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Purpose: Stem cell transplantation (SCT) can definitely cure chronic myeloid leukemia (CML), a rare disease in childhood. We prospectively evaluated the results of early SCT in pediatric CML after standardized pretreatment with hydroxyurea+/-interferon., Patients and Methods: Between 1995 and 2004, 200 children (median age: 12.4 years) were enrolled and stratified: given the availability of an HLA-matched related donor (MRD), SCT was scheduled within 6 months and otherwise from an unrelated donor (UD) within 12 months following diagnosis., Results: 176 patients underwent SCT; from MRD within median 4 months and from UD within median 11 months after diagnosis. At SCT, 158 patients were in chronic phase (CP1 or CP2), 9 patients were in accelerated phase and 9 patients were in blast crisis (BC). The conditioning regimen - total body irradiation or busulfan - exerted no different impact on overall survival (OS). Probability of OS at 5 years was 87+/-11% if grafted from a sibling (n=41), 52+/-9% from matched UD (MUD, n=71), and 45+/-16% from mismatched donors (MMD, n=55), respectively. A trend for better OS in CP1 was observed if SCT was performed within 6 months (n=49; 74+/-9%), compared to 7-12 months (n=52; 62+/-15%), and >12 months (n=43; 62+/-17%) after diagnosis, respectively (p=0.157). Probability of relapse at 5 years was 20+/-12%. Transplant-related mortality and graft-versus-host disease mainly contributed to the inferior outcome in UD and HLA-mismatched SCT., Conclusion: These data from the first prospective trial on CML restricted to children and adolescents might be considered for decision making when balancing the risks of SCT against the increasing use of imatinib as upfront treatment for CML., (Georg Thieme Verlag KG Stuttgart.New York.)

Background: Unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) is accepted as a therapy for leukaemic diseases and varying inborn diseases if a suitable related donor cannot be found. The goal of immunosuppressive therapy with UD-HSCT is an effective prevention of graft-versus-host-disease (GvHD) on one hand. On the other hand an optimal balance with immunocompetence of the transplanted bone marrow is desirable in order to prevent graft failure, infection and, in the case of leukaemic diseases, potentially control the underlying disease., Patients and Methods: Between 1992 and 2000 49 patients aged 11 months to 16.7 years received an UD-HSCT in Hamburg. Underlying diseases were leukaemia or MDS in 35, of these ALL in 21, hemophagocytic lymphohistiocytosis (HLH) in 9, immunodeficiency or inborn error of metabolism in 5 patients. GvHD-prophylaxis consisted of a combination of Cyclosporin A (CSA), methotrexate (MTX), metronidazole, IgM-enriched iv-immunoglobulin (ivIg) (Pentaglobin(R)) or ivIgG and anti-thymocyte-globulin (ATG). Within the same time span 10 patients with ALL received a matched related donor HSCT (MRD-HSCT). GvHD-prophylaxis in these patients was done without ATG in 8 of 10 cases. UD-HSCT were analyzed for survival, relapse and toxicity. Probability of survival of the patients with ALL after UD-HSCT was compared with results of MRD-HSCT in children with ALL., Results: The Kaplan-Meier estimates of three year overall-survival (OS) were 74 % for all patients. Probability of disease-free survival (DFS) at three years was 62 % for leukaemia/MDS-patients and 100 % for the HLH-patients. Acute GvHD (aGvHD) grades II or III occurred in 51 % of patients. Chronic GvHD (cGvHD) occurred in 22 % of patients. There were 5 cases of treatment-related mortality (TRM). Probability of DFS for patients with ALL at three years was 65 % after UD-HSCT and 30 % in the patients after MRD-HSCT., Conclusions: UD-HSCT in children is an effective and safe therapy. A GvHD-prophylaxis regimen combining the standard immunosuppressive agents CSA and MTX with ivIg, metronidazole and serotherapy using ATG may result in a low incidence of severe GvHD-complications and low TRM rate without increase in relapse rates.

