Twenty years of Polish experience with three consecutive protocols for treatment of childhood acute myelogenous leukemia.

Until 1983, results of treatment of acute myelogenous leukemia (AML) in Poland with different regimens were very poor. In 1983, the Polish Pediatric Leukemia/Lymphoma Study Group introduced a unified treatment protocol--a modified version of BFM-83 protocol. This led to an increase in the curability of AML from 15% to approximately 32%. In 1994, a modification was made: the high-risk patients (>5% blasts in bone marrow on day 15 of therapy and all M5 cases) received two additional cycles with intermediate-dose cytarabine (ID-ARAC). This led to a nonsignificant improvement in the 5-year event-free survival (EFS) rate from 32 to 36%. A new treatment protocol employing idarubicin in place of daunorubicin was introduced in 1998 and produced better initial responses, increase in the number of patients attaining remission after induction therapy and proportional increase of standard-risk patients. The probability of 5-year EFS (pEFS) for the whole group of patients increased from 36 to 47%. In standard- and high-risk groups, the 5-year pEFS was 62 and 33%, respectively. The probability of 5-year disease-free survival was 58% in the whole group, and there were no differences between risk groups. Unsatisfactory treatment results in children classified into the high-risk group are principally due to the low remission rate.

Incidental neuroblastoma.

The diagnosis of neuroblastoma in its early stage, especially in asymptomatic children, with the so-called incidentally diagnosed disease, may be associated with a good prognosis. The aim of this study is an attempt at analyzing this problem. Between 1 January 1993 and 30 April 1998, 40 children with newly diagnosed neuroblastoma started therapy at the authors' department. The disease was diagnosed incidentally in 5 (12.5%) patients. In no incidentally diagnosed child was stage IV disease detected, while in the remaining patients its incidence was 71%. All the children (median age 2 months) with incidental diagnosis have remained alive (median 39 months) in continuous remission without treatment. Among 35 children (median age 2 years and 7 months) with overt neuroblastoma, 18 died (median survival time 14.5 months). Seventeen patients have remained alive (median 45 months). The results show that children with incidentally diagnosed neuroblastoma are characterized by a more favorable prognosis than children with clinical disease.

[High risk acute lymphoblastic leukaemia in children. Preliminary report after introducing a new version of New York (1997) protocol adjusted to the age of the patients. Report of the Polish Paediatric Leukaemia/Lymphoma Study Group]. / Ostra bialaczka limfoblastyczna u dzieci w grupie duzego ryzyka. Wstepne obserwacje po wprowadzeniu kolejnej modyfikacji (1997) protokolu Nowy York dostosowanej do wieku. Raport Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczki i Chloniaków.

The paper presents the experience of the Polish Paediatric Leukaemia/Lymphoma Study Group in the treatment of high-risk acute lymphoblastic leukaemia in children using a new version of the New York (1997-1999). Protocol with treatment intensity adjusted according to the age of the patients. From April 1997 to December 1999 a group of 49 children with leukocytosis ranging from 50 900/mm3 to 580 000/mm3 (median 122 000/mm3) and 6 children with leukocytosis below 50 000/mm3 and poor response to steroids were treated with this protocol. Children below 10 years (43 patients) were treated according to the previous protocol, children above 10 years (12 patients) were treated with intensified protocol (high doses of ARA-C in consolidation and intermediate doses of Mtx in maintenance). Induction was identical for all patients. Complete remission was achieved in 92.6% patients. There were 2 relapses. Six children died - 3 without remission, 2 due to a relapse, 1 due to treatment complications. The current opinions concerning classification of HRG-ALL and treatment possibilities in this group of children are discussed.

[Results of treatment of children with chronic myelogenous leukaemia (CML) obtained by the Polish Paediatric Leukaemia/Lymphoma Study Group]. / Wyniki leczenia dzieci chorych na przewlekla bialaczke, szpikowa (CML) w materiale Polskiej Pediatrycznej Grupy ds Leczenia Bialaczek i Chloniaków u Dzieci.

