Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.

ASHAP--an effective salvage therapy for recurrent and refractory malignant lymphomas.

BACKGROUND: This study was performed to examine the efficacy and toxicity of the combination of adriamycin (ADR), methylprednisolone (solumedrol), cytarabine (Ara-C), and cisplatin (CDDP) in patients with recurrent and refractory malignant lymphomas. PATIENTS AND METHODS: Sixty-five patients with Hodgkin's disease (HD) (n=14) or non-Hodgkin's lymphomas (NHL) (n = 51) were enrolled in the study. The ASHAP therapy consisted of ADR (40 mg/m2 by continuous infusion (CI) over 96 h), methylprednisolone (500 mg i.v., days 1-5), Ara-C (2 g/m2 as a 2-h infusion on day 5), and CDDP (100 mg/m2 by CI over 96 h). RESULTS: Twenty-five patients (38%) achieved complete remission (CR) and 20 (31%) were taken into partial remission (PR) for an overall response rate of 69%. Thirty-two patients with CR or PR following ASHAP underwent high-dose therapy (HDT) with subsequent hematopoietic stem cell transplantation. After a median follow-up of 52 months, 13 patients are in continuous CR (CCR), the 3-year event-free survival (EFS) was 30% for responders and 21% for all patients. The median overall survival (OS) was 12 months (range 0-70 months), and the OS rate after 3 years was 32%. Unfavorable prognostic factors for EFS and OS by univariate analysis were an elevated value of the serum lactate dehydrogenase and refractory lymphoma. The most frequently observed side effects following ASHAP were leukocytopenia and thrombocytopenia of World Health Organization (WHO) grades III/IV in approximately 80% of all courses. Non-hematological toxicities such as gastrointestinal side effects, infections, mucositis, renal and neurotoxicity occurred more rarely and reached WHO grades III/IV only occasionally. No treatment-related mortality with ASHAP was observed. CONCLUSIONS: ASHAP is an effective and moderately toxic salvage therapy for patients with recurrent or refractory HD and NHL. The results in patients responding to ASHAP and afterwards undergoing HDT with stem cell support are comparable with other established protocols and indicate an improvement in survival if HDT is carried out as intensification.

[Radiotherapy of soft tissue sarcomas]. / Strahlentherapie der Weichteilsarkome.

Soft tissue sarcomas are uncommon neoplasms that represent approximately 1% of all malignancies. It is clear that sarcomas require a therapeutic approach that establishes local control and thereby eliminates the potential of metastasis for patients with truly limited disease. Localized sarcomas are generally treated by surgery. Excision must be complete, with a wide margin of normal tissue, and along anatomic planes, or recurrence will almost certainly follow. Amputations are still occasionally required, although limb salvage procedures are being used increasingly, particularly in the context of multimodality therapy with irradiation or chemotherapy. Radiotherapy can be highly effective for improving local control and is used as adjuvant therapy, either preoperatively or postoperatively. In case of non-in-sano-resection a salvage surgery is indicated. Use of adjuvant postoperative radiotherapy allows for more conservative surgery without compromising local control, and therefore often may allow limb salvage where amputation might otherwise be necessary, e.g. in case of R1- or R2-resection without a new resection, a close margin or large tumors with histologic G2 or G3 grading and in case of local relapses. Local control rate of 90% are reported for the combination of pre- and postoperative radiotherapy. Prognosis is still limited by distant metastases. In case of unresectable tumors neutron radiotherapy results in 50% local control. New approaches e.g. hyperfractionated-accelerated radiotherapy, interoperative radiotherapy and chemoradiotherapy are promising perspectives, which are being evaluated in clinical studies. Desmoid tumors benefit of postoperative radiotherapy in case of R1-resection or relapse.

Busulfan, cyclophosphamide and etoposide as high-dose conditioning therapy in patients with malignant lymphoma and prior dose-limiting radiation therapy.

