Early Versus Delayed Autologous Stem Cell Transplantation and Interferon Maintenance in Multiple Myeloma: Single-Center Experience of 18 Years.

BACKGROUND: Autologous stem cell transplantation (ASCT) has become the mainstay of 1st-line treatment in younger patients with multiple myeloma (MM), but statistical confirmation of its superiority over other therapies, especially in the era of novel agents, is still lacking. METHODS: We reviewed the results of all 548 myeloma ASCTs performed in our institute over the past 18 years. RESULTS: More than one-half of the patients had access to novel agents before their transplantations. Although the age of the transplanted patients increased significantly over the years, treatment-related mortality (TRM) was remarkably low, especially in 1st-line transplanted patients (100-day TRM, 0.3%). The median overall survival (OS) of the entire cohort was 98.4 months. Patients transplanted within 12 months from the start of their therapy had significantly better responses than those having delayed ASCT (complete response rate, 58.1% vs 46.8%; P = .016) and significant post-ASCT progression-free survival (PFS) benefit (30.2 [26.1-34.3] mo vs 23.3 [16.8-29.8] mo; P = .036), but we found no significant overall survival difference. The results were similar in patients treated with or without novel agents before ASCT. During a period of time, interferon maintenance was our standard approach to post-ASCT maintenance. Our analysis showed not only a significant PFS advantage with interferon, but also a highly significant overall survival benefit (150.4 [105.1-195.8] mo vs 86.1 [72.5-99.7] mo; P = .003). CONCLUSIONS: Our findings demonstrate that delayed ASCT can be feasible in selected patients.

The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) with high mortality rate. We retrospectively studied the frequency, clinical and genetic associations and prognostic effect of TA-TMA, in a total of 425 consecutive adult patients, who underwent allo-HSCT for a malignant haematological condition between 2007 and 2013 at our single centre. TA-TMA developed in 19% of the patients. Unrelated donor type (P<0.001), acute GvHD grades II-IV (P<0.001), myeloablative conditioning regimens (P=0.003), tacrolimus-based GvHD prophylaxis (P=0.003), CMV infection (P=0.003) and carriership for HLA-DRB1*11 (P=0.034) were associated with the development of TA-TMA. Survival was adversely affected by the presence of TA-TMA (P<0.001). Among patients with TA-TMA, the outcome of HLA-DRB1*11 carriers was significantly better compared with non-carriers (P=0.003). As a new finding, our observations suggest that the presence of HLA-DRB1*11 antigen contributes to the development of TA-TMA and affects the outcome.

Immunological importance of chimerism in transplantation: new conditioning protocol in BMT and the development of chimeric state.

Chimerism is an exceptional immunogenetic state, characterized by the survival and collaboration of cell populations originated from two different individuals. The prerequisits to induce chimerism are immuno-suppression, myeloablation, or severe immunodeficiency of the recipients on the one side and donor originated immuno-hematopoietic cells in the graft on the other. The pathologic or special immunogenetic conditions to establish chimerism are combined with bone marrow transplantation, transfusion, and various kinds of solid organ grafting. Different types of chimerism are known including complete, mixed and mosaic, or split chimerism. There are various methods used to detect the type of chimera state, depending on the immunogenetic differences between the donor and recipient. The induction of complete or mixed chimerism is first determinated by the effect of myeloablative therapy. The chimera state seems to be one of the leading factors to influence the course of the post-transplant period, the frequency and severity of GVHD, and the rate of relapse. However, the most important contribution of the chimeric state is in development of graft versus leukemia effect. A new conditioning protocol (DBM/Ara-C/Cy) for allogeneic BMT in CML patients and its consequence on chimera state and GVL effect is demonstrated.

Haemopoietic cell transplantation activity and results: a single institution experience.

Between February 1993 and November 1997, 62 patients with severe aplastic anaemia (SAA), acute myeloid (AML), acute lymphoid (ALL), or chronic myeloid leukaemia (CML) as well as two patients with NHL underwent allogeneic marrow transplantation (BMT) from HLA-identical or one-antigen mismatched sibling or unrelated donors. Patients received preparative regimens according to the baseline disease. Patients with SAA were conditioned with ATG/Cy (2 cases) and TAI/Cy (3 cases), AML, ALL and NHL with TBI/Cy (21 cases including two retransplantations) and CML with Mitobronitol/Ara-C/Cy except two patients conditioned traditionally with Bu/Cy. For GVHD prevention, patients received cyclosporin-A (CsA) with short course methotheraxe according to the Seattle protocol. Significantly better overall survival rates were associated with the Mitobronitol (DBM)/Ara-C/Cy conditioning regarded the patients as a whole. Autologous stem cell transplantation (bone marrow and/or peripheral blood) were performed in ten cases including 2 AML, 4 non-Hodgkin's lymphoma (NHL), 3 Hodgkin's disease (HD) and 1 patient with multiple myeloma (MM). Patients with AML and two patients with NHL were conditioned with TBI/Cy and the others with BEAM combined chemotherapy. Eight out of ten patients are leukaemia- or lymphoma-free survivors. One patient relapsed having conventional chemotherapy and interferon maintenance therapy. One patient died in a rapid relapse five months post-BMT.

