Barbara Wassmann

Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

Elderly patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ALL) have a poor prognosis, with a low complete remission (CR) rate, high induction mortality, and short remission duration. Imatinib (IM) has a favorable toxicity profile but limited antileukemic activity in advanced Ph+ALL. Imatinib in combination with intensive chemotherapy has yielded promising results as front‐line therapy, but its value as monotherapy in newly diagnosed Ph+ALL is not known.

Sustained Complete Molecular Remissions After Treatment With Imatinib-Mesylate in Patients With Failure After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia: Results of a Prospective Phase II Open-Label Multicenter Study

PURPOSE In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial. PATIENTS AND METHODS As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. Forty-four patients were enrolled and received the BCR-ABL tyrosine kinase inhibitor imatinib (IM) at a starting dose of 400 mg/d. The quality of molecular responses achieved then decided on discontinuation of IM or dose escalation up to 800 mg/d, and finally, on application of donor lymphocyte infusions. Results Seventy percent of patients achieved a complete molecular response (CMR), defined as nested PCR-negativity for BCR-ABL in three consecutive samples. Interestingly, in four out of 10 patients who discontinued IM, CMR was durable even after cessation of IM with a median follow-up of 494 days. This suggests the possibility of long-term tumor control in a subset of patients. CONCLUSION The treatment strategy showed that IM treatment was well-tolerated and highly efficacious in MRD after allogeneic SCT. Moreover, this study demonstrated that evaluation of a molecular end point within a multicenter trial can be a safe and effective tool for clinical decision making.

Prophylactic and interventional granulocyte transfusions in patients with haematological malignancies and life-threatening infections during neutropenia

Patients with haematological malignancies and prolonged periods of neutropenia after chemotherapy are at high risk for severe bacterial and fungal infections. Those infections have long time been considered as a contraindication for subsequent haematopoietic stem cell transplantation (HCT). We conducted a prospective, non-randomized study of granulocyte transfusions (GTX) to control acute life-threatening infections (44 episodes) and to prevent recurrence of severe fungal infections during HCT or intensive chemotherapy (23 episodes). GTX achieved control in 82% (36/44) of acute life-threatening infections. No single reactivation of a previous infection occurred under prophylactic GTX (0/23). Median survival was 170 days in the interventional group and 185 days in the prophylactic group; death in both patient groups was mainly due to underlying progressive malignant disease. We conclude that under GTX, the infection-related mortality even in high-risk patients is low. Due to a secondary prophylaxis with GTX, haematopoietic allografts can be safely given to patients with previous fungal infections.

Older patients with high-risk fungal infections can be successfully allografted using non-myeloablative conditioning in combination with intensified supportive care regimens

Leukaemic patients with advanced disease and severe fungal infections as well as older patients with substantial co‐morbidity are usually excluded from conventional allotransplantation because of increased morbidity and mortality. We approached allogeneic transplantation in four patients with a median age of 62 years (one chronic myeloid leukaemia in blast crisis, one high‐risk acute myeloid leukaemia (AML) in first complete remission (CR1), one AML in 2nd relapse, one AML in CR2 with pre‐existing fungal lung infections (two aspergillus, two mucor) and additional co‐morbidity (diabetes n = 2, aortic aneurysm n = 1, arterial sclerosis n = 2) by combining non‐myeloablative conditioning with an intensified supportive care regimen, including amphotericin B and 4–12 (median 9) prophylactic granulocyte transfusions from granulocyte colony‐stimulating factor (G‐CSF)‐stimulated volunteer donors. G‐CSF was also given to patients until neutrophil recovery. All four patients recovered to a neutrophil count of 0·5 × 109/l after a median of 11·5 d (range 11–13 d). Prophylactic granulocyte transfusions also reduced the need for platelet transfusions and minimized mucositis. All patients were discharged at a median of 25 d (range 18–59 d) and are alive and well after a median follow‐up of > 390 d (range 336–417 d) without evidence of leukaemia. Regression of the fungal lesions was documented in three patients, with a slight progression detected by computerized tomography scan of the chest in one patient. We conclude that pulmonary fungal infections are not a contraindication for allogeneic stem cell transplantation, if non‐myeloablative conditioning regimens are used in combination with granulocyte transfusions, intravenous amphotericin B and G‐CSF.

Hematologic and cytogenetic remission by STI571 (Glivec) in a patient relapsing with accelerated phase CML after second allogeneic stem cell transplantation.

