Improved outcome in patients with chronic myelogenous leukemia after allogeneic hematopoietic stem cell transplantation over the past 25 years: a single-center experience.

Although imatinib has become standard first-line therapy in chronic myelogenous leukemia (CML), allogeneic hematopoietic stem cell transplantation (HSCT) is still considered to be an important treatment alternative for patients with drug resistance or advanced disease. We retrospectively analyzed 175 adult CML patients who underwent HSCT at our institution between 1983 and 2007, with the aim to compare outcomes in patient subgroups and to identify prognostic variables. The median follow-up was 65 months. The probability of overall survival (OS) for all patients was 62%, with a significant improvement seen in the imatinib-era (2001-2007) compared to previous time periods (P <.05). Furthermore, a significantly better outcome for patients with chronic phase CML compared to patients with accelerated or blast phase could be observed (P < .05). Cumulative incidence (CI) of treatment-related mortality (TRM) was 9.7% at 100 days and 1 year after HSCT. CI of relapse was 5% at 1 year and 7.5% at 3 years after HSCT. Post-HSCT outcome was not influenced by pretreatment therapy with imatinib, donor type, or a conditioning regimen with total body irradiation (TBI). These data confirm earlier observations and suggest that allogeneic HSCT is still an important treatment option for high-risk patients with CML, and should thus remain an integral component in current and future treatment algorithms.

Spontaneous changes in tumour cell dissemination to bone marrow in colorectal cancer.

AIM: The study aimed to evaluate the incidence of disseminated tumour cells (DTCs) in bone marrow (BM) preoperatively and during follow up and to correlate these with established risk factors in patients with colorectal cancer. METHOD: We prospectively studied BM in 57 patients using the anti-cytokeratin antibody A45-B/B3. RESULTS: The overall detection rate of DTCs was 23% with a similar detection rate through all stages of the disease. No significant association was found between the presence of DTCs and clinicopathological parameters. After a median follow up of 35.4 months, no differences were found in relapse and overall survival between patients with and without DTC preoperatively. In 31 of 45 patients with local disease, we performed a follow-up BM examination after 1 year. In 26% of the patients, the BM status had changed as compared with the preoperative finding. CONCLUSION: This is the first study to report the follow up of DTC in BM in colorectal cancer using the A45-B/B3 antibody. The presence of tumour cells in the preoperative BM had no impact on outcome. The BM status had changed after 12 months in a quarter of patients.

Caspase-cleaved cytokeratin 18 fragment (M30) as marker of postoperative residual tumor load in colon cancer patients.

BACKGROUND: Soluble cytokeratin 18 (CK18; M65) and a caspase-cleaved fragment of CK18 (M30) have been used as biomarkers, corresponding to tumor cell death and apoptosis, respectively. METHODS: In the present study, M30 was quantified for the first time in serum samples of colon cancer patients pre- and postoperatively as well as during chemotherapy. Minimal residual disease (MRD) was assessed preoperatively by detection of pan-cytokeratin antibody A45-B/B3-positive cells in bone marrow aspirates. RESULTS: Out of 46 patients, those with colon tumors of stages I and IV had significantly elevated M30 serum concentrations compared to controls (n = 23). In 31 colon cancer patients, M30 determinations were performed prior to and seven days after tumor surgery. A group of 24 patients exhibited a significant decrease of M30 in response to tumor removal, in contrast to seven patients who revealed either persistent or higher M30 levels postoperatively. The frequency of MRD was not significantly different for patients with decreasing (4/24) and persisting (3/7) M30. However, M30 correlated significantly with the increased number of recurrences within 36 months in the group with persisting M30 (4/7 versus 2/24, p = 0.032; hazard ratio 8.3, p = 0.016). In a group of patients (n = 10) receiving capecitabine/oxaliplatin chemotherapy (CapOx), transient increases in M30 did not correlate with responses. CONCLUSION: The data obtained within the present limited pilot study in colon cancer patients demonstrate that perioperative changes of M30 may indicate systemic residual tumor load and increased risk of recurrence warranting further evaluation of this marker of apoptosis in a larger prospective clinical trial.

Bone marrow transplants from mismatched related and unrelated donors for severe aplastic anemia.