Lymphocyte subset reconstitution after allogeneic bone marrow transplantation using radiation-free conditioning regimen for patients with chronic granulocytic leukemia.

Conditioning regimens for BMT are important in determining transplant outcome. A radiation-free protocol containing Mitobronitol (DBM), Cytarabine (Ara-C) and Cyclophosphamide (Cy) was used for conditioning of patients with chronic granulocytic leukemia (CGL). Using this conditioning treatment, fewer transplant related complications, including acute GVHD, VOD and severe infections, were observed. Acute GVHD did not develop, but chronic GVHD, accompanied with graft-versus leukemia, was present in half of the cases. To determine the clinical effect of the DBM/Ara-C/Cy conditioning, the recovery of peripheral blood lymphocytes was examined after allogeneic BMT for patients with CGL in comparison with TBI/Cy conditioning. The lymphocyte subsets of 11 DBM patients were followed and analyzed periodically (30-90 days, 4-12 months and > 13 months) using ten monoclonal antibodies and flow cytometry. Decreased percentage of total T cells as well as CD4+ and CD8+ subpopulations, significantly decreased T cell activation and increased proportion of TCR gamma delta + cells were found to be characteristic in the early post-transplant period in the DBM group. Early recovery and consistently higher percentage of B cells were observed for the whole follow-up period of patients receiving DBM conditioning. A high proportion of NK cells was observed in all transplant recipients. These findings suggest that the characteristic pattern of recovering lymphocytes is associated with the lack of severe transplant-related clinical complications following DBM/Ara-C/Cy conditioning.

Secretory breast cancer in a 7.5-year old boy.

Breast cancer is extremely rare in children, and consequently no consensus has been reached on the optimal treatment modalities. The medical history and treatment plan for a 7.5-year old male breast cancer patient is described. Radical mastectomy with sentinel node biopsy was performed in October 2002. As no malignant cells were detected in the sentinel node, and no BRCA1-2 mutations were detected, no further radio- or chemotherapy was performed. A "wait-and-see" policy was decided on. Further treatment will be given if this becomes necessary with the development of metastases.

[Primary resection of obstructive left-sided colon and rectal tumors without intraoperative lavage]. / Elzáródást okozó bal oldali vastag- és végbéldaganatok primer resectiója bélmosás nélkül.

Of the study is to show the results of early postoperative period of left-sided large bowel obstruction (LBO) and methods of decompression without colonic lavage and primary resection. Retrospective analysis of 28 patients admitted to the Surgical Department with LBO between years 1996 and 2000 were treated with ortograde decompression, and primary resection without on table colonic lavage. The surgical method, complications and mortality are pointed out. The patients average age were 71 +/- 9.7 years and only one was free of comorbidity. The average time of operative interventions was 116 +/- 42 minutes. 9 patients out of 28 had rectum cancer their anastomosis were made by instrumental way and the others by hand. The bowel movement was restored (in 89%) on the fourth day of operation. Surgical complications were observed at 3/28 patients (10.7%), and non surgical complication at three patients. Mortality rate 3.5%, one patient was lost. The average hospital stay was 12 +/- 5 days, 70% of the patients were at home within 11 days. The emergency surgical treatment of left-sided colonic obstruction caused by cancer treated by ortograde decompression and primary resection without colonic lavage is a safe method in experienced surgeon hand. The patients have a short recovery period and better quality of life.

[A new radiation-free conditioning in bone marrow transplantation and dibromo-mannitol therapy in chronic myeloid leukemia]. / Uj, sugárzásmentes csontvelö-transzplantációs kondicionáló kezelés dibróm-mannitollal krónikus myeloid leukaemiában.

A new, radiation-free, conditioning protocol, containing the original Hungarian mitobronitol (DBM) (DBM/ cytosine arabinoside/cyclosphosphamide) has been applied to 36 chronic myeloid leukemia (CML) patients followed by bone marrow transplantation (BMT) from HLA identical sibling donors between 1990-1997. In spite of some prognostically disadvantageous factors (half of them were above 40 years, 10 out of 36 patients were in accelerated phase, the disease history was longer than 2 years in average) the overall survival (30/36) and the leukemia free survival rate (26/36) were in accordance with the best international results. Transplantation-related toxicity was remarkably reduced in comparison to bone marrow transplantation performed by total body irradiation/cyclophosphamide (TBI/Cy) or busulphan/cyclophosphamide (Bu/Cy) conditioning protocols. Acute graft versus host disease was present in lower percentage (9/36) and the number of serious cases was only 2/36. Chronic GVH disease, generally known to be associated with antileukemic effect (GVL), occurred in 25 of cases. Early haematological relapse among the 34 patients with functioning graft occurred in 6 patients which rate is slightly higher than reported after TBI/Cy or Bu/Cy conditioning treatment. There was no relapse among patients transplanted within one year post-diagnosis and patients having CML with accelerated phase. The leukemia free post-transplant period was in association with the chronic GVH disease and full chimeric state.