Retrospective analysis of 102 children with CML from 9 paediatric centres in Poland has been performed. A total number of 102 children: 58 boys and 44 girls aged 1-17 years (median 9.4 years old) with CML, treated in the period 1975-1999 were included in the study. Forty eight of 102 (47.1 %) children were treated with cytostatic drugs without IFN alpha: busulfan, hydroxyurea, 6-mercaptopurine or etoposide (VP-16). Fifty four of 102 (52.9%) patients were treated with interferon alpha (IFN alpha) after cytoreductive pretreatment. Thirty out of 102 (29.4%) patients underwent stem cell transplantation (SCT): 24 - matched related donor allo-BMT, 2 - matched unrelated donor allo-BMT, 1 - partially matched related donor T-cell depleted allo-PBPCT, 1 - syngeneic allo-BMT and 2 - autologous PBPCT. Overall survival analysis revealed that 46 of the 102 (45.1%) children remained alive: 5/35 (14.3%) children treated with cytostatics alone, 22/37 (59.5%) children treated with IFN alpha and 19/30 (63.3%) children treated with SCT. Among SCT survivors there are 10/17 (58.8%) children treated with IFN alpha prior to SCT and 9/13 (69.2%) children treated with cytostatics alone prior to SCT. The probability of 5-year survival is 0.51 in the group treated with SCT (median follow-up 58 months); 0.43 in the group treated with IFN alpha (median follow-up 53 months) and 0.23 in the group treated with cytostatics (median follow-up 31 months). Our data show, that BMT is the treatment of choice in CML in children. IFN alpha could be successfully applied as an alternative treatment for those, who do not have a suitable donor for allogeneic SCT. Better outcome in post BMT children, who were not treated with IFN alpha prior to SCT requires confirmation by studies on larger groups of patients. However, it seems to be justified to stop IFN alpha therapy at least 3 months before SCT. The main reason for unsuccessful treatment outcome in patients with CML in Poland remains the still insufficient access to MUD-BMT.

[Preliminary results of BFM 96 protocol in treatment of childhood ALL relapse in the experience of the Polish Paediatric Leukaemia /Lymphoma Study Group]. / Wstepne wyniki leczenia i nawrotu ostrej bialaczki limfoblastycznej cobl wg programu BFM 96 u Dzieci w Materiale Polskiej Grupy ds. Leczenia Bialaczek i Chloniaków.

Between 1998 and 1999, 36 children aged from 3 months to 18 years (10 girls and 26 boys) with first relapse of acute lymphoblastic leukaemia were included in the study. The children were treated according to the BFM 96 relapse protocol. There were 24 cases with early (including 9 children with very early) and 12 cases with late relapse ( BM-20, local extra BM-6, combined 10). The overall second complete remission (CR) rate was 83,33%. The probability of overall EFS after 2 years was 73,3%. The results obtained with BFM 96 chemotherapy in children with first late relapse are acceptable. For children with early relapses, megachemotherapy with BMT in second remission should be used.

[Abdominal presentation of B-cell non-Hodgkin's lymphoma (B-NHL) - surgical treatment and its results. Report of the Polish Paediatric Leukaemia/Lymphoma Study Group]. / Manifestacja brzuszna chloniaka B-komórkowego u dzieci - interwencja chirurgiczna i wyniki leczenia. Raport PPGLBC.

The aim of this study was to analyse the effect of LMB-89 protocol and surgical procedure at initial laparotomy on the outcome in children with abdominal B-cell NHL. The initial surgery intervention was: complete resection (20% pts), subtotal resection (20%), partial resection (4%), biopsy (36%). Postoperative complications occurred in 5 children. Complete recovery (CR) was achieved in 92% pts. There were 4% non responder patients. Two patients died before CR evaluation (tumour lysis syndrome; bleeding and multi organ failure after initial surgery). One patient died in CCR from sepsis probably influenced by the previous local operation. 10.8% patients relapsed. The estimate EFS for all patients with AB-NHL is 81%, 85% for stage III and 73% for stage IV. Major surgery in advanced stages is not recommended since it delays chemotherapy and fails to improve overall survival.

[G-CSF and GM-CSF in treatment of neutropaenia after chemotherapy in children with neoplasms]. / G-CSF i GM-CSF w leczeniu neutropenii po chemioterapii nowotworów u dzieci.

