Felix Keil

Light Chain–Induced Acute Renal Failure Can Be Reversed by Bortezomib-Doxorubicin-Dexamethasone in Multiple Myeloma: Results of a Phase II Study

PURPOSE To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain-induced acute renal failure. PATIENTS AND METHODS Sixty-eight patients with light chain-induced acute renal failure and glomerular filtration rate (GFR) less than 50 mL/min received bortezomib (1.0 mg/m(2) on days 1, 4, 8, and 11), doxorubicin (9 mg/m(2) on days 1 and 4), and dexamethasone (40 mg on days 1, 4, 8, and 11); if well tolerated after two cycles, bortezomib could be increased to 1.3 mg/m(2) and doxorubicin administered on days 1, 4, 8, and 11. RESULTS By intent-to-treat analysis a myeloma response was obtained in 72% of 18 previously and 50 not previously treated patients (complete response [CR]/near CR [nCR], 38%; very good partial response [VGPR], 15%; partial response [PR], 13%; minor response [MR], 6%). Renal response was achieved in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Median progression-free survival was 12.1 months. One- and 2-year survival rates were 72% and 58%, respectively. Survival did not differ between patients with and without renal response but was inferior in previously treated patients (P < .001). In multivariate analysis, baseline GFR and tumor response correlated with renal response, and pretreatment status, lactate dehydrogenase, and myeloma response correlated with survival. The most common grade 3 or 4 toxicities were infection (19.1%), thrombocytopenia (14.7%), neutropenia (14.7%), fatigue/weakness (10.3%), and polyneuropathy (8.8%). CONCLUSION BDD induced a high rate of myeloma and renal responses, and treatment was well tolerated.

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.

Severe immune hemolysis after minor ABO‐mismatched allogeneic peripheral blood progenitor cell transplantation occurs more frequently after nonmyeloablative than myeloablative conditioning

BACKGROUND : Hemolysis as a result of donor‐recipient minor ABO mismatching is a complication of allogeneic peripheral blood progenitor cell (PBPC) transplantation (PBPCT). The increased B‐lymphocyte content of PBPC grafts and immunosuppressive regimens without methotrexate (MTX) may increase incidence and severity of this event.

ABO mismatch increases transplant-related morbidity and mortality in patients given nonmyeloablative allogeneic HPC transplantation

BACKGROUND: ABO mismatch has not been thought to affect the outcome of patients undergoing myeloablative conditioning and allogeneic HPC transplantation. Data on transplant‐related complications after ABO‐mismatched transplantation after nonmyeloablative conditioning are limited.

Competitive CBFbeta/MYH11 reverse-transcriptase polymerase chain reaction for quantitative assessment of minimal residual disease during postremission therapy in acute myeloid leukemia with inversion(16): a pilot study.

PURPOSE (1) Quantification of minimal residual disease (MRD) by competitive CBFbeta/MYH11 reverse-transcriptase polymerase chain reaction (RT-PCR) in patients with acute myeloid leukemia (AML) and inversion(16) [inv(16)] during postremission therapy, (2) comparison of this method with conventional two-step RT-PCR, and (3) evaluation of a potential prognostic value. PATIENTS AND METHODS MRD of six consecutive adult patients with AML and inv(16)(p13;q22) or t(16;16)(p13;q22) who entered complete remission (CR) was monitored by competitive CBFbeta/MYH11 RT-PCR in their bone marrow (BM) during postremission therapy with high-dose cytarabine (HiDAC) or after BM transplantation with a matched unrelated-donor marrow (MUD-BMT) during an observation period of 4.5 to 27 months after initiation of treatment. RESULTS Competitive PCR showed a gradual decline by at least 4 orders of magnitude after 7 to 9 months in patients in continuous CR (CCR), while one patient who relapsed after 13.5 months only achieved a reduction by 2 orders of magnitude at the end of consolidation therapy. A rapid decrease below the detection limit was observed within 1 month in two patients after MUD-BMT. A temporary reappearance of molecular MRD was observed in these patients during immunosuppression for graft-versus-host disease (GvHD). After reduction of immunosuppression, the level of MRD dropped again below the PCR detection limit. Molecular monitoring by conventional two-step RT-PCR yielded comparable results only when multiple assays per time point were performed, while single-assay RT-PCR gave misleading results. CONCLUSION Competitive RT-PCR is a valuable tool for molecular monitoring during postremission chemotherapy, as well as after BMT.

Successful lung transplantation for bronchiolitis obliterans after allogeneic marrow transplantation.

Background. Bone marrow transplantation (BMT) is an established therapy for a variety of hematological diseases with curative potential. However, despite improvements in supportive care, pulmonary complications remain a significant cause of morbidity and mortality. Methods. We report on a patient who received a double lung transplantation (LTX) for therapy-refractory bronchiolitis obliterans (BO) associated with extensive chronic graft-versus-host disease (GVHD) after allogeneic BMT. Results. At present, 38 months after BMT and 23 months after LTX, the patient is in complete hematological and cytogenetic remission and without signs of respiratory distress. Conclusions. This case illustrates that lung transplantation could be a therapeutic option in selected patients with BO after allogeneic BMT that is associated with extensive chronic GVHD and who are refractory to conventional immunosuppressive therapy.

