Helmut Löffler

Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia

BACKGROUND Fludarabine seems to be a promising treatment for patients with advanced chronic lymphocytic leukaemia (CLL). We compared fludarabine therapy with the combination of cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of CLL in a randomised, multicentre prospective trial. METHODS Patients older than 18 years of age were entered into the study if they presented with previously untreated B-cell lineage CLL (B-CLL) of Binet stages B or C or relapsed B-CLL pretreated with chorambucil or similar non-anthracycline-containing regimens. Patients were randomly assigned to either fludarabine (25 mg/m2 per day on days 1-5) or CAP (cyclophosphamide 750 mg/m2 per day and doxorubicin 50 mg/m2 per day on day 1, and prednisone 40 mg/m2 per day on days 1-5), both given for six courses. FINDINGS Of 196 evaluable patients, 100 were previously untreated whereas 96 patients had received prior therapy. Remission rates were significantly higher after fludarabine than CAP, with overall response rates of 60% and 44%, respectively (p = 0.023). A higher response rate to fludarabine was observed in both untreated (71% vs 60%, p = 0.26) and pretreated (48% vs 27%, p = 0.036) cases, although the difference was statistically significant only in pretreated cases. In the latter group, remission duration and survival did not differ between treatment groups with a median remission duration of 324 days after fludarabine and 179 days after CAP (p = 0.22) and median survival times of 728 days and 731 days, respectively. In untreated cases, on the other hand, fludarabine induced significantly longer remissions than CAP with the median not yet reached after fludarabine and a median of 208 days after CAP (p < 0.001). This effect also translated into a tendency towards longer overall survival after fludarabine (p = 0.087). Treatment-associated side-effects consisted in both regimens of predominantly myelosuppression and in particular granulocytopenia. CAP-treated patients had a higher frequency and severity of nausea and vomiting (25% vs 5%, p < 0.001) and alopecia (65% vs 2%, p < 0.001). INTERPRETATION Fludarabine provided an effective and well-tolerated therapy for patients with advanced CLL, which compared favourably with CAP as one of the most effective standard regimens. In second-line therapy, fludarabine induced a significantly higher rate of complete and partial remissions, while in first-line therapy a significant prolongation of remission was obtained, which may translate into an improvement of overall survival.

Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients

The clinical significance of complex chromosome aberrations for adults with acute myeloid leukaemia (AML) was assessed in 920 patients with de novo AML who were karyotyped and treated within the German AML Cooperative Group (AMLCG) trials. Complex chromosome aberrations were defined as three or more numerical and/or structural chromosome aberrations excluding translocations t(8;21)(q22;q22), t(15;17)(q22;q11–q12) and inv(16)(p13q22). Complex chromosome anomalies were detected in 10% of all cases with a significantly higher incidence in patients  60 years of age (17·8% vs. 7·8%, P < 0·0001). Clinical follow‐up data were available for 90 patients. Forty‐five patients were < 60 years of age and were randomly assigned to double induction therapy with either TAD‐TAD [thioguanine, daunorubicin, cytosine arabinoside (AraC)] or TAD‐HAM (high‐dose AraC, mitoxantrone). Twenty‐one patients achieved complete remission (CR) (47%), 20 patients (44%) were non‐responders and 9% of patients died during aplasia (early death). The median overall survival (OS) was 7 months and the OS rate at 3 years was 12%. Patients receiving TAD‐HAM showed a significantly higher CR rate than patients receiving TAD‐TAD (56% vs. 23%, P = 0·04). Median event‐free survival was less than 1 month in the TAD‐TAD group and 2 months in the TAD‐HAM group, respectively (P = 0·04), with a median OS of 4·5 months vs. 7·6 months (P = 0·13) and an OS after 3 years of 7·6% vs. 19·6%. Forty‐five patients were  60 years of age: 28 of these patient were treated for induction using one or two TAD courses and 17 cases received TAD‐HAM with an age‐adjusted reduction of the AraC dose. The CR rate was 44%, 38% were non‐responders and 18% experienced early death. The median OS was 8 months and the OS rate at 3 years was 6%. In conclusion, complex chromosome aberrations in de novo AML predicted a dismal outcome, even when patients were treated with intensive chemotherapy. Patients under the age of 60 years with complex aberrant karyotypes may benefit from HAM treatment during induction. However, long‐term survival rates are low and alternative treatment strategies for remission induction and consolidation are urgently needed.