For patients with acquired severe aplastic anemia without a matched sibling donor and not responding to immunosuppressive treatment, bone marrow transplantation from a suitable alternative donor is often attempted. We examined risks of graft failure, graft-versus-host disease and overall survival after 318 alternative donor transplants between 1988 and 1998. Sixty-six patients received allografts from 1-antigen and 20 from >1-antigen mismatched related donors; 181 from matched and 51 from mismatched unrelated donors. Most patients were young, had had multiple red blood cell transfusions and poor performance score at transplantation. We did not observe differences in risks of graft failure and overall mortality by donor type. The probabilities of graft failure at 100 days after 1-antigen mismatched related donor, >1-antigen mismatched related donor, matched unrelated donor and mismatched unrelated donor transplants were 21, 25, 15 and 18%, respectively. Corresponding probabilities of overall survival at 5 years were 49, 30, 39 and 36%, respectively. Although alternative donor transplantation results in long-term survival, mortality rates are high. Poor performance score and older age adversely affect outcomes after transplantation. Therefore, early referral for transplantation should be encouraged for patients who fail immunosuppressive therapy and have a suitable alternative donor.

Clinically demonstrable anti-autoimmunity mediated by allogeneic immune cells favorably affects outcome after stem cell transplantation in human autoimmune diseases.

To determine the role of allogeneic, autologous and syngeneic hemopoietic stem cell transplantation (SCTx) as a treatment for severe autoimmune disease (AID) we performed a literature search employing Medline, Cancer Lit and abstract books for reports on transplants for blood disorders and a concomitant AID. All reviews, case reports and abstracts available between June 1977 and September 2001 were used and attempts made to update them by e-mail by the corresponding authors. Disease-free survival (DFS) after allogeneic SCTx for 23 patients with severe aplastic anemia was 78% at 16 years and survival in unmaintained remission of concomitant AID was 64% at 13 years. DFS after allogeneic SCTx for 24 patients with hematologic malignancies was 87% at 15 years and survival in unmaintained remission for concomitant AID was 70% at 11 years. DFS after autologous SCTx for 24 patients with hematologic malignancies was 48% at 6 years and survival in unmaintained remission for concomitant AID was 29% at 3 years. Among 30 patients given allogeneic SCTx 19 developed graft-versus-host disease (GVHD) and 11 did not. Upon clinically justified discontinuation of all immunosuppressive therapy, 3/11 patients without GVHD relapsed with their concomitant AID (freedom of AID-relapse 69% at 9 years), whereas none of 19 patients with GVHD did so (log rank: P = 0.0135). Freedom of AID-relapse was superior after allo SCTx compared to autologous SCTx (89% at 18 years vs 38% at 5 years; log rank: P = 0.0002). Our data suggest that a graft-versus-autoimmunity effect after allogeneic hemopoietic SCTx mediates elimination of autoimmunity.

Long-term outcome and quality of life of patients who are alive and in complete remission more than two years after allogeneic and syngeneic stem cell transplantation.

We assessed long-term outcome in 155 patients who had undergone an allogeneic/syngeneic stem cell transplant (SCT) and were in complete remission for more than 2 years after transplant. Probability of late transplant-related mortality was 6%, and affected only patients with chronic graft-versus-host disease (cGVHD). Thirteen percent of patients experienced relapse. Overall survival projected at 10 and 15 years was 83% and 76%, respectively. Secondary malignancies occurred in two patients, 7.5 and 11 years after SCT. Three female and four male patients parented children 19 to 84 months after SCT. Quality of life (QoL) was assessed in a cross-sectional study by the means of a 30-item questionnaire (QLQ-C30) of the EORTC. The questionnaire was sent to 127 patients remaining alive and answered by 106 patients. Seventy-three percent reported a good to very good QoL within 5 years after SCT and 78% after this time point. However, patients with cGVHD had significant impairment of physical, role and social functioning and only 60% of them were fit for work. These results from long-term survivors show that high cure rates with good to very good QoL can be achieved by allogeneic or syngeneic SCT.

[Significance of minimal residual disease for the estimation of the prognosis and for therapeutic decisions in solid tumors]. / Der Stellenwert der minimalen Resterkrankung für die Einschätzung der Prognose und für Therapieentscheidungen bei soliden Tumoren.