A total number of 608 cycles of G-CSF and/or GM-CSF was applied in 280 patients aged from 6 months to 20 years during neutropaenia associated with chemotherapy of children's neoplasms (NHL-124, NBL-42, RMS-36, Nephroblastoma-18, Osteosarcoma-17, Ewing's Sarcoma-14, Hepatoblastoma-6, Neurofibrosarcoma-6, PNET-5, Medulloblastoma-3, Fibrohistiocytoma-3, Angiosarcoma-2, other - 4). G-CSF - Neupogen (Filgastrim, Hoffman La Roche - 492 cycles) and GM-CSF - Leucomax (Molgramostim, Shering Plough - 116 cycles) were administered 5 mg/kg/day s.c. Forty one children with malignancies (NHL -21 cases, solid tumours -17) treated before cytokines were in use served as a control group. Our study demonstrated that G-CSF and GM-CSF therapy, gives a shorter period of neutropaenia, reduction of the number of febrile days, decreased frequency of infection and shortened its duration.

[Implementation of a psychological support program for children with cancer in Poland. Preliminary report]. / Wdrazanie programu wsparcia psychologicznego u dzieci leczonych w Polsce z powodu choroby nowotworowej doniesienie wstepne.

Intensive chemotherapy programme in children with cancer may result in psychological mal adjustment. Treatment facilities as well as psychological support are of great importance to minimize these side effects. In 1998 the programme of psychological support was introduced in 7 Polish paediatric haematology / oncology centres. Psychological adjustment of patients treated in each centre was examined 5 yrs after the termination of therapy. At the same time children with new diagnosis of cancer were monitored psychologically along with the psychological support programme. Psychological status of each patient was examined with the following tests: Cattell's questionnaires (CPQ, HSPQ), Manifest Anxiety Scale, Spielberger's inventories (STAI, STAIC), Wechsler Intelligence Scale. The programme of psychological support was based on guidelines of SIOP Psychosocial Committee and included such elements as informing about diagnosis and treatment, explaining any doubt, maintaining an open communication, educational care in the periods of treatment, encouraging to activity even during periods of discomfort. The analysis showed that most of the participating centres could only provide some elements of the support programme. The main problem was to convince medical staff to inform children on diagnosis and treatment plans. Preliminary results of the study indicate that full psychological support for children with cancer and their families from the beginning of therapy can result in improvement in psychological adjustment. During the ensuing period, patients and their parents appreciate the possibilities to contact a psychologist.

Childhood stage IV Hodgkin disease: therapeutic results of the Polish pediatric leukemia/lymphoma study group.

BACKGROUND: The therapeutic management in patients with stage IV Hodgkin disease is still controversial. PROCEDURE: Among 783 children with Hodgkin disease treated from 1971 to 1996, 56 patients (7.3%) were diagnosed with stage IV. The treatment consisted of MVPP or MVPP/B-DOPA chemotherapy combined with involved-field radiotherapy in 50 children. RESULTS: The results of treatment of stage IV patients were compared in the three sequential time periods, during which the therapy was modified. In these periods, the first complete remission was obtained in 67%, 86%, and 90% of children, respectively, and the 10-year event-free survival was 42%, 64%, and 85%, respectively. CONCLUSIONS: Alternate multidrug chemotherapy combined with low-dose involved-field radiotherapy is at present a satisfactory therapeutic method in children with stage IV Hodgkin disease.

[Hodgkin's disease in two children of mother treated with nitrogranulogen]. / Choroba Hodgkina u dwojga dzieci matki uprzednio leczonej powtarzanymi kuracjami nitrogranulogenu.

Hodgkin's disease was diagnosed in a 12-year old boy and a 2-year old his sister whose mother had been treated with repeated cycles of nitrogen mustard for optic neuritis. The mother received the first treatment two years prior to the boy's birth, and subsequently, in recurrent optic neuritis, three years prior to the birth of the girl.

[Treatment outcome for myelodysplastic syndromes (MDS) obtained by the Polish Children's Leukemia/Lymphoma Study Group]. / Wyniki leczenia zespolów mielodysplastycznych (MDS) uzyskane przez Polska Grupe ds Leczenia Bialaczek i Chloniaków u Dzieci.