Background: In the multicenter trial AML-BFM 93 daunorubicin or idarubicin was randomly applied in all patients during induction in combination with cytarabine and etoposide. After induction all patients were stratified to the standard or high risk group. To improve outcome in high risk patients high dose cytarabine and mitoxantrone (HAM) was introduced. The placing of HAM as either the 2nd or 3rd therapy block was randomized to evaluate the efficacy and toxicity accordingly., Patients and Methods: 471 children with de novo AML entered the trial AML-BFM 93 (161 standard risk, 310 high risk)., Results: Overall, 387 of 471 (82 %) patients achieved remission, 5-year survival, event free survival (EFS), and disease free survival were 60 % SE 3 %, 51 % SE 2 % and 62 % SE 3 %, respectively. Idarubicin-based induction resulted in a significantly better blast cell reduction in the bone marrow on day 15 (25 of 144=17 % patients with > 5 % blasts compared to 46 of 149=31 % patients after daunorubicin, pchi(2)=0.01). This was, however, mainly seen in high risk patients treated with idarubicin (19 % vs. 38 %, pchi(2)=0.007). Cardiotoxicity, WHO grade 1 - 3 shortening fraction reduction after induction occurred in 6 % patients in both arms. In the total group of patients probabilities of five years event-free survival and disease-free survival were similar for patients treated with daunorubicin or idarubicin. However, in patients presenting with more than 5 % blasts on day 15 there was a trend for a better outcome after treatment with idarubicin (p logrank 0.06). Outcome in high risk patients was superior in study 93 compared to study 87 (remission rate and 5-year pEFS in study AML-BFM 93 vs. study 87: 78 % vs. 68 %, p=0.007, and 44 % vs. 31 %, p logrank=0.01). The placing of HAM as the 2nd or 3rd therapy block was of minor importance. However, patients who received the daunorubicin treatment during induction benefited from early HAM., Conclusion: Compared to study AML-BFM 87 treatment results in study AML 93 improved significantly in high risk patients. This can partly be contributed to the better response on day 15 after idarubicin induction but is mainly due to the introduction of HAM.

Unlabelled: The detection of minimal residual disease (MRD) is a major prognostic factor for treatment in acute lymphoblastic leukemia (ALL) of childhood. Several groups showed the predictive value of MRD after 5 weeks of chemotherapy (at the end of induction therapy). Patients with more than 1 leukemic cells in 100 cells (> or = 10(-2)) at this time-point have a significantly higher relapse rate. The MRD measurement has been shown to be an independent prognostic factor at several time points in the BFM study (ALL-BFM 90) as well as in the EORTC study. The aim of our investigations was the detection of MRD at the end of induction therapy within the COALL studies which is different from the above studies. In the COALL studies, therapy starts with a 1 week DNR prephase (24 h infusion on day one) and i.th. MTX. Induction therapy consisted of 3 drugs over a period of 4 weeks (Prednisolone, Vincristine and Daunorubicin), asparaginase is given later in consolidation. At the end of induction therapy, bone marrow was obtained for cytomorphologic and molecular analysis., Patients and Methods: We investigated bone marrow samples from 76 patients. All patients were in morphologic remission at the end. of induction therapy. For MRD analysis, DNA was isolated from bone marrow mononuclear cells. Clonal T-cell-receptor (TCR) or immunoglobulin gene (IgH) rearrangements were identified by PCR. Monoclonal products were either sequenced directly (TCR) or after excision from high resolution agarose gels. Subsequently patient-specific oligonucleotides for allele-specific PCR were generated. PCR analysis was performed with 1 microgram DNA for each reaction within a semiquantitative matter. This method reached sensitivities down to 10(-5)., Results: Eighty-four percent of the analysed samples were MRD positive at the end of induction therapy. 20 out of 76 patient samples (26%) were highly positive (> or = 10(-2)), 28 patients had levels of about 10(-3) (37%), 16 had levels around 10(-4) (21%) and 12 patients had no detectable residual cells (16%). All analysed 15 T-ALL patients had detectable residual disease at this timepoint. Until now, 5/20 patients with very high MRD level at the end of induction therapy suffered a relapse., Discussion: Patients with very high MRD level at the end of induction therapy showed an elevated risk of relapse, but the predictive value is much poorer than for example in the BFM 90 MRD-study. We suggest, that a high MRD level at this timepoint results from a different induction therapy compared to the BFM 90 study. In the COALL studies asparaginase is given only after induction therapy to decrease the risk of thrombosis. We would like to conclude that this differences were compensated later during therapy as the event free survival of both studies is similar. In conclusion, an optimal information from MRD studies is strongly associated with the given therapy. Therefore we initiated an additional MRD time-point after the first chemotherapy block in consolidation.