The detection of disseminated tumor cells in bone marrow and blood is increasingly used for staging and therapeutic decisions in breast cancer and other solid tumors. Molecular biological methods improve the diagnostic accuracy. Limitations of the approach relate to the lack of disease-specific marker genes. The detection of tumor cells in the bone marrow after primary therapy is a negative prognostic parameter in many solid tumours. Axillary lymph node dissection and histopathology remain the standard staging procedure in breast cancer, but nodal negative patients exhibiting tumor cells in the bone marrow have an inferior outcome and may benefit from adjuvant therapy. The immunohistochemical and molecular detection of tumour cells in lymph nodes reduces the number of truly nodal-negative patients considerably. Tumour cells in bone marrow and blood may be used to directly monitor therapeutic responses.

[Immunocytochemical and molecular detection of minimal residual disease in blood and bone marrow in colorectal cancer]. / Immunzytochemischer und molekularer Nachweis der minimalen Resterkrankung in Blut und Knochenmark bei kolorektalem Karzinom.

Immunocytochemical and molecular biological methods to analyze minimal residual disease (MRD) in colorectal cancer in blood and bone marrow were compared. The concept of a study in the Donauspital will be presented which will permit a comparative judgement of minimal residual disease in blood and bone marrow in patients with colorectal cancer.

Blood stem cell transplantation for breast cancer: new approaches using pre- peri- post-transplant immunotherapy.

Autologous peripheral blood stem cell transplantation (auto-PBSCT) after high dose chemotherapy is usually offered to breast cancer patients carrying a high risk of relapse or having chemosensitive metastatic disease. Whether progression free and overall survival of such patients is improved after auto-PBSCT compared to conventional chemotherapy is a matter of debate. Currently available results of randomised trials could not uniformly prove or disprove auto-PBSCT being advantageous. Yet such studies have not employed any manipulation of the stem cell graft or any post-transplant immunomodulation exploiting the unique immunological environment for tumour eradication which exists only after auto-PBSCT. Preliminary data have discussed the ex vivo and in vivo generation of cytotoxic effector cells employing IL-2 and/or IFN-alpha/gamma in the auto-PBSCT setting. Other cytokines such as IL-12, IL-15 and prolactin have likewise been considered. Several anticancer vaccine protocols after auto-PBSCT are ongoing using monovalent vaccines or anti-idiotypic antibodies. Polyvalent anticancer vaccines, cytokine secreting tumour cells, tumour pulsed or hybridised dendritic cells (DC) enhanced with cytokines are studied. Monoclonal antibodies (mAb) could assist: unlabelled for pretransplant exvivo purging, post-transplant for enhancing antibody-dependent cell mediated cytotoxicity (ADCC) or radioimmunoconjugated as an additive cytotoxic part of the conditioning regimen. Autologous graft versus host induction and allogeneic stem cell transplantation (probably with non-myeloablative conditioning followed by donor lymphocyte infusions) are other approaches. Evaluation of successful combinations, optimal dosages and appropriate timing schedules is the subject of future investigations. Since breast cancer patients belong to countless subgroups, a large number of protocols need to be addressed in order to avoid over treatment and prevent relapse.

Successful treatment of invasive mould infection affecting lung and brain in an adult suffering from acute leukaemia.

We describe in detail a 67-yr-old woman who was treated with a cytostatic combination chemotherapy for newly diagnosed common-acute lymphoblastic leukaemia. At the end of induction therapy, the patient acquired invasive mould infection affecting lung and brain. The patient entered complete remission of her leukaemia. Treatment with liposomal amphotericin B was initiated along with surgical excision of the fungal brain abscess. Intrathecal instillation of amphotericin B deoxycholate was started using an Ommaya reservoir because of an anatomical connection between the postoperative cavity and the ventricle. Full dose cytostatic chemotherapy was continued with little delay. A computerised tomography scan of the chest performed 2 months later revealed no fungal abscesses. Magnetic resonance imaging of the brain did not reveal any fungal manifestation. During maintenance therapy/week 69, the patient relapsed from leukaemia. High doses of intravenous liposomal amphotericin B were administered prophylactically. The patient's leukaemia proved refractory to reinduction chemotherapy and the patient died from pneumonia 8 wk later. Post mortem microbiological investigation and histopathological examination of lung and brain tissue did not reveal any macroscopical or microscopical fungal manifestations. This case underlines the feasibility and successful application of combined antileukaemic, antifungal and surgical therapy in a patient with acute leukaemia.