Double induction strategy including high dose cytarabine in combination with all- trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia

A prospective multicenter study was performed to investigate the clinical and molecular results of intensified double induction therapy including high-dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years maintenance therapy. Fifty-one patients, diagnosed and monitored from December 1994 to June 1999, were evaluated. The median age was 43 (16–60) years. The morphologic diagnosis was M3 in 40 (78%) and M3v in 11 (22%) patients. In 15 (30%) patients the initial white blood cell counts were ⩾5 × 109/l. The cytogenetic or molecular proof of the translocation t(15;17) was a mandatory prerequisite for eligibility. The diagnosis was confirmed by karyotyping in 46 and by RT-PCR of the PML/RARα transcript in 45 cases. The rate of complete hematological remission was 92% and the early death rate 8%. Monitoring of minimal residual disease by RT-PCR of PML/RARα (sensitivity 10−4) showed negativity in 29 of 32 (91%) evaluable cases after induction, in 23 of 25 (92%) after consolidation, and in 27 of 30 (90%) during maintenance, after a median time of 2, 4 and of 18 months after diagnosis, respectively. After a median follow-up of 27 months, the estimated actuarial 2 years overall and event-free survival were both 88% (79, 97), and the 2 years relapse-free survival 96% (90, 100). The high antileukemic efficacy of this treatment strategy is demonstrated by a rapid and extensive reduction of the malignant clone and by a low relapse rate. The results suggest that the intensity of the induction chemotherapy combined with ATRA is one of the factors which may have a critical influence on the outcome of APL. A randomized trial should assess the value of an induction therapy including ATRA and high-dose ara-C in comparison to standard-dose ara-C.

Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission.

OBJECTIVE To compare efficacy of intensive postremission chemotherapy with allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia (ALL) in first remission. DESIGN Retrospective comparison of two cohorts of patients. SETTING Chemotherapy recipients were treated in 44 hospitals in West Germany in two cooperative group trials; transplants were done in 98 hospitals worldwide. PATIENTS Patients (484) receiving intensive postremission chemotherapy and 251 recipients of HLA-identical sibling bone marrow transplants for ALL in first remission. Patients ranged from 15 to 45 years of age and were treated between 1980 and 1987. MAIN RESULTS Similar prognostic factors predicted treatment failure (non-T-cell phenotype, high leukocyte count at diagnosis, and 8 or more weeks to achieve first remission) of both therapies. After statistical adjustments were made for differences in disease characteristics and time-to-treatment, survival was similar in the chemotherapy and transplant cohorts: Five-year leukemia-free survival probability was 38% (95% CI, 33% to 43%) with chemotherapy and 44% (CI, 37% to 52%) with transplant. No specific prognostic group had a significantly better outcome with one treatment compared with the other (6% for the difference; CI, -3% to 15%). Causes of treatment failure differed: With chemotherapy, 268 (96%) failures were from relapse and 11 (4%) were treatment-related; with transplants, 43 (32%) failures were from relapse and 92 (68%) were treatment-related. CONCLUSIONS These results suggest that bone marrow transplants currently offer no special advantage over chemotherapy for adults with acute lymphoblastic leukemia in first remission.

Definition of a standard‐risk group in children with AML

To define paediatric AML patients with a favourable outcome in order to design a risk‐adapted therapy, we analysed 489 children under 17 years of age treated similarly in studies AML‐BFM 83 and 87. 369 patients (75.4%) achieved remission. Estimated probabilities of survival, event‐free survival (EFS) and disease‐free survival (DFS) at 5 years were 50% (SE 2%), 43% (SE 2%) and 58% (SE 3%), respectively. Multivariate analysis revealed bone marrow blasts on day 15, morphologically defined risk groups and hyperleucocytosis to be of prognostic value. EFS at 5 years estimated for patients with 5% and >5% blasts on day 15 were 56% (SE 3%) v 27% (SE 4%); for the favourable morphological subgroups (M1/M2 with Auer rods, M3 and M4eo) it was 60% (SE 4%) compared with other patients (33%, SE 3%), P (Kaplan‐Meier)  =  0.0001 each. Hyperleucocytosis proved to be an independent prognostic factor, indicating a high risk, especially for early failure. The specific karyotypes t(8;21), t(15;17) and inv16 were closely related to the favourable morphology and outcome was in the same range. We conclude that for the definition of a standard‐risk group a combination of morphological and response criteria may be sufficient. The standard‐risk group defined by favourable morphology and a blast cell reduction on day 15 (not required for M3) comprises 31% of all patients, P survival, pEFS and pDFS at 5 years were 73% (SE 4%), 68% (SE 5%) and 76% (SE 4%), respectively.

