Reduction of treatment for early stage Hodgkin's disease.
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Hodgkin Disease↗
Biomedical subjects
P Mauch
Publications and source records attributed to P Mauch.
Controversies in the use of diagnostic staging laparotomy and splenectomy in the management of Hodgkin's disease.
Considerable controversy exists over the routine use of diagnostic staging laparotomy and splenectomy in the workup of patients with Hodgkin's disease. With the development of effective, and perhaps less toxic chemotherapy the need for staging laparotomy has somewhat decreased. In the United States it is still common to recommend surgical staging for early stage patients when the results influence the choice of treatment. Since 20%-30% of clinically staged (CS) IA-IIA and 35% of CS IB-IIB patients with Hodgkin's disease will have occult splenic or upper abdominal nodal involvement not detected by LAG, CT, MRI, or gallium imaging, staging laparotomy allows for selection of patients either to receive limited radiation therapy alone (most PS I-II patients) or chemotherapy with or without radiation (PS III). In Europe, Canada, and South America most patients are clinically staged without a laparotomy. Patients are selected for treatment with radiation therapy alone or for chemotherapy with or without radiation on the basis of clinical prognostic factors. This article details the current arguments for and against the use of staging laparotomy.
Diagnostic Tests, Routine↗
International Database on Hodgkin's Disease: a cooperative effort to determine treatment outcome.
In an effort to better determine the outcome of patients treated for Hodgkin's disease, twenty institutions/cooperative groups in the western world agreed in 1988 to participate in the development of a large data base by sending data to be analyzed by a common statistical design. Data was obtained from both patients randomized on prospective trials and patients treated by standard protocol but not randomized. Overall statistics on 14,315 adult patients treated from the early 1960s to 1987 were collected. This data was first presented at the Paris International Workshop and Symposium held on June 28-30, 1989. The proceedings, published in 1990, include a detailed description of the data, and prognostic studies on laparotomy findings, response to initial therapy, relapse-free survival, overall survival, and secondary malignancies. The International Database on Hodgkin's Disease represents a compromise between two more classical approaches such as the use of randomized trials and metaanalyses. It should serve as a model for the study of other types of cancer. It has been successful because of interest, time, and the cooperation of physicians in academic centers from much of the western world.
Databases, Factual↗
Radiotherapy versus combined modality in early stages.
In early stage Hodgkin's disease the optimal choice of treatment for the individual patient is still an unresolved issue. So far, twenty-two randomized trials of radiotherapy alone versus radiotherapy plus combination chemotherapy have been carried out worldwide. The preliminary results of a global metaanalysis of these trials indicate that we still do not definitively know whether or not the addition of prophylactic chemotherapy up front improves survival. Arguments in favour of the addition of chemotherapy up front are: that laparotomy may be avoided, that radiation fields and doses may perhaps be reduced, and that the stress of experiencing a relapse is avoided in many patients. The major argument against the use of chemotherapy up front is: that by careful staging and selection of patients and by careful radiotherapy techniques the number of patients exposed to potentially toxic chemotherapy may be kept at a minimum. Recently, trials have been carried out testing chemotherapy alone. The results of these trials are however conflicting. In order not to jeopardize the good results achieved with the standard treatments developed over the last three decades, newer treatment approaches should be carefully tested in large randomized trials before being implemented for general clinical use.
Combined Modality Therapy↗
The effect of donor T lymphocytes and total-body irradiation on hemopoietic engraftment and pulmonary toxicity following experimental allogeneic bone marrow transplantation.
To study the effects of donor T lymphocytes on engraftment and graft-versus-host disease in relation to recipient total-body irradiation, we have returned small numbers of T cells to T-cell-depleted bone marrow transplanted across a minor histocompatibility barrier in mice (B10.BR-->CBA). T-cell-depleted B10.BR marrow (10(7) cells) was transplanted into CBA recipients prepared with TBI doses ranging from 4 to 14 Gy. Selected animals also received 10(4) (0.1%) and 10(5) (1.0%) measured B10.BR T lymphocytes. The extent of donor marrow engraftment was determined from hemoglobin and carbonic anhydrase phenotyping of peripheral blood at 3 months posttransplant. Toxicity was assessed from breathing-rate measurements, histopathology, and animal survival. Addition of T cells had a profound effect on survival related to radiation dose. The TBI doses resulting in an LD50 at 12 weeks were 6.9 Gy, 9.3 Gy, and 13.0 Gy for animals receiving 10(5), 10(4), and no T cells, respectively. Mortality was associated with pulmonary dysfunction as measured by an elevation of breathing rates. Autopsy and histological analysis revealed extensive damage to the lung parenchyma. In contrast to the toxicity data, addition of T cells to the donor marrow had no effect on the TBI dose required for equivalent erythroid engraftment. These results demonstrate that in combination with TBI small numbers of T cells in the transplanted marrow do not aid engraftment but do significantly increase the risk of pulmonary toxicity.
