[Severe hemolysis and SIADH-like symptoms induced by vincristine in an ALL patient with liver cirrhosis]

[Article in Japanese]

Nishihori Y, Yamauchi N, Kuribayashi K, Sato Y, Morii K, Hirayama Y, Sakamaki S, Honma H, Suzuki N, Kudo T, Niitsu Y.

Department of Internal Medicine (Section 4), Sapporo Medical University School of Medicine.

An 11-year-old boy was diagnosed as having acute lymphoblastic leukemia (ALL, L1) in 1987 and underwent treatment with an ALL high-risk protocol (prednisolone, vincristine (VCR), daunorubicin, 1-asparaginase), which resulted in complete remission. In 1990 he developed chronic hepatitis C and received interferon therapy. In December 1994, ALL recurred, and the patient was treated with VCR. He subsequently developed severe hemolysis (Hb 12.5 g/dl-->6.8 g/dl) with increases of indirect bilirubin, AST, and LDH. Furthermore, symptoms resembling a syndrome of inappropriate secretion of ADH (SIADH) and DIC developed. Upon incubation of the patient's red blood cells with VCR in vitro, extreme deformity of the cells was observed. These findings suggested that splenomegaly, due to liver cirrhosis which had developed rapidly from chronic hepatitis C while the patient was in an immunosuppressed state induced by anticancer drugs, had trapped the deformed red blood cells and resulted in severe hemolysis. The patient died on the 165th day after admission due to liver failure.

PMID: 11193445 [PubMed - indexed for MEDLINE]

[Syndrome of inappropriate secretion of antidiuretic hormone in a patient with myeloid antigen positive acute lymphoblastic leukemia after systemic chemotherapy including vincristine]

[Article in Japanese]

Yoshida M, Ogawa K, Sakamoto H, Motomura S, Ishigatsubo Y.

Dept. of Collagen Disease and Hematology, Fujisawa City Hospital.

We report a case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after the patient had received several anti-cancer drugs, including vincristine (VCR), in a patient with myeloid antigen positive acute lymphoblastic leukemia (My(+)-ALL). A 53-year-old woman presented at the hospital complaining of high-grade fever and general lassitude. Further examination revealed that she had My(+)-ALL. On admission, she was treated with anti-cancer drugs, including VCR. On day 24, after the first administration of VCR, a conscious disturbance suddenly occurred and she was diagnosed with SIADH. A plain head CT scan showed a low density lesion through the gray matter to the white matter in the bilateral occipital lobe, as well as diffuse swelling of the cerebrum. This was not seen on the follow up CT scan, and we concluded that it had been a transient abnormal finding due to SIADH. She achieved complete remission after induction chemotherapy and 3 added courses of consolidation chemotherapy. VCR was also administered 4 times in the second consolidation chemotherapy, but hyponatremia did not occur. This case suggests that a head CT scan is a useful procedure for the diagnosis and monitoring of SIADH, and that VCR may still be used in a patient who has suffered from VCR-induced SIADH.

PMID: 10660739 [PubMed - indexed for MEDLINE]

Severe vincristine toxicity in combination with itraconazole.

Gillies J, Hung KA, Fitzsimons E, Soutar R.

Department of Haematology, Monklands District General Hospital, Airdrie, UK.

We report two patients with acute lymphoblastic leukaemia (ALL) who were entered into the current MRC adult ALL trial (UKALL XII) in whom unusually severe vincristine induced neurotoxicity developed. This appeared to be the result of an interaction with itraconazole suspension.

PMID: 9681224 [PubMed - indexed for MEDLINE]

Bone marrow transplantation versus chemotherapy for maintenance of second remission of childhood acute lymphoblastic leukemia: a study of the Children's Cancer Group (CCG-1884).

Feig SA, Harris RE, Sather HN.

UCLA Children's Hospital, Los Angeles, CA, USA.

BACKGROUND: Maintenance of second remission of childhood acute lymphoblastic leukemia (ALL) with intensive chemotherapy is often unsuccessful. The major cause of treatment failure is relapse. MATERIALS AND METHODS: Of 96 children with ALL who relapsed in the marrow while on or within 1 year of completing initial therapy, 62 achieved a second remission. Nineteen patients underwent bone marrow transplantation in second remission, 11 from a human leukocyte antigen (HLA)-matched related donor, seven using autologous marrow, and one from a matched unrelated donor. The event-free survival (EFS) of transplanted patients was compared to that of patients treated with intensive chemotherapy using high-dose cytarabine, vincristine, escalating dose methotrexate, L-asparaginase, and an anthracycline (daunorubicin or idarubicin). Only those patients treated with chemotherapy who survived in second remission up to the mean time that patients were transplanted (135 days) were included in the control group (33 of 43 patients who achieved second remission). RESULTS: The actuarial 2-year event-free survival of transplanted patients is 37+/-22% (95% C.I.) compared to 18+/-13% for chemotherapy-treated patients (P=0.017). EFS for allo-transplant recipients was similar to that for auto-transplant recipients. Duration of initial remission was a strong predictor of the outcome of retrieval therapy. Patients whose initial remission was greater than 3 years had better EFS after achieving second remission (five of 11 still in remission, compared to four of 41 patients whose initial remission was less than 3 years). Adjustment in the multivariate analysis for duration of initial remission did not diminish the benefit of transplant over chemotherapy. CONCLUSIONS: While there remains considerable possibility for further improvement in EFS after achieving second remission of childhood ALL, bone marrow transplant is superior to chemotherapy in maintaining second remission.