Background: Idarubicin (IDR) is one of the most effective, but also toxic drugs in the treatment of AML. The standard dose used in children and adults is 8-12 mg/m2 during induction., Patients and Methods: To improve outcome, we increased the IDR dose from 12 mg/m2 (standard dose in study AML-BFM 93), applied over three days during induction therapy (AIE = Ara-C, Idarubicin, Etoposide) to 14 mg/m2 in a pilot study including 17 patients (16 with de novo AML, one with secondary AML). Outcome and toxicities were compared with the other patients of study AML-BFM 93, treated with 3 x 12 mg/m2 IDR or 6 x 30 mg/m2 daunorubicin (DNR)., Results: Patients of the pilot study achieved a good blast cell reduction in the bone marrow on day 15, a high CR rate of 94% and a low relapse rate (3/17 pts.), however, not significantly different to the IDR (12 mg/m2) group. Hematological toxicity was high, median duration until neutrophil recovery > 500/microliter was 25.0 (12-66) days, and similar to the IDR (12 mg/m2) and DNR groups. Duration of thrombocytopenia (time to > 20,000/microliter) was 21 (10-66) days in the pilot study compared to 19 (7-26) days in DNR patients (p = 0.08). Four of 17 pilot patients presented with severe WHO grades 3/4 of mucositis during induction. One patient died in long-lasting aplasia after the 3rd treatment block., Conclusion: Results of this pilot study show that the IDR 14 mg/m2 regimen was effective but also toxic. According to our results which, however, are based on small patient numbers, an improved outcome compared to the IDR 12 mg/m2 regimen seems to be unlikely, therefore the possibly increased toxicity might not be acceptable.

Unlabelled: The main objective of the multicenter study DAL-HD-87 was to evaluate for the involved-field irradiation a dose reduction by 5 Gy compared with the precursor studies HD-82 and HD-85. Moreover, the decisional strategy for selective laparotomy developed on the basis of retrospective analyses in study HD-82 was to be tested in a prospective design. Chemotherapy in group 1 (stages I, IIA) consisted in 2 OPA cycles (vincristine, prednisone, adriamycin). Group 2 (stages IIEA, IIB, IIIA) received 2 x OPA + 2 x COP(P), and group 3 (stages IIEB, IIIB, IV) 2 x OPPA (with procarbacine) + 4 x COP(P). For the subsequent radiotherapy, doses of 30, 25, and 20 Gy respectively were applied in the 3 groups. Fields with incomplete lymphoma regression were to receive an additional boost of 5-10 Gy. -Exploratory laparotomy was considered indicated in the event of abnormal findings in abdominal CT/ultrasonography and/or enlargement of lymph nodes at the pulmonary hilus., Results: From Dec. 1986 to Sept. 1990, 204 pts from 51 centres were enrolled in the study. 196 were evaluable. 109 pts (55.6%) were laparotomized, 58 (29.6%) splenectomized. The accuracy for the prediction of an abdominal involvement was 72.3% in case of abnormal findings in abdominal CT/ultrasound but only 36.4% in case of enlarged lymph nodes at the pulmonary hilus without abdominal abnormalities. 91.2% of the removed spleens were proven involved. -2 out of 196 pts suffered progression under treatment, and 22 relapsed (as of 1 Jan, 1994). 6 pts died, 4 of whom succumbed to Hodgkin's disease, and 2 to intercurrent infections. 2 pts in first remission developed a secondary malignancy, namely 1 malignant histiocytoma in radiation field and 1 ANLL. Another patient developed a thyroid carcinoma following salvage therapy for a relapse. The probabilities of event-free survival (EFS) and survival after 7 years are for the total group: 85% and 97%, in group 1: 84% and 99%, in group 2: 82% and 93%, and group 3: 89% and 95%. Comparison with the precursor studies HD-82 and HD-85 reveals that the dose reduction in radiotherapy has not affected the results. Differences in EFS are exclusively correlated with changes in chemotherapy.