Long-term clinical and molecular remission after allogeneic stem cell transplantation (SCT) in patients with poor prognosis non-Hodgkin's lymphoma.

From 1987 to 1999 35 patients with poor prognosis non-Hodgkin's lymphoma (NHL) underwent allogeneic stem cell transplantation (SCT) at the University Hospitals of Vienna and Graz. Initial biopsy specimens were reclassified according to the Revised European-American Classification of Lymphoid Neoplasms (REAL). All patients surviving 28 days engrafted. Twenty-eight of them (93%) attained clinical remission. At the last follow-up 14 patients were alive and disease-free at a median of 5.0 (range, 2.3-12.9) years after allogeneic SCT. The actuarial overall survival is 35%. Five patients relapsed 1.8 to 27.6 months after transplant, the probability of relapse is 23%. Of the 21 deaths following SCT, seven were due to relapse/refractory disease and 14 due to transplant-related causes. The probability of treatment-related mortality is 48%. After SCT, minimal residual disease (MRD) was monitored by polymerase chain reaction (PCR) in seven patients with a BCL-2/IgH translocation and in 13 with a clonal immunoglobulin heavy chain (IgH) rearrangement. All 20 patients attained clinical remission rapidly and converted to PCR negativity. In the follow-up nine of these patients are in long-term clinical and molecular remission, six PCR-negative patients died of transplant-related causes and five patients relapsed. In summary, allogeneic stem cell transplantation has a curative potential for patients with refractory and recurrent non-Hodgkin's lymphoma. In our series long-term disease-free survival was associated with molecular disease eradication after SCT. Treatment-related mortality rate was high, thus earlier referral of selected patients to allogeneic SCT should be considered.

Primary gastric B-cell lymphoma: results of a prospective multicenter study. The German-Austrian Gastrointestinal Lymphoma Study Group.

BACKGROUND & AIMS: Appropriate management of primary gastric lymphoma is controversial. This prospective, multicenter study aimed to evaluate the accuracy of endoscopic biopsy diagnosis and clinical staging procedures and assess a treatment strategy based on Helicobacter pylori status and tumor stage and grade. METHODS: Of 266 patients with primary gastric B-cell lymphoma, 236 with stages EI (n = 151) or EII (n = 85) were included in an intention-to-treat analysis. Patients with H. pylori-positive stage EI low-grade lymphoma underwent eradication therapy. Nonresponders and patients with stage EII low-grade lymphoma underwent gastric surgery. Depending on the residual tumor status and predefined risk factors, patients received either radiotherapy or no further treatment. Patients with high-grade lymphoma underwent surgery and chemotherapy at stages EI/EII, complemented by radiation in case of incomplete resection. RESULTS: Endoscopic-bioptic typing and grading and clinical staging were accurate to 73% and 70%, respectively, based on the histopathology of resected specimens. The overall 2-year survival rates for low-grade lymphoma did not differ in the risk-adjusted treatment groups, ranging from 89% to 96%. In high-grade lymphoma, patients with complete resection or microscopic tumor residuals had significantly better survival rates (88% for EI and 83% for EII) than those with macroscopic tumor residues (53%; P < 0.001). CONCLUSIONS: There is a considerable need for improvement in clinical diagnostic and staging procedures, especially with a view toward nonsurgical treatment. With the exception of eradication therapy in H. pylori-positive low-grade lymphoma of stage EI and the subgroup of locally advanced high-grade lymphoma, resection remains the treatment of choice. However, because there is an increasing trend toward stomach-conserving therapy, a randomized trial comparing cure of disease and quality of life with surgical and conservative treatment is needed.

Elevation of plasma prolactin in patients undergoing autologous blood stem-cell transplantation for breast cancer: is its modulation a step toward posttransplant immunotherapy?

