Prolonged thrombocytopenia after autologous bone marrow transplantation

Thirty two patients with hematologic malignancies and solid tumors were treated with intensive therapy and autologous bone marrow transplantation. In nine out of 32 patients, it took more than 50 days to achieve a sustained platelet count of 50,000/microliter or greater. Significant associations with poor platelet recovery were found for patient age, diseases, period of cryopreservation, the kinds of eradicative therapy and in vitro purging. But most of these factors overlapped each other in the same patients. No correlation was found between platelet recovery and number of cells or CFU-GM infused.     

Wernicke-like encephalopathy after autologous bone marrow transplantation

A 15-year-old boy with non-T ALL in early 2nd remission was autografted using a regimen with busulphan 4 mg/kg/day, po, from day -9 to -6, and cyclophosphamide 50 mg/kg/day, iv, from day -5 to -2. During busulphan administration he experienced a few generalized seizures, and starting on day 25 post ABMT he developed a progressively severe neurological symptomatology characterized by nystagmus, right VIth cranial nerve palsy, truncal ataxia and, finally, confusion and coma. MRI showed lesions in the periaqueductal gray matter, thalamus, mammillary bodies and putamen. Within 24 hours of treatment with thiamine he improved dramatically, but during the following weeks permanent neurologic damage with memory deficit, truncal ataxia and nystagmus became evident. To our knowledge this is the first case of Wernicke's encephalopathy reported after BMT. We suspect in this case a contribution of busulphan to the development of the syndrome.     

Pituitary abscess after autologous bone marrow transplantation

The first case of pituitary abscess arising in a patient during recovery from autologous bone marrow transplantation is reported. A 31-year-old man with a 9 month history of T-cell lymphoma died suddenly more than 60 days after successful treatment with high-dose cyclophosphamide, total body irradiation, and autologous bone marrow infusion. Autopsy revealed a pituitary abscess associated with clinically silent sphenoid sinusitis. Unique aspects of this case are presented and clinical and pathologic features of pituitary abscess are reviewed. Although rare, pituitary abscess may complicate recovery from bone marrow transplantation.     

Renal function after autologous bone marrow transplantation

Seventy-two out of 102 consecutive patients autografted for various hematologic and lymphoid malignancies had a relapse-free survival of greater than 6 months after autologous bone marrow transplantation (ABMT) and were evaluated for long-term effect of the treatment on the renal function. The myeloablative therapy included total body irradiation (TBI) in a single fraction of 7.5 Gy in 41/72 patients. Mean glomerular filtration rate (GFR) showed a significant decrease (p less than 0.01) and serum creatinine and serum urea an increase (p less than 0.05) 6 months after ABMT. Twelve of 72 patients (17%) developed renal dysfunction defined as greater than 25% decrease in GFR, in most cases accompanied by hematuria and proteinuria. Onset was 3-6 months after ABMT. Some patients have later improved considerably, but others continue to deteriorate in renal function. The single most important risk factor for renal dysfunction after ABMT was irradiation. Renal damage was most frequent in lymphoma patients conditioned with BEAC (carmustine [BCNU], etoposide, cytarabine, cyclophosphamide) followed by irradiation, suggesting that this drug combination might have potentiated the toxicity of irradiation. Nephrotoxic antibiotics probably contributed to renal damage in individual cases. Young age did not appear to be a risk factor. Our data indicate that combined treatment with BEAC and TBI should be used with caution and that renal function should be monitored in all patients after bone marrow transplantation to detect any new toxicity patterns of the various conditioning regimens currently used.     

Cutaneous mastocytosis after autologous bone marrow transplantation

A 41-year-old male patient developed cutaneous mastocytosis 3 months after autologous bone marrow transplantation (ABMT). The ABMT was performed as part of consolidation treatment for a high-grade malignant non-Hodgkin's lymphoma. There was no evidence for systemic mastocytosis. Recurrence of the lymphoma could not be shown. Mast cell proliferation frequently coexists with dysplastic and neoplastic disorders of myeloid and, more rarely, of lymphoid cells. Mast cells are growth factor responsive and ultimately originate from the pluripotent hematopoietic stem cell. After autologous bone marrow transplantation, hematological reconstitution may in rare cases lead to an abnormal proliferation of mast cells possibly due to unbalanced production of growth factors.     

Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation

Cytomegalovirus (CMV) infection was detected in 65 of 143 (45%) autologous bone marrow transplant (BMT) patients. CMV pneumonitis occurred in only 2% of the patients and CMV retinitis occurred in none. Infection occurred in half of the 40 initially seronegative patients and 47% of the 94 initially seropositive patients. Among initially seropositive patients, platelet recovery was slower in infected patients than in those not infected (97 v 35 days median, P = .003), and neutrophil recovery was slightly delayed in infected patients (31 days v 24 days, P = .02). Although the incidence of CMV infection was comparable in autologous and allogeneic BMT patients, CMV pneumonitis was less frequent in autologous BMT patients (2% v 12%, P less than .001). The risk for CMV pneumonitis in autologous BMT patients was comparable with that in allogeneic BMT patients without graft-v-host disease (GVHD) (2% v 6%), but significantly lower than the risk in allogeneic BMT patients with GVHD (2% v 23%, P less than .001).     