Complete remission (CR) rates of 80% are achieved with the AML-BFM protocols but one third of patients relapse within the first three years. There are few reports of treatment of relapsed childhood AML, and these deal with the evaluation of new drugs for frontline therapy. We performed a retrospective analysis to investigate how patients previously treated with the AML-BFM-83 protocol were treated after relapse and how many long term remissions were achieved. 48 of 139 patients relapsed after having achieved complete remission with the AML-BFM-83 protocol which consists of continous infusion of ARA-C 100 mg/m2 day 1-2, ARA-C 200 mg/m2 day 3-8, Daunorubicin 60 mg/m2 day 3, 4, and 5, and VP-16 150 mg/m2 day 6, 7, and 8, and an 8 week consolidation therapy consisting of Prednisolone, Thioguanine, Vincristine, ADR, ARA-C, Cyclophosphamide, intrathecal ARA-C and cranial irradiation followed by maintenance therapy. Duration of first remission ranged from 1.5 months to 66.3 months. Excluding 5 children with either isolated or combined extramedullary relapses and another 4 patients for missing data, 39 children were evaluable. 20 children received no therapy or palliative therapy while 16 patients received chemotherapy and another 3 children were transplanted in relapse. Although 9 different intensive chemotherapy regimens were used for reinduction, a high number (12 of 16 = 75%) of second complete remissions was achieved. Several therapeutic options were used to maintain a second remission: regular maintenance therapy (7 patients), allogeneous bone marrow transplantation (BMT) (2 patients), autologous BMT (3 patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Study AML-BFM-87 compared prospectively if cranial irradiation could be abandoned by adding two blocks of intensification with high dose ARA-C and VP-16 after consolidation and furthermore, improve prognosis compared to study -83. 210 children were enrolled in study AML-BFM-87 until March 31, 1991. 164 (78%) achieved complete remission. Probabilities for event-free survival (EFS) and event-free interval (EFI) of 5 years were: .45 (SD .04) and .57 (SD .05). In the first 2.5 years of the study irradiation was randomized (n = 31), selected or refused (n = 24). However, during this period irradiation was mandatory in patients with leukocyte count greater than 70,000/mm3, and also in children with initial CNS involvement. Since July 1989 prophylactic cranial irradiation was abandoned. Patients of the group with mandatory irradiation (n = 39) presented with more unfavourable risk parameters than the group of non-irradiated children, who were enrolled in the study after randomisation had been stopped. Nevertheless, results showed in randomized and selected patient groups as well as in the total cohort a longer relapse-free interval (RFI) in irradiated (n = 66) compared to non-irradiated (n = 94) patients (RFI of 5 years: .70, SD .04 vs. .51, SD .07, p less than .05). Relapses in non-irradiated children occurred mainly in the bone marrow and less often in the CNS. The increase in relapse rate was seen especially in non-irradiated patients of the low risk group as defined in study AML-BFM-83 (RFI: .40, SD .14 vs. .79, SD .09 with irradiation, p less than .01). In the high risk group, however, the differences were not significant. Our results suggest that cranial irradiation is an important part of therapy in childhood AML, and that the good prognosis of the low risk group in study AML-BFM-83 was probably based on the combination of intensive chemotherapy and cranial irradiation.

The analysis of the N-myc gene in bone marrow specimens at the time of initial diagnosis and as well at the time of relapse from patients with Neuroblastoma stage IV and bone marrow infiltration could give some informations about the N-myc status of these patients. In stage IV neuroblastoma patients with bone marrow infiltration an estimation of the N-myc gene amplification should be attempted, if otherwise no information about the tumor content of the N-myc gene could be gathered. In our investigation we could demonstrate a Southern-blot-analysis of 27 bone marrow specimens with respect to the N-myc gene status which correlated qualitatively well to the N-myc amplification detected later on in the corresponding tumor tissue. In six cases the tumor infiltrated bone marrow showed a clear amplification of the N-myc gene. Because of the contamination by non malignant cells in bone marrow there was a quantitative difference in the calculated N-myc gene copies between the examined bone marrow specimens and corresponding tumor tissue.

In a native osteosarcoma specimen of a patient cured of a bilateral retinoblastoma eight years before we found a homozygous deletion of a 7.5 kb Hind III-fragment within the retinoblastoma gene and a hemizygous deletion of the same fragment in its constitutional cells. In a native osteosarcoma tissue of a lung metastasis of a patient with sporadic osteosarcoma the Rb-gene-analysis did not reveal any deletion within the gene. This might be due to the fact that the used c-DNA-probe did not detect point mutations. Nevertheless, the possibility of additional or alternative transforming events should be kept in mind.