Early and late gastrointestinal complications after myeloablative and nonmyeloablative allogeneic stem cell transplantation

Upper and lower gastrointestinal symptoms are major and serious complications after stem cell transplantation. Their main causes are gastrointestinal graft-versus-host disease (GVHD), infections, toxicity, or preexisting gastrointestinal diseases. The clinical presentation of each disease is nonspecific. The diagnostic procedure for this study included physical exam, stool cultures, endoscopy with biopsies, and abdominal computed tomography (CT). The study was designed prospectively with consecutive patients and performed at our institution in a clinical stem cell transplantation setting. Between January 1996 and September 2001, we analyzed 42 consecutive patients who had been admitted at our institution for gastrointestinal complaints after allogeneic stem cell transplantation for hematologic diseases. Diagnostic procedures revealed in decreasing order: GVHD (62%), gastritis/esophagitis (19%), cytomegalovirus (CMV) enteritis (11%), bacterial enteritis (6%), and toxic mucosal damage (2%). CT showed unspecific findings. Gastrointestinal GVHD and infectious colitis accounted for the majority of gastrointestinal complications after allogeneic stem cell transplantation in our patient population. The diagnosis was mainly based on endoscopically obtained biopsies.

Low curative potential of bone marrow transplantation for highly aggressive acute myelogenous leukemia with inversion inv (3)(q21q26) or homologous translocation t(3;3) (q21;q26)

Abstract Structural rearrangements of the long arm of chromosome 3 involving bands 3q21 and 3q26 and leading either to a paracentric inversion inv (3)(q21q26) or a translocation between both homologous chromosomes – t (3;3)(q21q26) – have been reported in patients with acute myelogenous leukemia (AML), myelodysplastic syndromes, myeloproliferative disorders, and chronic myelogenous leukemia in blast crisis. We describe three patients with de novo AML with these structural abnormalities who received multiple courses of conventional chemotherapy followed by unrelated donor (n=2) and autologous (n=1) bone marrow transplantation (BMT). All three patients had early relapse: patients 1 and 2 had relapse 69 days and 306 days after BMT, respectively, and patient 3 immediately after autologous BMT. Despite further chemotherapy, they died without achieving another remission. These findings, together with other recorded similar cases, show that AML with structural abnormalities of the long arm of chromosome 3 as described has an extremely poor prognosis even with the most potent anti-leukemic treatment modalities.

Microangiopathy following allogeneic marrow transplantation. Association with cyclosporine and methylprednisolone for graft-versus-host disease prophylaxis.

A microangiopathic syndrome was observed in 3 of 14 (21%) patients receiving cyclosporine and methylprednisolone (CSA-MP) for graft-versus-host disease (GVHD) prophylaxis between January 1991 and June 1992 at our center. The syndrome consisted of neurological abnormalities, arterial hypertension, intravascular hemolysis with red cell fragmentation, and a drop in platelet counts after allogeneic bone marrow transplantation (BMT) for hematological malignancy, and it occurred around day 50 after BMT. Treatment with plasma exchanges against fresh-frozen plasma resulted in a decrease of serum lactate dehydrogenase and an improvement of neurological symptoms. We compared CSA-MP patients retrospectively with patients who had received cyclosporine and methotrexate (CSA-MTX) for GVHD prophylaxis (n = 70) at our institution. All patients in both groups engrafted. Day 100 survival (80% vs. 79%) and transplant-related mortality (16% vs. 14%) were identical in the two groups. CSA-MP patients had significantly more acute GVHD II-IV (57% vs. 17%, P < 0.01). Arterial hypertension (P < 0.01) and neurological symptoms (P < 0.01) were significantly more frequent in the CSA-MP group. The 11 asymptomatic CSA-MP patients had significantly higher lactate dehydrogenase levels (P < 0.01) and lower platelet counts (P < 0.01) at 40, 60, and 100 days after BMT, which suggests the presence of a subclinical form of microangiopathy. Significantly higher plasma levels of von Willebrand factor antigen in CSA-MP patients on day 50 after BMT (P < 0.05) and absence of large von Willebrand factor multimers on gel electrophoresis in 4 of 13 (31%) CSA-MP patients compared with 0 of 14 (0%) CSA-MTX patients (P < 0.01) further suggest profound endothelial damage in patients receiving CSA-MP for GVHD prophylaxis.

Prolonged red cell aplasia after major ABO-incompatible allogeneic hematopoietic stem cell transplantation: removal of persisting isohemagglutinins with Ig-Therasorb immunoadsorption.

Summary:Delayed donor red cell engraftment and prolonged red cell aplasia (PRCA) are well-recognized complications of major ABO-incompatible myeloablative and nonmyelo-ablative hematopoietic stem cell transplantation (HSCT). There is an intense debate about the impact on outcome, severity of hemolysis, association with graft-versus-host disease and survival after blood group-incompatible stem cell transplantation. Therefore, therapeutic strategies should be considered to avoid these possible complications. We present five patients, who received allogeneic HSCT from human leukocyte antigen-identical donors for hematological malignancies, which were treated with Ig-Therasorb® immunoadsorption (five treatments/week) to remove persisting incompatible isohemagglutinins. After a median of 17 treatments (range 9–25), all the patients became transfusion independent with the presentation of donors blood group. No side effects occurred during treatment. Ig-Therasorb® immunoadsorption seems to be a promising therapeutic method for rapid, efficient and safe elimination for persisting isohemagglutinins for patients with PRCA after allogeneic hematological stem cell transplantation.