Alleles↗
Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow.
PURPOSE: Acute and chronic graft-versus-host disease (GVHD) continues to be the major causes of morbidity and mortality after allogeneic bone marrow transplantation (BMT). In this study, we have evaluated the clinical effects of selective in vitro T-cell depletion of donor allogeneic bone marrow by using a single monoclonal antibody ([MoAb] anti-T12, CD6) and rabbit complement. This antibody recognizes mature T cells, but not other cellular elements such as natural-killer (NK) cells, B cells, and myeloid precursors. PATIENTS AND METHODS: From August 1983 to April 1991, 112 consecutive adult patients with hematologic malignancies underwent BMT with bone marrow from HLA-identical sibling donors. Marrow was harvested and depleted of mature T lymphocytes ex vivo by the use of three rounds of incubation with an anti-T12 antibody and rabbit complement. The preparative regimen consisted of cyclophosphamide and fractionated total body irradiation (TBI) in 108 patients. No patients received prophylactic immune suppression post-BMT. Purgation by anti-T12 was used as the only method for the prevention of GVHD. RESULTS: Twenty patients (18%) developed acute GVHD (grade 2 to 4); only eight patients developed chronic GVHD. The incidence of GVHD did not increase significantly with age. Only three of 112 patients (2.7%) exhibited acute graft failure. One patient developed late graft failure that was associated with cytomegalovirus (CMV) infection. Within the subset of 50 patients who had not previously undergone unsuccessful conventional therapy (acute leukemia in first remission or chronic myelogenous leukemia [CML] in stable phase), we estimated by the Kaplan-Meier method that the probability of disease-free survival was 50% at 3 years post-BMT, with a median follow-up of 44 months. The treatment-related mortality rate in this group was only 14% and was independent of patient age. CONCLUSIONS: We conclude that selective in vitro T-cell depletion with an anti-T12 monoclonal antibody effectively reduces the incidence of both acute and chronic GVHD after allogeneic BMT without compromising engraftment. Moreover, depletion of CD6-positive cells from donor marrow obviates the need to administer immune suppressive medications to the majority of patients. This approach reduces the morbidity and mortality of allogeneic BMT and permits the BMT of older patients.
Adult↗
The Second International Symposium on Hodgkin's Disease. Workshop I: Review on prognostic factors.
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Hodgkin Disease↗
Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin's lymphoma.
Sixty-nine patients with a history of low-grade B-cell non-Hodgkin's lymphoma (NHL) in sensitive relapse or incomplete first remission underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody (MoAb)-treated autologous bone marrow transplantation (ABMT). At ABMT, 51 patients had low-grade histology and 18 patients had a history of low-grade NHL that had undergone histologic transformation to a higher-grade NHL. Before ABMT, only 20 of the 51 low-grade patients and 10 of the 18 patients with transformed histologies were in complete remission. Moreover, at the time of marrow harvest, 24 of the low-grade and eight of the transformed histology patients had histologic evidence of lymphoma cells infiltrating the marrow. Following high-dose therapy, only one acute, in-hospital death was observed. There was no significant difference in the disease-free survival (DFS) between patients with low-grade and patients with transformed histologies. Among patients with low-grade NHL, the patients in complete remission before ABMT experienced significantly longer DFS than those in partial remission (P less than .05). This preliminary study suggests that some patients with relapsed low-grade NHL may experience prolonged DFS following high-dose ablative therapy.
Adult↗
Hepatic dysfunction following T-cell-depleted allogeneic bone marrow transplantation.