PMID: 9324340 [PubMed - indexed for MEDLINE]

Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group.

Childhood AlL Secretariat, CTSU, Radcliffe Infirmary, Oxford, UK.

BACKGROUND: The effects on long-term outcome in childhood acute lymphoblastic leukaemia (ALL) of the duration and the intensity of maintenance chemotherapy need to be assessed reliably. With this objective the Childhood ALL Collaborative Group coordinated a worldwide overview of all randomised trials that began before 1987. METHODS: Individual patient data were sought for about 3900 children in trials of longer vs shorter maintenance (eg, 3 vs 2 years), 3700 in trials of intensive "reinduction" chemotherapy during maintenance, and 4400 in trials of various other questions, including 1300 in trials of pulses of vincristine and prednisone (VP) during maintenance. Analyses were of survival in first remission, overall survival, and cause-specific mortality. FINDINGS: Deaths during remission were increased by longer maintenance (2.7 percent vs 1.2 percent), VP pulses (4.0 vs 3.2 percent), and intensive reinduction (4.8 percent vs 3.3 percent), but these increases were counterbalanced by reductions in relapses. Total events (relapse or death) were significantly reduced by longer maintenance (23.3 percent vs 27.6 percent), VP pulses (31.2 percent vs 40.4 percent) and intensive reinduction (27.8 percent vs 35.8 percent) (each 2p<0.001). Many of those who relapsed were successfully re-treated, however, and only for intensive reinduction was overall survival significantly improved (18.5 percent vs 22.3 percent; 2p=0.01). INTERPRETATION: Intensive reinduction chemotherapy in these trials produced an absolute improvement of about 4 percent in long-term survival; if the extra deaths in remission had been avoided, this would have been a 5 percent benefit. Further improvements in survival seem more likely to be obtained with intensive treatment than with longer low-level maintenance.

Publication Types: Meta-Analysis

PMID: 8667921 [PubMed - indexed for MEDLINE]

Liver function studies in children with acute lymphocytic leukemia after cessation of therapy.

Bessho F, Kinumaki H, Yokota S, Hayashi Y, Kobayashi M, Kamoshita S.

Department of Pediatrics, University of Tokyo Hospital, Japan.

We investigated liver function in 27 children with acute lymphocytic leukemia (ALL) after cessation of therapy. Induction therapy consisted of prednisolone+vincristine (VP regimen) alone (16 patients) or with addition of daunorubicin (4 patients) or L-asparaginase (7 patients). Patients treated with VP regimen received short courses of VP regimen every 12 weeks for the first year of maintenance. Twenty-five patients remained in first complete remission and had completed 3-year maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) 1-7 years prior to this study. Twenty-three patients had received transfusions of packed red blood cells or fresh whole blood (1-11 units; median: 2 units) but none had evidence of either hepatitis B or hepatitis C. Alanine aminotransferase (ALT), which was measured every 3 months during maintenance therapy, had values more than three times the upper limit of the normal range in 25% of the measurements in more than half of the patients. However, by 3 months after the completion of maintenance therapy, ALT had normalized in all patients and remained normal in all but two patients until the time of this study. Serum bilirubin, serum albumin, and prothrombin time were all within normal limits. Fasting and 2-hour postprandial total serum bile acids were high in 5 of 13 patients and in 6 of 13 patients, respectively. The ratio of cholic acids+deoxycholic acids to chenodeoxycholic acids+lithocholic acids was below 1 in all but two patients, whereas this ratio was above 1 in all controls. Our bile acid profile results indicate the necessity of careful long-term follow-up of survivors of ALL treated with hepatotoxic chemotherapy during childhood.

PMID: 8202032 [PubMed - indexed for MEDLINE]

6-Mercaptopurine cumulative dose: a critical factor of maintenance therapy in average risk childhood acute lymphoblastic leukemia.

Dibenedetto SP, Guardabasso V, Ragusa R, Di Cataldo A, Miraglia V, D'Amico S, Ippolito AM.