[Clinical and immunopathological significance of chimerism in bone marrow and organ transplantations] / A kimerizmus immunpatológiai és klinikai jelentosége csontvelô-transzplantációban és szervátültetésekben.

Chimerism is an exceptional immunogenetic state, characterized by the survival and collaboration of cell populations originated from two different individuals. The prerequisites to induce chimerism are immunosuppression, myeloablation or severe immunodeficiency of the recipients on one side and donor originated immuno-hematopoietic cells in the graft on the other. Special immunogenetic conditions to establish chimerism are combined with bone marrow transplantation, transfusion and various kinds of solid organ grafting. There are various methods to detect the type of chimera state depending on the immunogenetic differences between the donor and recipient. The chimera state seems to be one of the leading factors to influence the course of the post-transplant period, the frequency and severity of graft-versus-host disease (GVHD), and the rate of relapse. However, the most important contribution of the chimeric state is the development of graft versus leukemia (GVL) effect. A new conditioning protocol (DBM/Ara-C/Cy) for allogeneic BMT in CML patients and its consequence on chimera state and GVL effect is demonstrated.

Successful treatment of renal failure caused by multiple myeloma with HLA-identical living kidney and bone marrow transplantation: a case report.

Here we have described a successful HLA-identical living allogeneic kidney transplantation after bone marrow transplantation in a patient with end-stag liver disease caused by multiple myeloma (MM). Our case is unique, because this combined transplantation is rarely possible and because of our unique immunosuppressive and management strategies. A 45-year-old man with ESRD MM and κ light-chain nephropathy was diagnosed. Cytostatic treatment resulted in partial remission, so autologous peripheral stem cell transplantation (SCT) was performed leading to a complete remission; however the patient remained anuric. The patient's HLA-identical brother offered to be a donor of peripheral stem cells for collection and cryopreservation. Kidney transplantation was performed with a combination of tacrolimus sirolimuns, and methylprednisolone. With a well-functioning kidney graft, allogeneic SCT was performed in the incipient relapse phase of MM, after total body irradiation. Severe oropharyngeal infections, diarrhea, sepsis, and renal failure. Fearing acute renal rejection, we administered steroid bolus. He experienced therapy with gradual restoration of kidney function. Then, steroid-responsive acute graft-versus-host disease (grade II, predominantly bowel) was diagnosed on the background of diarrhea, which returned once. Later he experienced a left subclavian vein thrombosis at the site of a central venous catheter and sepsis. Having recovered from these events, the patient enjoys good health, with stable kidney function and normal protein excretion. After the steroid was stopped, a bone marrow biopsy revealed full-donor type normocellular hemopoiesis. Because of the chimerism, we gradually discontinued the immunosuppression including, sirolimus and finally tacrolimus, since with minimal trough levels there were no complications. Bone marrow biopsy showed a complete remission. In MM with ESRD HLA-identical combined kidney and bone marrow transplantation from a living donor may offer not only complete remission and good renal function, but also good health without immunosuppression.

Study of serum and urine hydroxyproline level of patients with prostatic cancer.

The serum and urine hydroxyproline levels of patients with prostatic cancer were regularly studied for 30 months. Bone metastases were found in 4 patients at the beginning of the study; metastases formed in 8 patients during the test period, and in 9 patients no metastases formed during the study. At the time of X-ray diagnosis of metastasis, significantly higher serum and urine hydroxyproline levels and enzymatic phosphatase were found, but in the tests performed 3 months earlier, in spite of the negative X-ray results, the hydroxyproline results differed significantly from the reference values. The above findings support the use of the hydroxyproline test for the diagnosis of metastases.

Remarkably reduced transplant-related complications by dibromomannitol non-myeloablative conditioning before allogeneic bone marrow transplantation in chronic myeloid leukemia.

A non-myeloablative conditioning protocol containing dibromomannitol (DBM/cytosine arabinoside/cyclophosphamide) has been applied to 36 chronic myeloid leukemia (CML) patients followed by bone marrow transplantation (BMT) from sibling donors. Risk factors include: accelerated phase (10 patients), older age (17 patients over >40 years) and long interval between diagnosis and BMT (27 months on average). Severe mucositis did not occur. Venoocclusive liver disease was absent. Infectious complications were rare. Although grade II-IV acute graft-versus-host disease (GVHD) was present in 9 (25%) cases, there were only 2 serious (III-IV) ones. Chronic GVHD occurred in 25 (69%) cases, preceded by acute GVHD in 9 of the 25 affected patients. Early hematological relapse, 7-29 weeks after BMT, developed in 6 patients (17.6%). No relapse was noted in the completely chimeric patients, however molecular genetic residual disease was observed in 6 patients, in most of them after transient short-term mixed chimeric state. Overall actual survival rate is 83.3% for the 36 cases, and leukemia-free survival is 72.2% for the 34 engrafted patients.