We reviewed the medical records of 97 patients undergoing T cell-depleted allogeneic bone marrow transplantation at our institution from 1984 to 1990 to determine the incidence of hepatic dysfunction, including venoocclusive disease of the liver following BMT. All patients received allogeneic marrow that had been purged with monoclonal antibody to the CD6 surface antigen (T12) and rabbit complement as the sole method of graft-versus-host disease prophylaxis. No additional immunosuppressive agents were routinely administered to these patients. Overall, 55% of patients in our series developed two-fold elevations in serum bilirubin, SGOT, or alkaline phosphatase within the first 30 days following BMT. A five-fold elevation in any liver function test was noted in only 19% of patients. Logistic regression analysis revealed that the presence of GVHD, female sex, and administration of amphotericin B all were independently associated with laboratory evidence of hepatic dysfunction. While LFT abnormalities were common in our series, they were generally mild, and the development of VOD was rare. Only three patients (3.1%) fulfilled clinical criteria sufficient to establish a diagnosis of VOD. Among the 86 patients whose ablative regimen consisted of cyclophosphamide (60 mg/kg x2) and total-body irradiation (1200-1400 cGy in 200 cGy fractions), only 1 patient (1.2%) developed VOD. Our experience suggests that patients undergoing allogeneic BMT are at low risk for VOD and other serious hepatic complications when they receive high-dose cyclophosphamide, fractionated TBI, and T cell-depleted marrow without hepatotoxic medications for GVHD prophylaxis.
Adolescent↗
Total lymphoid irradiation to prevent graft rejection in recipients of HLA non-identical T cell-depleted allogeneic marrow.
Patients who undergo transplantation with genotypically non-identical T cell-depleted bone marrow are at high risk of graft failure. We have previously shown that graft failure in this setting is an active immunologic process in which CD3+ CD8+ host T cells specifically cytotoxic for donor hematopoietic cells mediate rejection of the graft. In order to reduce the incidence of graft rejection in these patients, we conducted a pilot trial of total lymphoid irradiation (TLI) as an adjunct to total body irradiation (TBI) in an attempt to suppress the activity of residual host derived alloreactive lymphocytes capable of mediating rejection. Ten adults (ages 17-42 years) with hematologic malignancies were treated with TLI prior to hospitalization for allogeneic bone marrow transplantation (BMT). The BMT preparative regimen consisted of cyclophosphamide (60 mg/kg x 2) followed by TBI. The majority of patients received 750 cGy TLI delivered to two complementary radiation ports in five equal 150 cGy fractions. Nine of 10 recipients of genotypically non-identical CD6-depleted marrow who were pre-treated with TLI experienced full hematologic engraftment compared with none of four similar patients previously transplanted without TLI (p = 0.001). TLI induced significant lymphopenia in patients prior to marrow infusion, but had no suppressive effects on the reconstitution of donor lymphocytes. TLI, in combination with T cell depletion of donor marrow, may decrease the rate of graft rejection in individuals who lack perfectly matched HLA-identical sibling donors.
Adolescent↗
T-cell-depleted autologous bone marrow transplantation therapy: analysis of immune deficiency and late complications.
Fourteen patients with T-cell-derived leukemia and lymphoma underwent high-dose chemoradiotherapy and anti-T-cell monoclonal antibody-treated autologous bone marrow transplantation (ABMT). All patients were either in sensitive relapse or had adverse prognostic features, and five patients had a history of bone marrow involvement with disease. Patients received a median of 2 (1 to 3) prior chemotherapy regimens; 10 patients received local radiotherapy. After high-dose ablative therapy, greater than 500/mm3 granulocytes and greater than 20,000 untransfused platelets/mm3 were noted at a median of 23 (13 to 48) and 26 (15 to 43) days post-ABMT, respectively. Natural killer (NK) cells, T cells (predominantly T8+), and monocytes were noted within the first 1 to 2 months post-AMBT, as seen in other series. Disease-free survival was a median of 10.1 months, 5.9 months for patients with T acute lymphoblastic leukemia or lymphoblastic lymphoma and 25.6 months for patients with T non-Hodgkin's lymphoma (NHL). Toxicities were common and severe. Thirty-six percent of patients developed bacteremias early post-BMT. Late complications included a skin rash consistent with graft versus host disease; infections with Herpes zoster, hepatitis, and Pneumocystis carinii; and the development of Epstein-Barr virus associated lymphoproliferative syndrome. Our findings suggest that patients who have undergone T-depleted ABMT have a profound immunodeficiency not reflected in the phenotypic reconstitution of the T and NK cells. Characterization of the functional deficiency may facilitate the development of methods to reduce the long-term toxicity of AMBT in these patients.
