mesna and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; B-Cell Activating Factor; Bone Marrow; Chemokine CXCL12; Drug Resistance, Neoplasm; Etoposide; Female; Filgrastim; Gene Expression Regulation, Leukemic; Humans; Ifosfamide; Interleukin-7; Male; Mesna; Middle Aged; Neoplasm Proteins; Neoplastic Stem Cells; Osteocalcin; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Salvage Therapy; Stem Cell Niche; Tumor Microenvironment; Young Adult

Approximately 25% of children newly diagnosed with acute lymphoblastic leukemia (ALL) will eventually experience leukemic relapse, with bone marrow being the most common site of recurrence. The ability to achieve a durable second remission is complicated by toxicity and resistant disease. We report a novel combination of chemotherapy for relapsed pediatric ALL.. Thirty pediatric patients with relapsed medullary (n = 18) and extra-medullary (n = 12) ALL were enrolled at three pediatric institutions. Following receipt of induction and the first Block A and Block B of intensification, each patient was evaluated for toxicity, efficacy in achieving remission, and long-term survival. Additionally, minimal residual disease (MRD) detection by multidimensional flow cytometry (MDF) was performed.. During induction, the major non-hematopoeitic toxicities were mucositis (30% of patients) and bacteremia (50% of patients). Two patients (7%) died of toxicity during induction. Toxicity during intensification Block 1A and 1B was markedly reduced. Eight-nine percent of patients with marrow disease achieved a remission following induction and intensification. The event-free survival (EFS) for all patients at 2 and 4 years were 60% (95% CI: 42-78%) and 49% (95% CI: 30-68%), respectively.. This regimen for patients with relapsed ALL was successful in achieving a second remission for the majority of patients with acceptable toxicity.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bacteremia; Bone Marrow Neoplasms; Child; Child, Preschool; Cytarabine; Dexamethasone; Etoposide; Female; Flow Cytometry; Humans; Idarubicin; Ifosfamide; Infant; Infusions, Intravenous; Leucovorin; Male; Mesna; Methotrexate; Mouth Mucosa; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Stomatitis; Thioguanine; Treatment Outcome; Vincristine

Ifosfamide has previously been shown to be active as a single agent and in combination with doxorubicin, etoposide, and teniposide in pediatric solid tumors and adult acute leukemia. The authors performed a dose-escalation trial of ifosfamide with a fixed dosage of etoposide, with mesna uroprotection, in children with multiply recurrent acute leukemia.. Chemotherapy was administered daily for 5 days. Etoposide 100 mg/m2 was followed by ifosfamide at an initial dosage of 1.6 g/m2. The ifosfamide was escalated in 20% increments to the maximum tolerated dosage in cohorts of three patients. Mesna 400 mg/m2 was given immediately before the ifosfamide and then at 3 and 6 hours after ifosfamide in the initial patients. Subsequent patients were treated with mesna 400 mg/m2 just before ifosfamide, and then every 2 hours to a total dosage equal to the ifosfamide dosage.. Forty-four heavily pretreated patients were entered on study. Forty were evaluable for toxicity and 36 for response as well. The maximum tolerated dosage of ifosfamide was 4.0 g/m2/d for 5 days (20 g/m2/course). Overall, 10 patients achieved complete remission, and 3 achieved partial remission. Remissions were brief, although four patients went on to bone marrow transplant while in remission. One patient is still alive.. The combination of etoposide and ifosfamide with mesna uroprotection showed promising activity in children with multiply recurrent acute leukemia.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Child; Drug Tolerance; Etoposide; Humans; Ifosfamide; Leukemia, Myeloid; Mesna; Neoplasm Recurrence, Local; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Urinary Tract

Nine patients (3 boys and 6 girls) with a median age of 9.5 years, with immediate type hypersensitivity reactions to chemotherapeutic agents were reviewed. The presenting symptoms were urticaria (4/9) and anaphylaxis (5/9). The causative agents were vincristine (2/9), L-asparaginase (2/9), mesna (1/9), cyclosporine (1/9), carboplatin (2/9) and cyclophosphamide (1/9). Three of the five patients with anaphylaxis were changed to alternative chemotherapeutic agents. In two cases alternative drugs were not available and the patients underwent safe and successful desensitization. Three of the 4 patients with urticaria were successfully exposed to graded challenges with cyclosporine, carboplatin and cyclophosphamide, respectively. In the other case with generalized urticaria, mesna was withdrawn due to a positive intradermal test. In patients with immediate type hypersensitivity reactions to chemotherapeutic drugs, if effective alternative chemotherapeutic agents are not available and/or the skin test is negative, a careful drug challenge and/or desensitization should be performed.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Carboplatin; Central Nervous System Neoplasms; Child; Child, Preschool; Desensitization, Immunologic; Drug Hypersensitivity; Female; Glioma; Humans; Hypersensitivity, Immediate; Male; Mesna; Practice Guidelines as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Skin Tests; Vincristine; Withholding Treatment

Topics: Antineoplastic Combined Chemotherapy Protocols; BK Virus; Cyclophosphamide; Cystitis; Cytarabine; Hemorrhage; Humans; Immunocompromised Host; Mesna; Papillomavirus Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Tumor Virus Infections; Vincristine