Relapse after transplant for malignant lymphomas remains the main cause of treatment failure. Most conditioning regimens contain total body irradiation (TBI). We investigated the toxicity and efficacy of an intensified chemotherapy conditioning regimen without TBI in patients with relapsed or high-risk malignant lymphoma who had received prior radiation therapy and were therefore not eligible for TBI. Twenty patients with a median age of 38 (18-56) and relapsed or high-risk malignant non-Hodgkin's lymphoma (NHL, n = 16) or Hodgkin's disease (HD, n = 4) underwent high-dose chemotherapy consisting of busulfan (16 mg/kg), cyclophosphamide (120 mg/kg) and etoposide 30 mg/kg (n = 8) or 45 mg/kg (n = 12) followed by peripheral stem cell support (n = 14), autologous bone marrow (n = 3), allogeneic (n = 2) or syngeneic (n = 1) transplantation. All but two had chemosensitive disease before high-dose chemotherapy. The main toxicity -- according to the Bearman score -- was mucositis II in 18 (90%) patients; five patients (25%) suffered a grade I hepatic toxicity. GI toxicity I occurred in three (15%) and renal toxicity I in two patients (10%). Sixty percent of the patients developed transient dermatitis with erythema and three of them (15%) had skin desquamation; one patient experienced asymptomatic pancreatitis. Toxicity was slightly higher in patients treated with 45 mg/kg etoposide. One patient (5%) died of treatment-related venoocclusive disease. After a median follow-up of 50 months (24-84) the disease-free and overall survival were 50% and 55%. One of the nine relapsing patients developed secondary AML 18 months after transplant. High-dose busulfan, cyclophosphamide and etoposide is an effective regimen resulting in long-term disease-free survival in 50% of patients with relapsed malignant lymphoma and prior radiation therapy. The toxicity is moderate with a low treatment-related mortality (5%).

Survival in patients with primary soft-tissue sarcomas treated within 6 years.

Since 1988, treatment strategies for our sarcoma patients have been determined by the same team and operations performed by one surgeon. The aim of this study was to analyse prognostic data on local recurrence and survival of 101 consecutive patients who presented in our institution with the primary tumour manifestation. After a median follow-up of 35 months, the local recurrence rate was 13.5%, the mean survival time was 68 months and the 5-year survival rate was 83%. Besides positive lymph nodes (only 3 patients) the quality of resection significantly influenced local recurrences (P < 0.05). Univariate predictors of mortality were tumour grade (P < 0.01), tumour size (P < 0.05), distant metastases (P < 0.01), and resection quality (P < 0.01). Multivariate predictors of mortality consisted of grade (P < 0.0001), positive lymph nodes (P < 0.001) and resection quality (P < 0.01). In this homogeneous group of patients, excellent recurrence and survival rates could be achieved. An optimized surgical treatment not only reduces the rate of local recurrences but also augments survival time.

Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy.

In advanced stage mantle cell lymphoma, conventional chemotherapy yields a complete remission rate below 40%, and the median survival rate is only about 3 years. Between 1991 and 1996 we treated nine such patients (six male; three female) with high-dose chemotherapy (six of these also with 12 Gy fractionated total body irradiation (TBI)) and peripheral stem cell support (n = 8) or allogeneic bone marrow transplantation (n = 1). The median age was 47 years (range, 28-61). At the time of high-dose chemotherapy, five patients were in first complete remission (CR), two in first partial remission (PR) and two in second remission (CR = 1; PR = 1). High-dose chemotherapy included TBI (12 Gy), etoposide and cyclophosphamide (patients 1-5), TBI and cyclophosphamide (patient 7), busulfan, etoposide and cyclophosphamide (patients 6 and 9), cyclophosphamide and busulfan (patient 8). The patterns of toxicity according to the Bearman score were usually mild (mucositis grade 2, n = 7; renal grade I, n = 2) with no therapy-related fatality. Only one patient developed hepatic toxicity grade III (veno-occlusive disease) but recovered completely. The median time to neutrophil engraftment was 10 days (range, 8-15). After high-dose chemotherapy all patients achieved complete remission. After a median follow-up of 22 months (range, 9.4-64) all patients remain in continuous complete remission. These encouraging results suggest that high-dose chemotherapy can be applied safely and leads to long-term disease-free survival in otherwise incurable disease.