Division of Pediatric Hematology-Oncology, University of Catania, Italy.

A multivariate survival analysis including gender, age, log white blood cell (WBC) count, liver and spleen size at diagnosis, mean log WBC count during maintenance therapy, and the prescribed cumulative doses of 6-mercaptopurine (6-MP), methotrexate (MTX), vincristine (VCR), and prednisone (PDN) during maintenance therapy was performed on 53 children with average-risk acute lymphoblastic leukemia (ALL). The 6-MP cumulative dose prescribed during maintenance therapy resulted in the most important statistically significant independent prognostic factor. Patients who received less than the median cumulative dose of 6-MP (86% of planned protocol dose) fared significantly worse than the other patients, regardless of WBC count at diagnosis, gender, age, and other factors studied. Therefore, 6-MP cumulative dose during maintenance therapy may be the critical factor for effective maintenance therapy in childhood ALL.

PMID: 8060809 [PubMed - indexed for MEDLINE]

Optimal current treatment of childhood acute lymphoblastic leukemia.

Simone JV.

The treatment of childhood acute lymphoblastic leukemia (ALL) has been remarkably successful over the past 30 years of the chemotherapy era. A substantial proportion of patients, perhaps 40%-50%, are apparently cured with currently available therapy. However, optimal therapy has not yet been devised because of substantial therapeutic failures in the form of relapse and unacceptable side effects. Remission induction therapy is the most settled aspect of therapy. The addition of asparaginase or an anthracycline to prednisone and vincristine is highly effective. Preventive central nervous system therapy is under revision and study, with a variety of approaches likely to prove equally effective. Continuation (maintenance) therapy is in the most need of revision because a majority of therapeutic failures are due to bone marrow relapse--the failure of systemic therapy to prevent emergence of resistant leukemia cells. The optimal duration of therapy has not been established, the relapse after cessation of therapy lasting 2-3 years currently being 20%-25%. Bone marrow transplantation during remission shows promise as a therapeutic modality. The most promising development, however, is our increasing understanding of biological subpopulations of leukemia cells. This ultimately may help us develop more effective and specific therapy for childhood ALL.

PMID: 7049384 [PubMed - indexed for MEDLINE]

Outlook for acute lymphocytic leukemia in children in 1982.

Simone JV.

The treatment of childhood ALL has been remarkedly successful over the past 30 years of the chemotherapy era. A substantial proportion of patients, perhaps 40--50%, are apparently cured with currently available therapy. However, optimal therapy has not yet been devised because of substantial therapeutic failures in the form of relapse and unacceptable side-effects. Remission induction therapy is the most settled aspect of therapy. The addition of asparaginase or an anthracycline to prednisone and vincristine is highly effective. Preventive central nervous system therapy is under revision and study. It is likely that a variety of approaches will be equally effective. Continuation (maintenance) therapy is in the most need of revision because of a majority of therapeutic failures are due to bone marrow relapse--the failure of systemic therapy to prevent emergence of resistant leukemia cells. The optimal duration of therapy has not been established, the relapse rate after cessation of therapy lasting 2-3 years currently being 20-25%. Bone marrow transplantation during remission shows promise as a therapeutic modality, particularly if autologous techniques are successful. The most promising development, however, is our increasing understanding of biological subpopulations of leukemia cells. This ultimately may help us develop more effective and specific therapy for childhood ALL.

Publication Types: Review

PMID: 7013662 [PubMed - indexed for MEDLINE]

Inappropriate secretion of antidiuretic hormone secondary to vincristine therapy.

Cutting HO.

PMID: 5095530 [PubMed - indexed for MEDLINE]

Vincristine neurotoxicity with hyponatremia.

Slater LM, Wainer RA, Serpick AA.

PMID: 4974027 [PubMed - indexed for MEDLINE]

[Severe hyponatremia in two cases of childhood acute myeloid leukemia--syndrome of inappropriate secretion of antidiuretic hormone secondary to vincristine therapy (author's transl)]

[Article in Japanese]

Tsunematsu Y, Kikuchi K, Koide R.

PMID: 4532692 [PubMed - indexed for MEDLINE]

Hyponatremia in association with vincristine therapy.

Nicholson RG, Feldman W.

PMID: 4501374 [PubMed - indexed for MEDLINE]

Vincristine neurotoxicity and abnormal secretion of antidiuretic hormone.

Robertson GL, Bhoopalam N, Zelkowitz LJ.

PMID: 4356234 [PubMed - indexed for MEDLINE]

[Electrolyte changes in acute leukemia in childhood]

[Article in German]

Gadner H, Martins da Cunha AC.