We describe the clinical activity of the ABL kinase inhibitor STI571 in a patient with accelerated phase of chronic myeloid leukemia (CML) relapsing after a second allogeneic BMT and with minimal levels of donor chimerism. STI571 resulted in rapid elimination of leukemic cells with ensuing prolonged severe leukopenia and neutropenia complicated by neutropenic fever and colitis. Subsequent hematopoietic recovery was driven by donor derived cells and was associated with grade 3 graft-versus-host disease (GVHD). STI571 induced sustained hematological and cytogenetic remission combined with controllable GvHD, therapeutic goals not achieved by two preceding allogeneic transplants and repeated donor lymphocyte transfusions (DLT). Bone Marrow Transplantation (2001) 28, 721–724.

A randomized multicenter open label phase II study to determine the safety and efficacy of induction therapy with imatinib (Glivec, formerly STI571) in comparison with standard induction chemotherapy in elderly (>55 years) patients with Philadelphia chromosome-positive (Ph + /BCR-ABL + ) acute lymphoblastic leukemia (ALL) (CSTI571ADE 10)

To assess the safety and efficacy of administering imatinib as first-line, single-agent induction therapy as well as concurrently with subsequent consolidation and reinduction chemotherapy, given for a duration of up to 1 year. Primary study endpoint is the hematologic remission rate following randomized induction therapy with either imatinib or multiagent chemotherapy specified by the GMALL protocol for elderly patients. Secondary endpoints are treatment-related mortality, particularly during induction, relapse rate, remission duration, disease-free and overall survival, and frequency of severe hematologic and nonhematologic toxicity (WHO grades 3 and 4). Accompanying studies examine the clinical relevance of minimal residual disease (MRD) levels determined throughout treatment in peripheral blood (PB), bone marrow (BM), and cerebrospinal fluid (CSF), imatinib concentrations in PB and CSF, and the ability of microarray-based gene expression analysis to predict treatment response.

Comparison of toxicity and outcome in patients with acute myeloid leukemia treated with high-dose cytosine arabinoside consolidation after induction with a regimen containing idarubicin or daunorubicin

Abstract The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one (n=6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses, and another (n=10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (<500 neutrophils/μl) following HDara-C/DNR was 31.2 ± 16 days (mean ±SEM) in the IDA group compared with 18.7 ± 5 days in the DNR group (p<.001 Mann-Whitney U-test). The duration of thrombocytopenia (platelets <25 000/μl) was 34.8 ± 20 days in the IDA group vs. 18.5 ± 6 days in the DNR group (p<.005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 ± 24 vs. 6.9 ± 5.2 days). A greater incidence, length (11 ± 8 vs. 1.2 ± 2 days), and severity of diarrhea were observed in the IDA-pretreated group. Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group 6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was 87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be proven in larger trials.

Stable molecular remission induced by imatinib mesylate (STI571) in a patient with CML lymphoid blast crisis relapsing after allogeneic stem cell transplantation

Summary:We report the response to the ABL kinase inhibitor imatinib mesylate (STI571) in a patient with chronic myeloid leukemia (CML) who relapsed twice after dose-reduced allogeneic stem cell transplantation (alloSCT) for B lymphoid blast crisis (BC) and failed to develop an antileukemic response despite grade 3 graft-versus-host disease (GvHD). Complete hematologic, cytogenetic and molecular responses were achieved within 9 weeks of therapy and are maintained after 27 months. Extensive chronic skin GvHD necessitating immunosuppressive therapy developed after 14 months. This case illustrates the ability of imatinib to induce sustained hematologic and molecular remissions in some patients relapsing with advanced stage CML after alloSCT.

Immunological Response to IL-2 and α-IFN-Treatment After Autologous BMT in Patients with BCR-ABL-positive ALL

Patients with Ph1+/BCR-ABL+ALL have an extremely poor prognosis after treatment with conventional chemotherapy [19, 31]. Bone marrow transplantation, however, offers a chance of cure for a proportion of these patients [1, 25]. Evidence from preclinical [9] and clinical studies at various institutions including our own [3, 4] suggests that maintenance immunotherapy with IL-2 may exert an additional “GvL”-like antileukemic effect after chemotherapy or autologous BMT in patients with AML [5, 6, 11, 15, 24, 28]. Less data are published on posttransplant therapy with IL-2 in patients with high risk ALL [5, 10, 24, 30]. Alternatively, some patients with Ph1-pos ALL were reported to receive maintenance therapy with α-IFN [14, 16, 26, 27]. We combined these approaches and initiated a pilot phase II study for patients with BCR-ABL-positive ALL to receive sequential cycles of rIL-2 and α-rIFN after autologous BMT as part of an ongoing ABMT-program [23].