Synchronization of Plasmapheresis and Pulse Cyclophosphamide in Severe Systemic Lupus Erythematosus

Two patients with severe systemic lupus erythematosus, who had not responded to conventional therapy, were treated with plasmapheresis and subsequent pulse cyclophosphamide. This approach uses the plasmapheresis-induced proliferation of pathogenic clones for partial clonal deletion by giving large doses of cytotoxic drugs during the assumed period of increased B-cell vulnerability. Both patients had a rapid and distinct improvement in clinical symptoms and laboratory parameters, including the control of a life-threatening case of lupus pneumonitis. Their conditions were stabilized by giving low-dose cyclophosphamide for the next 6 months. At 14-month follow-up, there were no clinical signs of relapse.

Long-Term Follow-up of Adults with Acute Lymphoblastic Leukemia in First Remission Treated with Chemotherapy or Bone Marrow Transplantation

Considerable controversy exists about whether chemotherapy or HLA-identical sibling bone marrow transplantation is the best therapy for adults with acute lymphoblastic leukemia in first remission [1-3]. Our 1991 study [1] compared 454 adults receiving chemotherapy with 234 adults receiving transplants. Chemotherapy recipients were treated in 44 hospitals in Germany in two consecutive trials of the German Acute Lymphoblastic Leukemia Therapy Trials Group. Transplantations were done in 98 centers, worldwide, that reported data to the International Bone Marrow Transplant Registry. Using statistical methods to adjust for leukocyte count at diagnosis, immune phenotype, time to first complete remission, and time to treatment, we found fewer relapses but higher treatment-related mortality with transplantation. Leukemia-free survival rates at 5 years were similar (about 40%) with the two treatments; this was true for both patients with favorable and patients with unfavorable risk factors. The median follow-up when the study was published was 3 years. Although the conclusions of that study were clear, there was speculation that a difference favoring transplantation might emerge with additional follow-up. This hypothesis was based on the prediction that persons receiving chemotherapy would continue to have relapses, whereas relapse would not occur or would occur less frequently in the transplantation cohort. This current study, which has a median follow-up of 7.5 years, updates our previous report and shows that 9-year leukemia-free survival rates were similar in patients treated with these two therapies. Methods Details of our previous analysis have been published [1]. The previous study included two series of consecutively treated patients. The chemotherapy cohort comprised 484 patients treated in two multicenter trials in Germany (January 1981 and February 1984) who achieved complete remission of acute lymphoblastic leukemia between 1 January 1980 and 30 June 1987 [4, 5]. The transplantation cohort comprised 234 patients with acute lymphoblastic leukemia in first remission who received bone marrow transplants from HLA-identical siblings between 1 January 1980 and 30 June 1987 and for whom complete information about prognostic factors was available. These patients had had no bone marrow or extramedullary relapse before transplantation. Data were reported to the International Bone Marrow Transplant Registry by 98 teams [6]. Analysis was restricted to patients between 15 years of age (the lower age limit for the chemotherapy trials) and 45 years of age (the age of the oldest person in the transplantation cohort) at the time of treatment. Patients with B-cell acute lymphoblastic leukemia and hybrid leukemia [7] were excluded because there were so few of them. Details of the two cohorts and their treatments have been previously described [1]. Median follow-up at the time of this study was 7.5 years (range, 0.1 to 13.5 years); it was 7.0 years (range, 0.1 to 13 years) in the chemotherapy cohort and 8.3 years (range, 2.3 to 13.5 years) in the transplantation cohort. Outcome The primary end point was duration of leukemia-free survival (survival without recurrent leukemia) after first remission. Patients were considered treatment failures at time of relapse or at time of death from any cause and were censored only at time of last follow-up. Probabilities of relapse and treatment-related deaths were also determined. Recurrence of leukemia was defined in both cohorts as recurrence of more than 5% lymphoblasts in the bone marrow or detection of leukemia cells in the blood or extramedullary sites. In estimations of probabilities of relapse, patients in continuous complete remission were censored at time of death from nonleukemic causes or at time of last follow-up. Treatment-related deaths were defined as deaths occurring in patients in continuous complete remission after treatment; these patients were censored at time of relapse or at time of last follow-up. Statistical Analysis Comparison of transplantation and chemotherapy requires adjustment for two sources of bias: 1) differences in the baseline characteristics of patients chosen for each treatment and 2) a difference in time to treatment in the two cohorts. To address the second source of bias, which arises because patients in the transplantation cohort must survive in remission long enough for transplantation to be done, we used a left-truncated Cox regression model to estimate the effects of covariates