Electrolyte imbalance in leukemia can be due to either organ infiltration and cell death or to a side effect of cytostatic drugs. From the wide variety of these disturbances seen in acute leukemias in childhood, the excess of potassium is most dangerous. Further electrolyte changes, which are however less evident, are hyperphosphataemia, hyperphosphaturia, and hypocalcaemia. The destruction of a large amount of cells during aggressive induction therapy can boost the electrolyte imbalance and therefore lead to renal failure. Such situations are demonstrated in two cases. Following Vincristine and Cyclophosphamide administration, electrolyte changes such as acute or prolonged decrease of sodium in the serum and urinary loss of sodium are seen frequently. Based on the data from 20 patients with acute lymphoblastic leukemias we describe the dynamics of this process. These changes are probably caused by the syndrome of inadequate ADH-secretion. The clinical importance of these findings are discussed and procedures for improving therapy are set out.

PMID: 3857551 [PubMed - indexed for MEDLINE]

[Successful vindesine treatment in the patient with blastic crisis of CML complicated with syndrome of inappropriate secretion of ADH secondary to vincristine]

[Article in Japanese]

Nishinarita S, Sasaki I, Hiranuma M, Sugai Y, Yoshizawa T, Sawada S, Amaki I.

PMID: 3469429 [PubMed - indexed for MEDLINE]

[Inappropriate ADH syndrome and other toxic effects in the course of childhood ALL treated with vincristine]

[Article in Spanish]

Indiano JM, Gonzalez A, Oria de Rueda O, Sanchez E.

Universidad del Pais Vasco, Departamento de Pediatria, Hospital de Basurto, Bilbao.

PMID: 3214029 [PubMed - indexed for MEDLINE]

Vincristine overdose: experience with 3 patients.

Comment in: Pediatr Hematol Oncol. 1991 Apr-Jun;8(2):ix.

Kosmidis HV, Bouhoutsou DO, Varvoutsi MC, Papadatos J, Stefanidis CG, Vlachos P, Scardoutsou A, Kostakis A.

Department of Oncology, Children's Hospital, A. Kyriakou, Athens, Greece.

Vincristine overdose (7.5 mg/m2) was accidentally administered to 3 children with acute lymphoblastic leukemia. Treatment included double-volume exchange transfusion, phenobarbital administered prophylactically, and folinic acid rescue 18 mg every 3 hours for 16 doses. Vincristine levels were also assayed and showed a dramatic decline in postexchange levels in the 2 patients who survived and an almost unchanged value in the patient who succumbed. Early signs of toxicity in the 2 survivors were peripheral neuropathy (day 4), bone marrow toxicity (day 5), gastrointestinal toxicity (days 6 and 7), and hypertension (days 7 and 8). Marrow aplasia lasted for 4 and 10 days, peripheral neuropathy for 15 and 42 days, gastrointestinal toxicity for 3 and 5 days, and hypertension for 5 and 14 days. The 2 children were discharged on days 13 and 16 and cytostatic therapy was restarted on days 18 and 25. Both are alive without evidence of leukemia. The third patient developed liver and marrow toxicity on day 3 and died on day 9. Postmortem examination showed leukemia infiltration of the liver and spleen.

PMID: 1863543 [PubMed - indexed for MEDLINE]

Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine.

Stuart MJ, Cuaso C, Miller M, Oski FA.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been recognized to occur following treatment with vincristine. None of the reports have provided information regarding its potential for recurrence on further challenge with vincristine (VCR), an agent generally required for repeated use in patients with malignancies. Symptomatic hyponatremia and SIADH that occurred 8 days following administration of VCR in a child with acute lymphatic leukemia was documented with specific radioimmunoassay of urinary ADH levels. The further occurrence of recurrent elevations in ADH excretion 8-10 days following repeated treatment with VCR was also observed. However, SIADH was prevented by prophylactic rigorous fluid restriction. The occurrence of SIADH following VCR therefore does not preclude the further safe usage of this drug.

PMID: 1054263 [PubMed - indexed for MEDLINE]

[Inappropriate secretion of antiduiuretic hormone during acute leukaemia treated with vincristine. Two cases (author's transl)]

[Article in French]

Philip T, Souillet G, Gharib C, Geelen G, Allevard AM, Hartemann E, David M.

One the basis of two special typical cases, the authors detail the symptoms and signs and consider the physiopathology of inappropriate secretion of antidiuretic hormone related to vincristine. Urinary ADH was measured in both cases. ADH levels could be studied on ten consecutive occasions during the course of one of the cases (obs. n 1). Eleven similar cases have been found in the literature. ADH was measured in only three of them. Methods of treatment are considered, with particular emphasis on the role of demeclocycline.

PMID: 112579 [PubMed - indexed for MEDLINE]