[Secondary resection of soft tissue sarcomas within the scope of a multimodality therapy concept]. / Nachresektion von Weichteilsarkomen im Rahmen des multimodalen Therapiekonzeptes.

We treated 95 patients with primary soft tissue sarcoma of the extremities or trunk between 1988 and 1995, who were operated on initially elsewhere and their tumors were supposed to be excised completely. We performed a primary re-excision in all patients and found residual tumor in 46%. After a median follow-up of 61 months, 16 patients developed a local recurrence and 6 patients died due to the tumor disease. Primary re-excision is therefore indicated in most cases where the histology report of an assumed benign tumor reveals malignancy.

Chromosomal abnormality inv(3)(q21q26) associated with multilineage hematopoietic progenitor cells in hematopoietic malignancies.

We have identified ten patients with acute myeloid leukemia (AML) and one patient with chronic myeloid leukemia with megakaryocytic crisis who displayed an inv(3)(q21q26). Seven of them had an additional monosomy 7. Most of them had a myelodysplastic syndrome (MDS) preceding AML, normal or increased platelet counts, increased number of megakaryocyte, megakaryocytic dysplasia, and erythroid dysplasia. There was a high incidence of resistance to induction chemotherapy, short remission time, and early relapse. Seven patients were immunologically analyzed. The main immunophenotypes were as follow: CD7+, CD34+, HLA-DR+, CD38+, CD13+, CD33+, CDw65+, CD2-, CD3-, CD4-, CD8-, CD19+, CD20-, CD11b-. Our results suggest that the leukemia with inv(3)(q21q26) represents a new cytogenetic-clinicopathologic subtype, characterized by 1) abnormal megakaryopoiesis and multiple hematopoietic lineage involvement; 2) an antecedent MDS; 3) poor response to conventional chemotherapy; and 4) expression of CD7, CD34, CD38, HLA-DR, CD13, and CD33 antigens. We propose that the malignant transformation in patients with inv(3)(q21q26) occurs in an early stem cell prior to lineage commitment.

Reinterpretation of G-banded complex karyotypes by fluorescence in situ hybridization with chromosome-specific DNA painting probes and alpha-satellite centromere-specific DNA probes in malignant hematological disorders.

In this study, we have performed fluorescence in situ hybridization (FISH) with chromosome-specific DNA painting probes 1, 2, 3, 4, 6, 8, and 12 and centromere-specific DNA probes 7,10,12,17,18, and X after G-banding on the same metaphase spreads from four patients with malignant hematological disorders to more precisely interpret their complex karyotypes. The findings demonstrated that the application of combined G-banding and FISH can more accurately explain complex karyotypes of hematological malignancies. FISH can detect not only the origin of marker chromosomes, but also the complex rearrangements that cannot be identified by routine banding techniques. This approach is very important to complement the cytogenetic analysis of malignant disorders and to evaluate the role of chromosome change in the development, progression, and prognosis of tumors.

Cytogenetic studies in malignant fibrous histiocytoma.

Among soft tissue sarcomas, malignant fibrous histiocytoma is considered to be the most commonly encountered tumor-type of late adult life. Cytogenetic data are, however, sparse and contradictory, without any specific anomalies. We are describing the results of cytogenetic studies in 20 malignant fibrous histiocytomas of various subtypes and gradings. Although we saw two single and therefore possibly primary rearrangements, t(13;14) and t(5;7), most tumors had complex rearrangements without sharing any characteristic aberrations. In our opinion, the heterogeneity of these findings supports the concept that malignant fibrous histiocytoma is not a distinctive entity but merely a name for a group of as yet poorly defined sarcomas.