Fourty children with MDS treated in seven centres of The Polish Children's Leukemia Lymphoma Study Group in period 1975-1998y were included to the study. In 16 children RAEB-T, in 2 CMML in 10 RA and in 12 RAEB were diagnosed. Our and literature data showed that BMT is the best therapy for children with MDS. For children, who don't have a donor for BMT. Roacutan therapy seems to be the most effective.

[Does residual mediastinal mass in children with completed treatment of Hodgkin's disease affect the incidence of relapses?]. / Czy resztkowy guz sródpiersia przetrwaly po zakonczeniu leczenia choroby Hodgkina u dzieci ma wplyw na czestosc wystepowania wznów?

Four hundred and four children with Hodgkin's disease (stage I-IV) were treated in seven cooperating centers of Polish Paediatric Leukaemia/Lymphoma Study Group between 1988 and 1996. Mediastinal masses and/or hilar involvement were found in 261 (65%) patients. Remission was obtained in 256 (98%) of this group. In 31 (12%) children residual mediastinal/hilar masses were found after completing the treatment. For this reason in 13 cases the number of chemotherapy courses and/or the dose of radiation therapy were increased. In two cases thoracotomy or thoracoscopy were performed, and in one case gallium scan was performed. In none of these patients active disease was found. Relapses occurred in 4 (12.9%) from the group of 31 children with residual mediastinal/hilar involvement 8-15 months after cessation of the therapy. Twenty seven children have been in first remission for 5-113 months (median, 34). In 225 patients with a complete resolution of their mediastinal/hilar masses, relapses occurred in 13 (5.7%) cases. Patients with residual mediastinal mass should be carefully evaluated before making a decision to complete their treatment, including CT scan, MRI, and gallium scan. In doubtful cases histopathological verification should be done.

[The efficacy of BFM-90 program in the treatment of acute lymphoblastic leukemia in children in the studies of Polish pediatric leukemia/lymphoma group]. / Skutecznosc programu BFM-90 w leczeniu nawrotów ostrej bialaczki limfoblastycznej u dzieci w materiale Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków: analiza niepowodzen.

Between years 1993 and 1998, 113 children aged from 6 months to 18 years (41 girls and 72 boys) with first relapse of acute lymphoblastic leukaemia (ALL) were included in the study. All children were treated according to BFM-90 relapse protocol. Thirty-two cases were classified as very early relapses, 56 as early and 25 as late relapses. Sixty-one children had isolated bone marrow relapse, in 30 children extramedullary relapse occurred (in 21 children in central nervous system and in 16 children in testes). There were 23 combined relapses. Remission was achieved in 12 children with very early relapse (78.12%), 32 children with early relapse (85.71) and 19 children with late relapse (96%). Event-free survival in 30 months of follow-up was 29.2%, 59.0% and 73.2% for very early, early and late relapses, respectively. Sixteen children with relapsed ALL after chemotherapy according to BFM-90 relapse protocol underwent high-dose therapy with hematopoietic stem cell transplantation (in 3 cases autologous and in 13 cases allogeneic). In 6 children isolated bone marrow relapse occurred after transplantation, all of them died during subsequent chemotherapy. Ten children is alive and well from 2 to 43 months after transplantation. The results obtained with BFM-90 chemotherapy in children with first early relapses are not acceptable. Such patients require high-dose chemotherapy and transplantation of hematopoietic progenitor cells.

[The analysis of failures in the treatment of children with non-B non-Hodgkin's lymphoma. Polish pediatric leukemia/lymphoma study group report]. / Analiza niepowodzen w leczeniu dzieci z nieziarniczym chloniakiem zlosliwym typu NB. Raport Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków zlosliwych u dzieci.

The aim of the study was to evaluate the results of treatment of 46 children with non B non-Hodgkin's Lymphoma registered in 7 centers of Polish Paediatric Leukaemia/Lymphoma Study Group from 1993 to 1998. The patients were treated according to BFM-90 protocol based on German regimen. The overall probability of event-free survival for the all children after 4 years of follow-up was 71%, for patients in stage III--65%, stage IV--70%. The achieved results were not as positive as in the BFM Study Group, what was related to: the great number of children with advanced stage of disease (54.3%), the late final diagnosis, the great number of recurrences (22.5%) and deaths caused by the toxicity of medication (6.5%) (infections, drug toxicity).