Prolactin is a suspected promotor of breast cancer cell growth, and it shares pleiotropic immunoregulatory properties. We studied plasma prolactin and its drug-induced modulation in 20 women with breast cancer undergoing high-dose chemotherapy and autologous blood stem-cell transplantation. Plasma prolactin levels were serially assayed before and during conditioning and within and beyond 30 days after transplant. Before transplant, prolactin plasma levels were in the age-adjusted range of normal women. During conditioning and within 30 days after transplant, prolactin levels increased in all patients (p < 0.0001), but remained in the normal range. Antiemetic drugs such as metoclopramide and phenothiazines, known to enhance pituitary prolactin secretion, further elevated prolactin plasma levels (p < 0.00001). Patients remaining in continuous complete remission after transplant (median follow-up, 3 years) disclosed higher prolactin levels compared with those obtaining only partial remission or ensuing early relapse. Prolactin levels are regularly elevated during conditioning and within 30 days after autologous transplantation for breast cancer. Further elevations of prolactin plasma levels are induced by metoclopramide and other antiemetic drugs. Elevated plasma prolactin had no adverse effect on disease-free survival after transplant. We propose to investigate further the upregulation of prolactin after transplant aiming to induce a posttransplant consolidative immune reaction.

Excellent disease eradication by myeloablative therapy and stem-cell transplantation in patients with acute myelogenous leukemia.

Between February 1982 and 1999, 118 consecutive patients (65 male, 53 female) with acute myelogenous leukemia (AML), with a median age of 35 years (range 17-56 years), received stem-cell grafts from a human leukocyte antigen-identical sibling (n = 71), one-antigen-mismatched family member (n=2), matched unrelated donor (n=15), one-antigen-mismatched unrelated donor (n = 4) or an autologous (n = 26) graft. At the time of transplant, 56 patients were in the first complete remission (CR), 27 in the second CR, 6 in untreated relapse, 17 in primary refractory, and 12 in refractory relapse. The French-American-British classification (FAB) subtypes were as follows: M1 (n=25), M2 (n=28), M3 (n=11), M4 (n =32), M5 (n=16), M6 (n = 6). For conditioning, most patients underwent total body irradiation-containing regimens. As of 28 February, 1999, probability of leukemia-free survival (LFS) is 58% for patients after related and 45% after unrelated stem-cell transplantation (SCT). The probability of LFS is 70% for patients given allogeneic transplants in the first CR compared with 33% for those beyond the first CR at SCT. In autologous stem-cell graft recipients, the probability of LFS is 37%. Transplant-related mortality was 28% after related, 20% after unrelated, and 4% after autologous SCT. Probability of relapse for patients given related-donor stem-cell grafts in the first CR and beyond the first CR is 30% and 67%, 55% after unrelated and 63% after autologous stem-cell grafting. Thus, myeloablative therapy followed by allogeneic stem-cell infusion has a high curative potential for patients with AML in remission and offers substantial benefits to patients in advanced disease.

Regeneration of erythropoiesis after related- and unrelated-donor BMT or peripheral blood HPC transplantation: a major ABO mismatch means problems.

BACKGROUND: Blood group incompatibility in allogeneic BMT is common but does not appear to affect the outcome in terms of incidence of graft rejection or delayed engraftment. However, major ABO incompatibility may be associated with prolonged erythroid aplasia. STUDY DESIGN AND METHODS: In a retrospective analysis of 286 allogeneic transplant recipients, the prevalence of prolonged erythroid aplasia, including pure RBC aplasia, was determined. RESULTS: Patients receiving major ABO-incompatible grafts showed a significant delay in reticulocyte engraftment (median, 32 days; range, 12-347) from that in patients receiving ABO-identical (20; 10-152) or minor ABO-incompatible (21; 12-47) grafts. Pure RBC aplasia occurred in 7 (3%) of 240 evaluable recipients and was observed only in the major ABO-incompatible group (7/43, 16%). Treatment of pure RBC aplasia consisted of either plasma exchange, which resulted in a response within 16 to 68 days, or immunoadsorption, in which the response occurred between Days 119 and 204 after initiation of treatment. CONCLUSION: Major ABO incompatibility may lead to delayed reticulocyte engraftment, resulting in prolonged transfusion dependency and increased risks of transmission of infection and iron overload. Therefore, therapeutic strategies should be taken into consideration to allow erythroid reconstitution in these patients.

[Autologous transplantation of hematopoietic stem cells--therapeutic spectrum and future developments]. / Autologe Transplantation von Blutstammzellen--therapeutisches Spektrum und zukünftige Entwicklungen.