High dose chemotherapy with busulfan, cyclophosphamide, and etoposide as conditioning regimen for allogeneic bone marrow transplantation for patients with acute myeloid leukemia in first complete remission.

We explored the combination of busulfan/cyclophosphamide/etoposide as conditioning regimen prior to bone marrow transplantation in 31 patients with acute myeloid leukemia (AML) in first complete remission. The preparative regimen consisted of 16 mg/kg busulfan, 30-60 mg/kg VP-16, and 120 mg/kg cyclophosphamide. With a median follow-up of 30.5 months (range, 5-60 months), 25 patients are alive in continuous complete remission. Estimated disease-free survival at 5 years is 80.5%. Death was due to transplant-related toxicity (graft-versus-host disease and cytomegalovirus infection, graft-versus-host disease and pneumonia, sepsis and mucositis, respectively). None of the patients have relapsed. As demonstrated by the results of this analysis, the conditioning regimen busulfan/cyclophosphamide/etoposide is effective and well tolerated in patients with AML in first complete remission. Main nonhematological toxicities were mucositis and hepatotoxicity. The low mortality and relapse rate appears to justify allogeneic bone marrow transplantation for patients with AML in first complete remission who have an HLA-identical donor. Whether this regimen offers a substantial improvement in disease-free and overall survival over presently used regimens warrants further investigation.

Philadelphia chromosome-positive secondary acute myeloid leukemia following high-dose chemotherapy with peripheral blood progenitor cell support for relapsed low-grade non-Hodgkin's lymphoma.

We report the case of a 47-year-old patient who developed acute myelogenous leukemia (AML) 18 months after receiving high-dose chemotherapy with peripheral blood progenitor cell support (PBPCT) for relapsed low-grade follicular non-Hodgkin's lymphoma (NHL). Cytogenetic analysis of the leukemic cells showed the translocation (9;22)(q34;q11). In three mitoses, an additional Philadelphia chromosome (Ph1) was present. In the literature, Philadelphia chromosome-positive secondary AML has been described only once before in a patient with multiple myeloma.

Increase of mobilized CD34-positive peripheral blood progenitor cells in patients with Hodgkin's disease, non-Hodgkin's lymphoma, and cancer of the testis.

G-CSF (filgrastim) can effectively mobilize peripheral blood progenitor cells (PBPC) when administered during steady-state hematopoiesis. In this single center study, we compared the effectiveness of two different doses of G-CSF on the mobilization of peripheral blood stem cells in patients with Hodgkin's disease, non-Hodgkin's lymphoma, and cancer of the testis. A first group including 33 patients received 10 micrograms G-CSF/kg BW per day (group A), whereas a second group comprising 34 patients was treated with 24 (2 x 12) micrograms G-CSF/kg body weight (BW) per day (group B) prior to the leukapheresis. A significant difference (P = 0.015) in the total number of CD34+ cells between group A: 11.32 x 10(7) (range 0.34-110.2) and group B: 48.25 x 10(7) (range 1.33-447.4) has been observed in the first leukapheresis product. Moreover, the total number of CFU-GM increased significantly from 34.79 x 10(4) (range 1.07-300.9) to 147.69 x 10(4) (range 1.03- 1204.0) (P < 0.005), and the number of MNC increased from 1.35 x 10(10) (range 0.41-3.09) group A) to 2.93 x 10(10) (range 0.66-9.7) (group B) (P < 0.001). Comparable results were obtained in the second leukapheresis. Our data indicate, that the application of higher doses of G-CSF can significantly improve the effectiveness of mobilizing PBPC during steady-state conditions, and thereby considerably contribute to a safe and fast engraftment as well as a reduced number of leukapheresis procedures to achieve sufficient number of PBPC.

t(1;19)(q23;p13) in a case of acute monocytic leukemia.