Unlabelled: It was the aim of the cooperative therapy study HD-82 for children with Hodgkin's disease to reduce chemo- and radiotherapy and to investigate of a strategy for selective splenectomy previously developed in the Hodgkin study HD-78. Between December 1981 and December 1984 207 patients (131 boys and 76 girls) below 16 years of age were enrolled in this study. In 174 out of 207 patients (84.1%) the criteria for selective splenectomy were applied i.e. the spleen was only removed when the splenic surface was nodular or when the lymphnodes at the splenic hilus and/or the pancreatic tail were enlarged. 69 out of 174 patients (39.7%) had a splenectomy. 50 of the removed 69 spleens (72%) showed histological evidence of Hodgkin's disease. These results were comparable to the 36% and 73% predicted from the retrospective analysis in the HD-78 study. According to the stage of Hodgkin's disease three different treatment groups with 2, 4 and 6 cycles of OPPA/COPP were formed (stage I/IIA, IIB/IIIA and IIIB/IV). Radiation therapy was given as involved field irradiation with a total dose of 35, 30 and 25 Gy depending on the extent of the chemotherapy. 203 patients were treated according to the protocol. Until the 30th of November 1985 3 patients died from intercurrent disease during a follow-up period of 11 to 47 months (median 29 months). 5 patients relapsed. The probability for disease-free survival after 3 1/2 years is 96% for the total group and 99%, 96% and 87% for the three treatment groups including 100, 53 and 50 patients in each group respectively., Conclusions: 1. The OPPA/COPP chemotherapy eliminates reliably occult microfoci. 2. The radiation doses in combination with the chemotherapy are sufficient to prevent local recurrences. 3. The decisional model for selective splenectomy has proved to be extremely valuable prospectively.

In order to reduce the toxicity of the otherwise very effective childhood ALL treatment protocol BFM 76/79 asparaginase was omitted from the 4-drug induction regimen and placed as single drug before the intensification phase. In addition the effect of 3-monthly intermediate dose methotrexate (ID-MTX) pulses versus conventional vincristine (VCR) pulses during maintenance therapy was studied. Of 145 evaluable patients 124 (85.5%) survive in continuous and complete remission (CCR) at a median observation time of 21 (1,5-47) months. The expected rate of patients in CCR at 4 years is 75% respectively 80% after exclusion of 4 patients with fatal complications and one remission failure. These relapse free survival data re equal to the BFM 76/79 and 79/81 results. There was very few therapy related morbidity and no mortality from the COALL-80 induction therapy modification. The intensification phase, however, which was adopted from the BFM study without modification was difficult to manage and was not free of life threatening mostly infectious complications which were fatal in 4 cases. ID-MTX pulses did not prove superior to conventional VCR pulses. The relapse rate in patients with the c-ALL subtype was markedly lower than in any other subtype, remarkably also than in the undifferentiated type.

The initial findings and the course of 20 children and adolescents with adult CML from 10 children hospitals were analyzed retrospectively. The Philadelphia chromosome was found in 18 patients. Initial findings, the course and the prognosis were similar to those published from adult patients. 7 of the 11 children who received chemotherapy alone are still alive with a median survival time of 26 months (range: 14 to 68 months). One patient survived the third blast crisis. For 9 children with a bone marrow transplantation during the chronic phase (median time before transplantation 30 months) the follow-up of 7 months is still too short. 4 of these patients died following graft versus host reaction, 5 show no signs of a renewed occurrence of CML so far. Since CML is rare in children, there is little large scale experience. Hence, there is an urgent need for the prospective and cooperative study of these patients.

The clinical application of an antiserum recognizing common ALL associated antigen (cALL-AG) is very useful in classifying leukemias and diagnosing bone marrow relapse as well as CNS-leukemia. We could demonstrate that sera of common ALL (cALL) patients contain cALL-AG; its partial biochemical characterization is described. The anti cALL serum (cALL-AS) was raised in rabbits with cALL-cells precoated with rabbit antiserum against normal human lymphocytes. After appropriate absorbtion the cALL-AS was highly specific for cALL cells. The isolation of serum cALL-AG was performed by ammoniumsulfat precipitation, gel chromatography and affinity chromatography on agarose lens culinaris hemagglutinin A (lentil lectin). The apparent molecular-weight of the serum glycoprotein is 125 000. Two cALL-AG active structures could be solubilized from cALL cell membrane. The apparent molecular-weights were calculated to be 55 000 and 110 000.