Adult↗
Renal insufficiency after total body irradiation for pediatric bone marrow transplantation.
Between 1980 and 1987, 59 children with acute lymphoblastic leukemia (ALL) or stage IV neuroblastoma (NB) underwent allogeneic or autologous bone marrow transplantation (BMT). Thirty-nine of these patients were alive and in remission 6 months post BMT and were evaluable for this analysis. Sixteen have developed renal dysfunction. Eight were transplanted for relapsed ALL and received an autologous transplant. Preparation included tenopiside (VM 26), cytosine arabinoside, and cyclophosphamide followed by total body irradiation (TBI). One patient received 850 cGy in a single fraction, while all other patients received fractionated TBI (1200-1400 cGy in 6-8 fractions over 3-4 days). Eight of 11 evaluable patients who received a BMT for NB have developed late renal problems (4-7 months after BMT). The preparation for neuroblastoma patients included VM 26, cis-platinum, melphalan, cyclophosphamide and fractionated TBI (1200-1296 cGy). All 8 neuroblastoma patients had received cis-platinum as induction treatment prior to transplantation. All patients presented with anemia, hematuria and elevations of BUN and creatinine. Renal biopsies were consistent with radiation nephropathy. In conclusion, a high incidence of renal dysfunction has occurred after BMT in children with neuroblastoma and ALL. The clinical and laboratory features are consistent with either radiation nephropathy or hemolytic-uremic syndrome. The relatively young age of these patients and conditioning with intensive multi-agent chemotherapy may decrease the tolerance of the kidney to radiation injury.
Age Factors↗
Thoracic irradiation in Hodgkin's disease: disease control and long-term complications.
A total of 590 patients with Stage IA-IIIB Hodgkin's disease received mantle irradiation at the Joint Center for Radiation Therapy between April 1969 and December 1984 as part of their initial treatment. Recurrence patterns as well as pulmonary, cardiac and thyroid complications were analyzed. Pulmonary recurrence was more frequently seen in patients with large mediastinal adenopathy (LMA); 11% of patients with LMA recurred in the lung in contrast to 3.1% with small or no mediastinal disease, p = 0.003. Hilar involvement, when corrected for size of mediastinal involvement, was not predictive of lung relapse. Patients with LMA also had a high rate of nodal relapse above the diaphragm (40%) following radiation therapy (RT) alone as compared to similarly treated patients with small or no mediastinal adenopathy (6.5%), p less than 0.0001. This risk of nodal recurrence was greatly reduced (4.7%) for LMA patients receiving combined radiation therapy and chemotherapy (CMT), p less than 0.0001. Sixty-seven patients (11%) with hilar or large mediastinal involvement received prophylactic, low dose, whole lung irradiation. No decrease in the frequency of lung recurrence was seen with the use of whole lung irradiation. Radiation pneumonitis was seen in 3% of patients receiving radiation therapy alone. In contrast, the use of whole lung irradiation was associated with a 15% risk of pneumonitis, p = 0.006. The risk of pneumonitis was also significantly increased with the use of chemotherapy (11%), p = 0.0001. Cardiac complications were uncommon with pericarditis being the most common complication (2.2%). Thyroid dysfunction was seen in 25% of patients and appeared to be age-related. These data suggest that the long-term complications of mantle irradiation are uncommon with the use of modern radiotherapeutic techniques. The use of prophylactic whole lung irradiation is no longer recommended since its use did not reduce pulmonary relapse but did increase the risk of pneumonitis. Chemotherapy is also associated with an increased risk of pneumonitis, however, its use in patients with large mediastinal adenopathy appears justified.
Adolescent↗
Response to "Dilemmas and decisions".
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Combined Modality Therapy↗
Late complications following total-body irradiation and bone marrow rescue in mice: predominance of glomerular nephropathy and hemolytic anemia.
Late mortality and pathology were assessed in various mouse strains following total-body irradiation (TBI) and bone marrow transplantation. A, C57BL/6, B6AF1, LP and C3H mice received TBI in two fractions 3 h apart at total doses of between 11 and 15 Gy. They were then transplanted with syngeneic bone marrow cells providing sufficient reconstitution to avoid hemopoietic failure. Long-term survival data revealed both radiation dose- and strain-dependent onset of mortality between 1 and 2 years post-treatment. Renal damage appeared to have contributed to the late mortality in most treatment groups as shown by glomerular lesions, elevated blood urea nitrogen and an accompanying fall in hematocrit. Hemolysis was deduced to be the major cause of anemia, as concluded from results of 51Cr-labeled erythrocyte survival. No decrease in erythropoiesis was evident as seen from spleen and bone marrow 59Fe uptake. These findings are together consistent with the manifestation of a hemolytic uremic syndrome (HUS) with kidney glomeruli representing the principal sites of injury responsible for both renal dysfunction and microangiopathic hemolysis.