Translocation (1;19)(q23;p13) is considered a specific chromosome aberration in acute lymphoblastic leukemia (ALL). We report a case of M5 acute nonlymphocytic leukemia (ANLL) with t(1;19). In all mitoses studied from peripheral blood (PB) cells, the pathological karyotype 51,XX,t(1;19)(q23;p13),+8, +der(19)t(1;19)(q23;p13), +3mar was detected. No rearrangement of the E2A gene was detected. We believe this case shows that cytogenetically indistinguishable aberrations may be accompanied by quite different molecular events.

[Results of radiotherapy in recurrences of soft tissue sarcomas]. / Ergebnisse der Radiotherapie bei Weichteilsarkom-rezidiven.

PURPOSE: Published data for radiotherapy in soft tissue sarcomas refer in most of the cases to the use of irradiation for primary tumors. Experiences of radiotherapy in local recurrences are limited. The own treatment results of a multimodal treatment approach in a large number of patients will be analyzed for local tumor control rates, survival rates, side effects and prognostic factors and will be compared to the literature. PATIENTS AND METHODS: At the University Hospital Hamburg-Eppendorf a total of 98 patients with local recurrences of soft tissue sarcomas were irradiated between 1980 and 1993. The median age of the patients was 55 years. There was a large variety of different histologies. Grading was evaluable in 95 cases: G1 24 patients, G2 21 patients and G3 50 patients. Localisation was dominated by the extremities with 64.3%. Recurrences were reclassified: 21 patients had rT1-tumors and 77 patients had rT2-tumors. Twelve cases showed lymph node metastases and 9 patients distant metastases. Generally treatment included surgery and postoperative irradiation. R-classification showed R0 in 25, R1 in 20 and R2 in 48 cases. Neutrontherapy was prefered in 57 cases and neutron- and photontherapy in 22 cases. Local tumor control rates and survival rates were calculated using the Kaplan-Meier method. Side effects were scored using the RTOG/EORTC scoring system. Univariate and multivariate analyses were applied to evaluate prognostic factors. RESULTS: Local tumor control rates at 5 years were 56.4%, for G1 75.2%, G2 52.5%, G3 47.1%, rT1 66.0%, rT2 53.6%, R0 63.4%, R1 42.3% and R2 53.2%, N0 61.1% vs. N1 31.7%. Survival rates at 5 years were 45.2%, for G1 64.8%, G2 66.9%, G3 25.0%, rT1 60.0%, rT2 41.5%, R0 64.2%, R1 49.3% and R2 32.7%. Acute side effects were scored as grade 1 and grade 2. The rate of grade 3 and 4 late effects was about 6%. Lymph node status was a significant factor for local control. Grade, residual tumor status, type of irradiation and the applied neutron dose were significant factors for survival. CONCLUSIONS: Nowadays no standard treatment exists for local recurrences of soft tissue sarcomas. Treatment should be interdisciplinary. Local recurrences should be avoided by the consequent use of surgery and radiotherapy. It is important that local recurrences should be detected early. Neutrontherapy may bring advantages for local control of recurrences with macroscopic tumor residuals.

Trisomy 8 preceding diagnosis of acute nonlymphocytic leukemia by 2 years in a patient with multiple myeloma without cytological evidence of myelodysplasia.

A case of acute nonlymphocytic leukemia (ANLL) occurring 2 years after the diagnosis of multiple myeloma (MM) that had been treated by only one course of melphalan/prednisone chemotherapy is reported. Cytogenetic and fluorescence in situ hybridization analysis of peripheral blood cells revealed trisomy 8 as the sole cytogenetic defect at the time of diagnosis of ANLL. Two years earlier, when MM was diagnosed without any cytological evidence of co-existent myelodysplasia, chromosomal analysis of bone marrow cells showed the same pathological karyotype 47, XY, +8 in 14 of 20 mitoses studied. Our interpretation of this unusual cytogenetic finding is that at the time of diagnosis of MM, in spite of lacking cytological signs of myelodysplasia, an unrecognizable myelodysplastic syndrome must have been present which then evolved to ANLL.