on treatment-related mortality, relapse, and leukemia-free survival [8, 9]. Using this method, the risk set at each time point in the chemotherapy cohort consists of all patients in the initial cohort still being studied. In the transplantation cohort, the risk set at each time point includes only those who had a waiting time to transplantation of less than the current time point and who are still being studied. We adjusted for differences in baseline characteristics by including as fixed covariates factors predictive of leukemia-free survival in stepwise regression analysis of all patients using the left-truncated Cox model. The following factors were correlated with outcome: age, immune phenotype (T-cell or others), leukocyte count at diagnosis (loge), and time to first remission. Other potential prognostic factors considered but not significant in the stepwise analyses were the presence of a mediastinal mass at diagnosis (P = 0.22) and year of diagnosis (P = 0.32). We tested for interaction between significant covariates and type of treatment and found that the effect of leukocyte count at diagnosis differed in the two cohorts. A high leukocyte count at diagnosis had a greater negative effect on leukemia-free survival in the chemotherapy than in the transplantation cohort. Hence, in the final models, single covariates were used for age, immune phenotype, and time to remission, whereas separate covariates by treatment type were used for leukocyte count at diagnosis. Transplantation was considered to be a time-dependent covariate: Treatment effect differed for 12 or fewer months after first remission compared with more than 12 months after first remission. Adjusted probabilities of treatment-related mortality, relapse, and leukemia-free survival were generated from the above Cox models using the mean covariate value for each prognostic factor from the pooled sample [10]. Odds rations are based on these estimated probabilities. For subgroup analysis, the basic Cox model was refit to the data in specified groups. In all cases, reported probabilities represent predicted outcomes for similar groups of patients receiving each treatment. P values for comparison of survival probabilities at fixed points in time are based on the standardized difference in estimated survival obtained from fitted Cox models in the two groups. None of the commercial sponsors acknowledged for their support of this research were involved in study design, gathering or interpretation of data, or manuscript preparation. Results Adjusted probabilities of treatment-related mortality at 9 years were 5% (95% CI, 3% to 7%) for persons receiving chemotherapy and 53% (CI, 45% to 61%) for persons receiving transplants (P < 0.0001). Most treatment-related deaths occurred within 1 year of treatment. Among patients surviving in remission for 3 years, the probability of treatment-related death in the subsequent 6 years was 1% (CI, 0% to 2%) with chemotherapy and 9% (CI, 3% to 15%) with transplantation (P = 0.01). Adjusted probabilities of relapse at 9 years were 66% (CI, 61% to 70%) for persons receiving chemotherapy and 30% (CI, 22% to 37%) for persons receiving transplants (P < 0.0001). Late relapses occurred in both groups. Among patients surviving in remission for 3 years, the actuarial probabilities of having relapse in the subsequent 6 years were 18% (CI, 12% to 24%) with chemotherapy and 5% (CI, 1% to 9%) with transplantation (P = 0.0004). The latest relapses seen occurred at 6.6 years in the chemotherapy cohort and at 4.2 years in the transplantation cohort. Adjusted probabilities of leukemia-free survival at 9 years for persons receiving chemotherapy or transplants are shown in Table 1. At 9 years, chemotherapy and transplantation did not differ significantly (P > 0.2) either in the entire cohort or in groups defined by high- and low-risk prognostic factors. Among patients surviving in remission for 3 years, the probabilities of leukemia-free survival for the subsequent 6 years were 82% (CI, 76% to 88%) for chemotherapy and 87% (CI, 80% to 94%) for transplantation (P > 0.2). Table 1. Adjusted Probabilities of Leukemia-Free Survival 9 Years after First Remission according to Type of Therapy Received after Remission and Prognostic Factors Discussion Our data indicate that HLA-identical sibling transplantation is associated with fewer relapses than chemotherapy in adults with acute lymphoblastic leukemia in first remission. However, 9-year leukemia-free survival rates were similar for the two therapies. This conclusion applies to low- and high-risk groups as defined by leukocyte count at diagnosis, immune phenotype, and time to first remission. The prediction that a difference between chemotherapy and transplantation might emerge with additional follow-up after our 1991 report was not confirmed. Although late relapses were less common in the transplantation cohort, this benefit was insufficient to overcome the increased treatment-related mortality seen with transplantation. Our conclusions apply to these treatments as given between 1980 and 1987. Little indication of improvement in chemotherapy results has been seen since then. Although some studies suggest modest improvement in transplantation outcome since 1987, it is uncertain whether this reflects increased efficacy or patient selection [11]. The results of our study are similar in some respects to those recently reported by the French Group for Therapy of