From 1971 through 1979 145 newly diagnosed patients with ALL have been treated within a series of consecutive studies. Study I corresponds to branch A of the 1972 DAL study. In the following studies the induction therapy has been escalated stepwise with the continuation therapy remaining mostly unchanged. Thereby the disease free survival rates increased from 75 to 94% after one year and from 32 to 60% after 4 years respectively. CNS-relapse mainly occurred during the second year of treatment. Their incidence rose from 5% to more than 10% in connection with a change in the radiation portal. Since another correction of the portals with special consideration of the paramedian lower border of the skull base no more CNS-relapses have been observed until now. The actual cooperative ALL-study follows a modified BFM-protocol with postponed asparaginase in hoping to achieve reduced initial morbidity and at least equal good survival times.

The German Society of Pediatric Oncology has initiated in 1983 a cooperative trial for the treatment of extratesticular germ cell tumors. The treatment plan is stratified according to histology, tumor site and tumor extension. Patients with unfavourable histology received depending on prognostic factors 4 courses of either vinblastine, actinomycin D and cyclophosphamide, or the combination of vinblastine, bleomycin and cisplatinum (4 courses) completed by 4 additional courses of VP 16, ifosfamide and cisplatinum. Within 3 years, 115 patients from 37 different institutions were entered into the trial. 55 of 72 protocol patients are under observation for at least 10 months since diagnosis. The disease-free survival rate according to Kaplan-Meier is 80% (+/- 6%) at 36 months. From the interim results of this ongoing study, the following conclusions are drawn: The chemotherapeutic regimens as delivered are tolerable. Radiotherapy does not seem necessary with the exception of ovarian dysgerminomas stage I a. In coccygeal teratomas the resection of the coccygeal bone decreases the hazard of local recurrences. Using the risk adapted regimen, the prognosis for teratomas with Yolk sac origin appears as favourable as for patients with mature teratomas.

The cooperative study COALL-80 is derived from the BFM-78-study. The aim of the study is a reduction of the initial therapy-morbidity and -mortality without loss of efficacy by omitting asparaginase from the four drug-induction regimen and interposing it between induction- and CNS-therapy phase. The expected two years disease free survival rate of a pilot study will be 82%. This finding is hitherto comparable with the BFM-study results.

Between December, 1978, and October, 1982, 151 children with acute myelogenous leukemia from 30 pediatric clinics entered the cooperative study. The treatment consisted of a 10-week intensive induction therapy and a subsequent maintenance therapy, which is terminated for children in complete continuous remission after 2 years. The induction treatment during the first 4 weeks consisted of a combination of prednisone, 6-thioguanine (TG), vincristine, adriamycin (ADR) and cytosine-arabinoside (ARA-C). In the following 4 weeks i.v. cyclophosphamide, i.th. methotrexate and prophylactic cranial irradiation were administered in addition to TG, ARA-C and ADR. 119 of the 151 patients (79%) achieved complete remission. 13 children (9%) died of early hemorrhages, 2 of them before onset of therapy. 5 patients died initially of other complications, another 6 after remission has been achieved. 13 children did not respond or responded poorly to the induction therapy. So far, 40 relapses occurred, mainly in the bone marrow. In 6 relapses the central nervous system was involved. The probability for a continuous complete remission for the total group is 0.41 +/- 0.05 (life table analysis) and for the total group 0.56 +/- 0.06 after 45 months. The corresponding probability for survival after 46 months are 0.43 +/- 0.06 for the remission group. The risk for occurrence of early fatal hemorrhages was higher in children with acute monocytic leukemia than in the other morphological subtypes. An initial leukocyte count of more than 100,000/microliters was found significantly more often in patients who did not achieve remission (early deaths and nonresponders) than in children of the remission group. So far, no factors could be identified which influence the risk for relapse. The present results of the study allow the conclusion, that with the applied treatment strategy it is possible to achieve not only in a high portion of children with AML remission but also to improve the chances for long-time remission and perhaps cure.