3p21 is a recurrent treatment-related breakpoint in myelodysplastic syndrome and acute myeloid leukemia.

In this study we report 11 cases with chromosome abnormalities involving 3p21. Nine cases were diagnosed as myelodysplastic syndrome (MDS), and two as acute myeloid leukemia (AML). Six of nine MDS cases were secondary to a primary malignant disease. In two patients, AML was secondary to breast cancer and polycythemia vera (PV). Seven of eleven patients had a history of intensive polychemotherapy and/or radiation therapy for 3.5 to 5 years. The mean interval from initial therapy to secondary disease was 13.2 years. Complex chromosomal aberrations were found in all 11 cases. Band 3p21 was involved in translocations in 9 patients and in deletions in 2 patients. A t(3;16)(p21;p13) was found in two cases. Additional abnormalities frequently included a -5, -7, as well as deletions or rearrangements of these 2 chromosomes. Data reported in this paper suggest that 3p21 is a recurrent treatment-related breakpoint in MDS and AML and is likely to contain a gene involved in the pathogenesis of this disease.

Correlations between karyotype and cytologic findings in multiple myeloma.

In multiple myeloma, correlations between cytogenetic and morphologic findings are hampered by the relatively scarce chromosomal data and the lack of a widely accepted morphologic classification. The aim of the analysis, comprising 111 patients with multiple myeloma, was to study possible correlations between karyotype and a morphologic classification proposed by Bartl et al. Grade of plasma cell infiltration, predominant cell types (Marschalko, small, cleaved, polymorphous, asynchronous, blastic) and grade of malignancy are the basis of this classification. A pathologic karyotype was found in the bone marrow of 39/111 patients (35%). The incidence of chromosomal anomalies closely correlated with the grade of infiltration, plasma cell type and grade of malignancy. Chromosomal anomalies were rarely detected in patients with low infiltration (16%), but they were frequently found in high-grade infiltration (69%). A low incidence was found in Marschalko (25%) or small cell type (15%); the incidence was much higher in cleaved (75%), asynchronous (65%) and basic cell types (71%). An abnormal karyotype was more frequently found in high (71%) than in intermediate (53%) or low (23%)-grade malignant multiple myeloma. The most consistent structural chromosomal aberration found in five patients was translocation t(11;14)(q13;q32). In four of the five patients small, often cleaved plasma cells were the predominant cell types. These reported correlations between morphological and cytogenetic findings must be confirmed by future studies.

Laparoscopic splenectomy. Technique and results in a series of 27 cases.

Between early 1992 and December 1994, laparoscopic splenectomy was performed in 27 patients with idiopathic thrombocytopenia (ITP), hairy-cell leucemia, HIV, or Hodgkin's disease. In all cases medical treatment, especially cortisone therapy, failed. In Hodgkin's disease the splenectomy was combined with liver biopsies and dissection of parailiacal, paraaortic, and mesenteric lymph nodes for abdominal staging. The operation was performed using four trocars; the splenic vessels were divided by a linear stapler. In general the spleen was removed in a bag through a slightly enlarged trocar incision or after morcellation. Three patients needed a small laparotomy for the removal (laparoscopic assisted). In a recent case of Hodgkin's disease the intact spleen was removed via posterior colpotomy. In 22 of 27 cases (81%) the operation was finished laparoscopically. Five times a conversion to conventional laparotomy was necessary because of bleeding of enlarged lymph nodes at the hilum. Wound infections occurred in two cases. In one patient with ITP the platelet count did not improve and continuous blood loss led to relaparotomy at the 1st postoperative day. No surgical bleeding was found. All patients tolerated a fluid diet at the 1st postoperative day and hospitalization time was 4.4 days (range 3-14). Regarding the low complication rate and the advantages of a smaller abdominal trauma in the postoperative period, the laparoscopic approach for elective splenectomy and laparoscopic abdominal staging has a substantial benefit for the patients.