Prognostic significance of additional chromosome abnormalities in adult patients with Philadelphia chromosome positive acute lymphoblastic leukaemia

The clinical and biological significance of additional chromosome aberrations was investigated in a large series of 66 adult patients with Philadelphia (Ph) chromosome positive acute lymphoblastic leukaemia (ALL). Additional chromosome changes were observed in 71% of the cases. 9p abnormalities were identified in 26%, and monosomy 7 as well as hyperdiploid karyotypes >50 were both found in 17% of cases. 9p anomalies were characterized by a low complete remission (CR) rate (58%) and an extremely short median remission duration (MRD; 100 d). In patients with monosomy 7, the poor treatment outcome was confirmed (CR rate 55%; MRD 113 d). In contrast, all patients with hyperdiploid karyotypes >50 achieved CR, and the overall survival was superior to all other Ph‐positive ALL patients except those without additional chromosome aberrations. Exclusive rearrangement of the minor breakpoint cluster region of the BCR gene and lack of coexpression of myeloid‐associated antigens in cases with 9p anomalies as well as a high frequency of rearrangements of the major breakpoint cluster region of the BCR gene in patients with monosomy 7 (89%) further substantiated that additional chromosome aberrations may characterize distinct subgroups of Ph‐positive ALL. Moreover, the necessity of the complementing use of chromosome banding analyses, polymerase chain reaction (PCR) assays, and fluorescence in situ hybridizations in the accurate identification of Ph‐positive patients has become evident due to variant Ph translocations in 3%, and negative PCR assays in 4% of the cases.

Acute Megakaryoblastic Leukemia

In 1985 acute megakaryoblastic leukemia was included in the FAB classification system of hematological neoplasias with the designation of AML M7. It occurs in all age groups with two peaks in distribution. The one is in adults and the other in children 1 to 3 years of age especially in those with Downs syndrome. The diagnosis of AML M7 requires more than 30% of the nucleated bone marrow cells being megakaryoblasts. The more common types of AML MO-M6 have to be excluded by morphological and cytochemical analysis whereas immunology is needed to exclude ALL. The megakaryocytic nature of the leukemia has to be proven by ultrastructural demonstration of platelet peroxidase or by immunological demonstration of CD61, CD42, CD41 on the surface of the leukemic blasts. Megakaryocytic/megakaryoblastic leukemias show a wide morphologic spectrum. In some instance small cells dominate, clearly showing megakaryocytic differentiation with scant amounts of cytoplasm and with nuclei showing dense chromatin. On the other hand, there are cases with larger cells resembling ALL-L2 blasts with moderate amounts of rather basophilic cytoplasm which in some instances contain azurophilic granules. Cytoplasmic blebs and protrusions are the most prominent feature of many cases. The nuclei of these cells are round with more finely reticulated chromatin and with prominent nucleoli. The megakaryoblastic nature of these cells can be suggested by morphology. However, according to our experience there are cases of c-ALL with the very same morphologic picture. Consequently, immunologic phenotyping of these cases is necessary in any instance. Cytochemistry is of limited diagnostic value in megakaryoblastic leukemias. Usually it is used to exclude the more common types of leukemia.

Randomized comparison of interferon α and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon α and hydroxyurea

The optimum treatment conditions of interferon (IFN) α therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.