Based on previous reports suggesting that an intravenous (i.v.) continuous infusion of alkylating agents produced a significant response rate in acute lymphoblastic leukemia (ALL), a phase I trial of ifosfamide/mesna (IFO/MES) was conducted in 11 adult patients with relapsed ALL. IFO/MES were administered as a 24-h i.v. continuous infusion in doses ranging from 5 g/m2 to 9 g/m2; the courses of treatment were repeated every 3 weeks. Patients were examined for toxicity after every cycle and responses were carefully defined and evaluated. All 11 admitted patients were evaluable for toxicity and response. Myelosuppression was the dose limiting effect and it was dose-related. Microscopic and/of macroscopic hematuria was detected in four (11%) out of 36 cycles administered. Ifosfamide produced a positive biological response with a preliminary response rate of 45.4%. Ifosfamide/mesna in a 24-h i.v. continuous infusion appears to be tolerated and produces a biological response in ALL. We recommend that phase II studies of this drug schedule be conducted at the initial dose of 7 g/m2 repeated every 3 weeks and combined with other antileukemic agents.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Clinical Trials, Phase I as Topic; Drug Combinations; Humans; Ifosfamide; Infusions, Intravenous; Mesna; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Respiratory System Agents

Chemotherapy induces high remission rates in high-grade lymphoma. However relapse remains a major problem. One approach to this is myeloablative chemotherapy with transplantation of autologous bone marrow or peripheral blood progenitor cells (PBPC). Immunological mechanisms have been suggested to play a role in the prevention of relapse after transplantation. We investigated the recovery of cellular immune functions after high-dose chemotherapy and PBPC transplantation in 5 patients with high grade non-Hodgkin's lymphoma. All patients showed rapid reconstitution of natural killer (NK) and inducible lymphokine-activated killer (LAK)-activity 10-14 days after transplantation. Four of 5 patients showed higher levels of LAK-generation in the post-transplant period compared with levels prior to myeloablative treatment. Absolute lymphocyte counts in peripheral blood reached 1.0 x 10(9)/l between days 10 and 13 with a predominance of CD8+ cells and an inversion of the CD4/CD8 ratio. Four of 5 patients had a transient increase in CD56+ and CD16+ cell counts post-transplant. No change in the proportion of CD25+ cells was noted. These results show that PBPC transplantation leads to a rapid recovery of cellular immune functions after myeloablative chemotherapy and provides evidence for an increased presence of LAK precursor cells early in the post-transplant period which can be activated by IL-2 to exert high levels of cytotoxicity.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Diseases; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Leukapheresis; Lymphocyte Count; Lymphocyte Subsets; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Melphalan; Mesna; Middle Aged; Podophyllotoxin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Time Factors; Treatment Outcome; Vincristine

The activity of the drug combination ifosfamide and etoposide (VP16) in refractory and relapsed childhood acute lymphoblastic leukemia (ALL) was assessed in a phase II study.. Twenty children with ALL, all heavily pretreated and in bone marrow relapse, were entered on the study. Drugs were given i.v. each day for 5 days at the following doses: ifosfamide 1.8 g/m2/day, VP16 100 mg/m2/day, and MESNA 2,880 mg/m2/day (as a uroprotectant); cycles were repeated every 28 days. At study entry, eight patients were in first relapse (five of whom had failed intensive reinduction regimens), seven were in second relapse, and five were in third relapse. All patients had received cyclophosphamide in regimens before relapse.. Eight patients (40%; 95% confidence interval 19-64%) achieved complete bone marrow remission with ifosfamide/VP16. Three patients subsequently relapsed in the bone marrow while on ifosfamide/VP16 therapy. Duration of remission ranged from 21 to 247 days. Treatment was generally well tolerated, with myelosuppression the most common toxicity; fever and neutropenia occurred in 18 of 31 evaluable cycles.. The combination of ifosfamide/VP16 has significant activity in recurrent and refractory childhood ALL with tolerable toxicity.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Etoposide; Female; Humans; Ifosfamide; Infant; Male; Mesna; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

We studied the efficacy of mesna as a protectant for urotoxicity in pediatric patients receiving chemotherapy including oxazaphosphorines. Nineteen patients with malignant diseases (5 neuroblastoma, 3 acute lymphocytic leukemia, 4 acute non-lymphocytic leukemia, 2 non-Hodgkin lymphoma, 3 osteosarcoma and 2 rhabdomyosarcoma) were treated with a total of 106 courses of therapy between June of 1986 and May of 1989. Of these, no gross hematuria were seen. Microhematuria transiently occurred only in 2 courses (5%) of 1 patient (2%). These data indicated that mesna was highly effective for urotoxicity of oxazaphosphorines without any side effects, especially in pediatric patients.

Topics: Bone Neoplasms; Child; Cyclophosphamide; Cystitis; Female; Hematuria; Humans; Ifosfamide; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptoethanol; Mesna; Neuroblastoma; Osteosarcoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rhabdomyosarcoma