Anemia, Hemolytic↗
Evidence that anti-asialo GM1 in vivo improves engraftment of T cell-depleted bone marrow in hybrid recipients.
Engraftment of T cell-depleted bone marrow was studied in a P----F1 murine bone marrow transplant model which features long-term stability of mixed chimerism of donor (B6) and host (B6AF1) cells after BMT. We report that a polyclonal antibody to asialo GM1 (anti-ASGM1) given in vivo after transplant was able to increase long-term donor bone marrow engraftment. In vivo anti-ASGM1 eliminated NK activity but did not affect the generation of cytotoxic T cells nor did it stimulate hematopoiesis in vitro. Anti-Thy 1.2, a pan-T cell monoclonal antibody, had no effect on donor engraftment. We conclude that ASGM1+ cells with NK activity inhibit the long-term engraftment of bone marrow stem cells in this model and that antibodies to NK cells can be used in vivo as an effective component of the transplant conditioning regimen.
Animals↗
Evidence that anti-LFA-1 in vivo improves engraftment and survival after allogeneic bone marrow transplantation.
The LFA-1 molecule is a member of the leukocyte adhesion complex (CD11/CD18) that is critical to adhesion and effector function of T cells and NK cells. Both T cells and NK cells play important roles in bone marrow graft rejection, and anti-LFA-1 MAbs inhibit in vitro T cell and NK cell cytotoxicity. We here describe the in vivo use of a monoclonal antibody to the alpha chain of LFA-1 (CD11a) to prevent rejection of T cell-depleted allogeneic bone marrow. Animals receiving anti-LFA-1 and 1100 cGy total-body irradiation showed improved hemopoietic and immunologic reconstitution one month after BMT when compared with animals receiving TBI alone. Animals in the anti-LFA-1 group showed significantly improved long-term survival, and had no deficits in long-term lymphohemopoietic reconstitution.
Animals↗
Prognostic factors for positive surgical staging in patients with Hodgkin's disease.
Staging laparotomy was performed as part of the routine recommended diagnostic evaluation following clinical staging (CS) in 692 patients presenting with supradiaphragmatic Hodgkin's disease (HD). Various clinical factors were analyzed by multivariate analysis for prediction of abdominal involvement. Factors that were statistically significant for predicting disease below the diaphragm included CS III-IV disease (P less than .001), B symptoms (P less than .001), mixed cellularity (MC) or lymphocytic depletion (LD) histology (P = .017), number of supradiaphragmatic sites greater than or equal to 2 (P = .001), male sex (P = 0.034) and age greater than or equal to 40 years (P = .004). Separate analyses were performed for various subgroups of CS IA-IIA, CS IB-IIB, CS IIIA-IVA, and CS IIIB-IVB patients. Upstaging was seen in 0% to 55% of CS I-II patients based on subgroup. Male sex, B symptoms, and number of sites above the diaphragm greater than or equal to 2 all independently predicted for positive surgical staging in CS I-II patients. Sixty-four percent of CS I-II patients who were upstaged had extensive abdominal disease by positive lower abdominal nodes or multiple splenic nodules (greater than or equal to 5). Downstaging (to pathological stage [PS] I-II) was seen in 9% to 68% of patients with CS III-IV disease based on subgrouping. Age greater than or equal to 40, MC or LD histology, and B symptoms all independently predicted for positive surgical staging in CS III-IV patients. Downstaging was more frequently seen in CS IIIA-IVA patients (55%) than in patients who were CS III-IVB (22%). Four subgroups of patients who had a low probability (less than 10%) of stage or treatment change following laparotomy were identified. These included CS IA female patients, CS IA male patients with lymphocyte predominance histology or high neck presentations, and patients with CS IIIB-IVB disease and account for 21% of the study population. Staging laparotomy altered the stage and treatment of a significant number of the remaining 79% patients and should continue to be recommended for this group of patients.
Abdominal Neoplasms↗