Autologous transplantation with haematopoietic blood stem cells (ASTx) is increasingly performed in blood cell disorders, in solid tumours and recently, in severe autoimmune disorders. In acute leukaemia, ASTx is usually offered to patients in complete remission who lack an HLA-identical donor. The chances and risks must be weighed against a transplant from a matched, unrelated donor. ASTx are routinely performed in aggressive lymphoma. Indications for ASTx in intermediate and low grade lymphoma await results of clinical trials. In Hodgkin's disease and myeloma, ASTx are routinely performed in first or subsequent remission, and in early stages, respectively. Among solid cancers, ASTx is an established part of the therapeutic measures in germ cell tumours. Patients with breast cancer may undergo ASTx in an adjuvant setting after complete tumour resection or in a palliative setting after progression. Initial enthusiasm has switched to a more awaiting view of this indication. Severe autoimmune disorders may undergo haemolymphatic ablation from conditioning and a stem cell transplant. The scientific evaluation of this approach should employ three sequential steps: The first step should employ vigorous immunosuppression followed by ASTx; the second step should employ stem cell autografts depleted from autoreactive immune cells; the third step should employ allogeneic stem cells from normal donors. A truly curative approach after complete haemolymphatic reconstitution is conceivable.

[High dosage therapy and autologous peripheral stem cell transplantation in breast carcinoma]. / Hochdosistherapie und autologe periphere Stammzelltransplantation beim Mammakarzinom.

42 breast cancer patients were treated by high-dose chemotherapy (HDC) and autologous peripheral stem-cell transplantation (ASTx) in the Donauspital between 1992 and 1999. 24 patients had stage II/III breast cancer with high risk for relapse. The other 18 patients underwent HDC and ASTx in chemosensitive stage IV. After previous conventional chemotherapy peripheral stem-cells were harvested by one cycle of mobilisation chemotherapy (epirubicin/taxol, FEC 120 or cyclophosphamide) followed by cytokine stimulation. 16 patients were treated by a tandem transplantation (conditioning protocol for 1st ASTx was melphalan 200 mg/m2 and for 2nd transplant it was CTC: cyclophosphamide 6 g/m2; thiotepa 500 mg/m2; carboplatin 800 mg/m2). The other 26 patients received one HDC with CTC as conditioning protocol. The HDC was well tolerated by all patients, there was no transplant-related mortality. The median survival and the progression-free survival (PFS) after HDC and ASTx in stage IV breast cancer patients were 28 and 11 months, respectively. The median survival and PFS were not yet reached in stage II/III patients after 55 months. The actuarial survival and PFS in that patient group were 70% after 55 months. Our data confirm the low risk and good efficacy of HDC and ASTx in breast cancer patients. Nevertheless randomised studies are necessary to evaluate the importance of HDC compared to intensified conventional protocols without ASTx.

[High dosage therapy with stem cell transplantation in neuroendocrine carcinoma]. / Hochdosistherapie mit Stammzelltransplantation beim neuroendokrinen Karzinom.

Neuroendocrine carcinoma and small-cell lung cancer (SCLC) are highly responsive to chemo- and radiotherapy. Nevertheless, most patients (pts.) experience relapse. At the 2nd department of medicine in the Donauspital, 4 pts. with neuroendocrine carcinomas of different primary sites underwent high-dose chemotherapy with autologous stem-cell transplantation (ASTx). Pt. 1 suffered from neuroendocrine lung cancer, pt. 2 from a small-cell carcinoma of the pancreas. Pt. 3 had a metastatic small-cell abdominal bulky tumor and pt. 4 presented with neuroendocrine carcinoma of the prostate. After 4-6 cycles induction chemotherapy pts. were consolidated with 1 cycle of HDCht and ASTx. Prior to HDCht pt. 1 and pt. 2 were in complete remission (CR) and pt. 3 and pt. 4 in partial remission. Pt. 3 converted in CR after HDCht. He is still in CR with a disease-free survival of 23 month after ASTx and 30 month after diagnosis. Pt. 1, 2 and 4 died from relapse 10, 16 and 5 month after ASTx and 16, 22 and 9 month after diagnosis. Pts. with neuroendocrine carcinomas might be suitable candidates for HDCht and ASTx.