[How to improve the results of treatment of myelodysplastic syndromes in the studies of Polish pediatric leukemia/lymphoma group]. / Co zrobic dla poprawy wyników leczenia zespolów mielodysplastycznych w Polskiej Pediatrycznej Grupie ds. Leczenia Bialaczek i Chloniaków.

Fourty two children with myelodysplastic syndrome (MDS) treated in seven centres of The Polish Paediatric Leukaemia/Lymphoma Study Group in period 1975-1998 were included in the study. In 16 children RAEB-T, in 3 CMML, in 10 RA and in 13 RAEB were diagnosed. BMT is the best therapy for children with MDS. For children, who have not a donor for BMT, Roacutan therapy seems to be the most effective.

[The analysis of failures in the treatment of children with chronic myelocytic leukemia in the studies of Polish pediatric leukemia/ lymphoma group]. / Analiza niepowodzen w leczeniu dzieci chorych na przewlekla bialaczke szpikowa w materiale Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

94 children with chronic myelocytic leukaemia--CML treated in period 1975-1998 were included in the study. Twenty seven of 60 children were treated with hydroxyurea or busulfan with 6 MP. In 33 children aged 1, 5-17 years IFN (Interferon alfa) was applied at the dose of 3 millions units every second day subcutaneously. Our data showed that IFN alfa could be applied as an alternative treatment in children with CML, who have not a donor for allogenic BMT (bone marrow transplantation).

[The efficacy of G-CSF and GM-CSF in the adjunctive treatment of infections complicating chemotherapy of solid tumors in children. Report of Polish Pediatric Leukemia/Lymphoma Treatment Group]. / Skutecznosc G-CSF i GM-CSF w leczeniu wspomagajacym zakazen wiklajacych chemioterapie guzów litych u dzieci. Raport PPG/LBC.

Total number of 306 cycles of GM-CSF-Leucomax Sandoz (5 mg/kg/day s.c.) and/or G-CSF Filgrastim Hoffmann-La Roche (5-10 mg/kg/day s.c.) was applied in 146 children aged from 0.5-18 years during neutropenia associated with chemotherapy of solid tumours. Seventeen children with malignancies served as a historical control group. Our study have demonstrated after both G- and GM-CSF therapy shorter period of neutropenia, reduction of the number of febrile days and a decreased frequency of infectious complications and infection's duration.

[Results of the treatment for infant acute lymphoblastic leukemia treated in the program Dana-Faber Cancer Institute. Report of Polish Pediatric Study Group for Leukemia and Lymphoma]. / Wstepne wyniki leczenia niemowlat chorych na ostra bialaczke limfoblastyczna leczonych programem Dana-Faber Cancer Institute--Raport Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

We present courses and treatment's results in 8 infants with acute lymphoblastic leukaemia (ALL) treated according Dana-Faber Cancer Institute protocol between 1994-1998 year. Complete remission (RC) was achieved in 8 children. Relapses were diagnosed between 6 to 20 month, only one achieved II RC. Four children are alive: in I RC-2, in II RC-1, in partial remission 1 and the treatment was ended in one. Treatment's results in infants with ALL are still unsatisfactory.

[The effectiveness of G-CSF and GM-CSF in the adjunctive treatment of infections complicating chemotherapy of non-Hodgkin's lymphoma in children. Report of Polish Pediatric Leukemia/Lymphoma Treatment Group]. / Skutecznosc G-CSF i GM-CSF w leczeniu wspomagajacym zakazen wiklajacych chemioterapie nieziarniczych chloniaków zlosliwych u dzieci. Raport PPG/LBC.

Total number of 252 cycles of GM-CSF-Leucomax Sandoz (5 mg/kg/day s.c.) and/or G-CSF Filgrastim Hoffmann-La Roche (5-10 mg/kg/day s.c.) was applied in 124 children aged from 0.5-20 years during neutropenia associated with chemotherapy of non-Hodgkin's lymphoma (NHL). Twenty four children with NHL treated according to the same chemotherapy protocol but without G-CSF and GM-CSF served as a control group. Our study have demonstrated the good efficacy of both G-CSF and GM-CSF therapy. They shortened the period of neutropenia, reduced the number of febrile days, infection's duration and decreased the frequency of infectious complications.