolite-based programmes, receive high-dose chemotherapy during the initial 6 months of treatment. In view of the more favourable results attained with reinduction therapy in recent CCG studies, these investigators also recommend such an approach for children with better-risk ALL. We fully agree. Regrettably, with the success of current regimens for higher-risk ALL, it has not been possible to exclude all toxic agents that may induce serious late complications.(ABSTRACT TRUNCATED AT 400 WORDS)

CNS-directed treatment is an essential component of therapy for both children and adults with acute lymphoblastic leukaemia. The choice between combinations of i.t. drugs, radiotherapy and high-dose systemic chemotherapy is not a clear one and will depend on the age of the patient, the type of leukaemia and indeed the available treatment facilities. A plea is made for any prospective trials of CNS-directed therapy to incorporate formal assessment of neuropsychological performance, and in the young child, of growth and pubertal progression.

In 1981 the BFM group introduced a new treatment strategy for B-ALL based on two alternating 5-day courses of chemotherapy delivered in short intervals up to a total of eight. The therapy courses were composed of fractionated cyclophosphamide, MTX 0.5 g/m2 (24-h infusion), i.t. MTX therapy, and ara-C/VM26 alternating with doxorubicin. The development of the therapy strategies during the subsequent two studies was characterized by shortening treatment duration from eight to six courses, and intensification of CNS chemotherapy in study ALL-BFM-83, and the introduction of HD-MTX (5 g/m2, 24-h infusion) in study ALL-BFM-86. In study ALL-BFM-81, CNS therapy consisted of ID-MTX in combination with i.t. MTX and RX. CNS-positive patients received complete neuroaxis irradiation. In study ALL-BFM-83, CNS chemotherapy was intensified by adding dexamethasone, while MTX/ara-C were administered intraventricularly. Spinal irradiation for CNS-positive patients was omitted. In study ALL-BFM-86, i.t. MTX/ara-C/prednisolone therapy was introduced in combination with HD-MTX but the intraventricular route of drug administration was no longer used. Radiotherapy was omitted completely. In all, 87 patients were enrolled, 22 (eight CNS positive) in study ALL-BFM-81, 24 (seven CNS positive) in study ALL-BFM-83, and 41 (none CNS positive) in study ALL-BFM-86. The estimated 5-year duration of EFS was 40% in study ALL-BFM-81, 50% in study ALL-BFM-83, and 78% in study ALL-BFM-86 (minimal follow-up 36 months). Nineteen of 24 relapses occurred while on therapy or shortly thereafter. In study ALL-BFM-81, the CNS was the most frequent site of failure. In ALL-BFM-83 there were no isolated CNS relapses but more BM relapses occurred. In ALL-BFM-86 localized manifestations were the predominant site of failure, no isolated BM relapses occurred, and only one CNS relapse was diagnosed. No single parameter exerted a consistent influence on outcome with one exception. The presence of residual disease after the first two courses was correlated with an increased risk of therapy failure. Our conclusions from the three studies are listed below. An intensive, short-pulse therapy delivered within a 4 month period is highly effective in the treatment of B-ALL. Prolonged therapy duration is of no value. In addition to fractionated cyclophosphamide-ifosfamide, a 24-h infusion of HD-MTX5 g/m2 in conjunction with an i.t. therapy is a very important component for prevention of both systemic and CNS relapses.(ABSTRACT TRUNCATED AT 400 WORDS)

Purpose: The Pediatric Oncology Group (POG) acute leukemia in childhood (ALinC) 13 study tested two treatment regimens that used different CNS chemoprophylaxis for children older than 12 months with non-T, non-B acute lymphoblastic leukemia (ALL) and with no demonstrable CNS disease at diagnosis., Patients and Methods: With the first regimen, standard (S), six injections of triple intrathecal chemotherapy (TIC), consisting of methotrexate (MTX), hydrocortisone (HC), and cytarabine (ara-C), were administered during intensification treatment and at every-8-week intervals throughout the maintenance phase for 17 additional doses. The second regimen, standard and MTX pulses (SAM), also specified six TICs during intensification, but substituted every-8-week pulses of intermediate-dose parenteral methotrexate (IDM; 1 g/m2) for the 17 maintenance TIC injections, with a low-dose intrathecal (IT) MTX boost administered with the first four maintenance IDM pulses. Otherwise, systemic therapy on regimen SAM was identical to regimen S. There were 1,152 patients randomized to the S and SAM regimens after stratification by risk group (age/leukocyte count) and immunophenotype., Results: The 5-year probabilities (+/- SE) of an isolated CNS relapse were regimen S: good risk (n = 381), 2.8% +/- 1.3%; poor risk (n = 196), 7.7% +/- 3.2%; good + poor risk (n = 577), 4.7% +/- 1.5%; regimen SAM: good risk (n = 388), 9.6% +/- 2.2%; poor risk (n = 187), 12.7% +/- 4.2%; good + poor risk (n = 575), 10.9% +/- 2.2%. In poor-risk patients, approximately one third of the isolated CNS relapses occurred before preventive CNS therapy was begun at week 9. Hence, regimen S has provided better CNS preventive therapy for both good- and poor-risk patients (P < .001 overall). The difference is statistically significant for good-risk patients (P < .001), but not for poor-risk patients (P = .20). Neither treatment has shown a significant advantage in terms of general outcome., Conclusion: TIC injections extended throughout the intensification and maintenance periods are superior to IDM pulses for prevention of CNS leukemia. Our results with TIC seem comparable with those achieved with other contemporary methods of CNS preventative therapy. Thus, extended TIC affords a reasonable alternative to CNS irradiation plus upfront IT MTX for patients with B-progenitor ALL.

Fifteen patients with lymphoid blast crisis of chronic myelogenous leukemia (LyBC-CML) and five patients with acute lymphoblastic leukemia converting to Philadelphia-positive (Ph+) chronic myeloid leukemia (ALL Ph + CML) were followed. Seven of 15 (46.7%) LyBC-CML patients developed meningeal leukemia within a median period of 6 months (range 2-11 months), while there was no medullary relapse. Five of these responded well to triple intrathecal therapy. In the ALL Ph + CML patients, in spite of central nervous system (CNS) prophylaxis with IT MTX and 18 Gy cranial radiation, two of five patients (40%) experienced meningeal leukemia, one isolated and the other with medullary relapse. The data confirm that LyBC-CML patients experience a high incidence of meningeal leukemia. The role of CNS prophylaxis is not very clear, but its use may delay development and reduce morbidity due to CNS disease.