Thyroid function after autologous bone marrow transplantation.

Thyroid function was prospectively analysed in 111 consecutive patients in relation to autologous bone marrow transplantation (ABMT). Median follow-up time was 12 (range 3-60) months. As part of the conditioning treatment 58 patients had received total body irradiation (TBI) as a single dose of 7.5 Gy (dose rate 0.15 Gy/min). Thyroxine, triiodothyronine, thyrotropin (TSH) and thyroid antibodies were analysed before ABMT, every third month during the first year afterwards and then once annually. Thyroid dysfunction was seen in 20 patients (after TBI in 16, after non-TBI treatments in four). Five of these, all treated with TBI, developed primary hypothyroidism and in 15 compensated hypothyrosis, transient in eight (40%), was seen. There was a highly significant (p less than 0.001) increase, within the normal range, in median TSH level, prior to ABMT compared with 1 year following ABMT. In patients who developed thyroid dysfunction, the TSH level before ABMT was significantly higher (p less than 0.001) than in those who remained euthyroid. In four patients persistent elevated thyroid antibody titers appeared and in two of them hypothyrosis developed. No correlation between thyroid dysfunction and age was noted. The findings are similar to those after allogeneic BMT described by others.     

Cytotoxic T-cell capacity after autologous bone marrow transplantation

A total of 19 patients, treated for aggressive tumors with high-dose chemo/radiotherapy and autologous bone marrow transplantation (BMT), were studied for concanavalin-A (Con A)-induced proliferation and Con-A-induced cytotoxicity. Ten patients with cytomegalovirus (CMV) antibodies before BMT showed increased Con-A-induced cytotoxicity before and from 100 days after BMT, while Con-A-induced proliferation decreased to less than 10% of control values after BMT and remained so. Nine CMV-negative patients showed normal cytotoxic capacity before and after BMT, while Con-A-induced proliferation recovered slowly from day +30 after BMT. Con-A-induced cytotoxicity was not significantly different between CMV-positive and CMV-negative patients, while Con-A-induced proliferation showed significant differences from day +100 onward.     

Herpes zoster infection after autologous bone marrow transplantation

One hundred fifty-three patients who underwent autologous bone marrow transplant (ABMT) were studied retrospectively to determine the frequency, outcome, and risk-factors associated with varicella-zoster infections (VZV). Forty-three patients (28%) developed VZV infection after transplant. The median onset of infection was the fifth month, with 91% of cases occurring within the first year. Thirty-three patients (77%) had localized herpes zoster, and ten patients (23%) had varicella. Cutaneous dissemination developed in 15% of patients and probable visceral dissemination developed in 5%. Overall morbidity was 25% and included scarring, alopecia, postherpetic neuralgia, and neurologic dysfunction. There were no deaths from VZV infection. The majority of patients (79%) were treated with intravenous (IV) acyclovir. The only significant risk factor associated with VZV infection was the underlying disease. VZV infection occurred most frequently in patients with Hodgkin's and non-Hodgkin's lymphoma (46%) as compared with patients with leukemia (23%) or solid tumors (9%) (P less than .002). The frequency of VZV infection in ABMT patients appears to be comparable to that reported for allogeneic BMT patients and other immunocompromised patients.     

Bronchiolitis obliterans after autologous bone marrow transplantation.

Two patients are reported who underwent autologous bone marrow transplantation for lymphoma and developed rapidly progressive respiratory insufficiency at posttransplant (PT) days 90 and 273. Clinical examination revealed persistent cough, exertional dyspnea, inspiratory rales, and expiratory wheezing. Results of pulmonary function studies were consistent with rapidly progressive severe respiratory disease in both patients. Despite aggressive immunosuppressive therapy, both patients had a progressive decline in respiratory function and died of respiratory insufficiency at PT days 400 and 446, respectively. Each patient had histologic evidence of bronchiolitis obliterans (BrOb). These cases demonstrate that life-threatening obliterative bronchiolitis is not limited to patients undergoing allogeneic bone marrow transplantation, but can also follow autologous transplant. Awareness that this group is also at risk for BrOb and severe respiratory compromise may lead to early diagnosis and treatment.     

Allogeneic bone marrow transplantation in patients with lymphoma relapsing after autologous marrow transplantation

Two patients who underwent autologous bone marrow transplantation for recurrent non-Hodgkin's lymphoma relapsed at 46 and 28 days after the transplant. Both patients had an HLA-identical sibling and were treated with high-dose chemotherapy and allogeneic marrow transplantation. One patient is now 24 months after the allogeneic transplant without evidence of disease. The second patient died on day 7 with interstitial pneumonia. We conclude that high-dose therapy and allogeneic bone marrow transplantation after failure of autologous transplantation for non-Hodgkin's lymphoma is feasible and should be considered in young patients with HLA-identical siblings.     

Characteristics of engraftment after repeated autologous bone marrow transplantation

The rate of engraftment after autologous bone marrow transplantation (ABMT) is extremely variable and largely unpredictable. To identify factors influencing engraftment, we studied 35 patients with refractory germ cell tumors undergoing high-dose chemotherapy with carboplatin (900-2000 mg/m2) and etoposide (1200 mg/m2) with bone marrow rescue. Prior to the initiation of chemotherapy, bone marrow sufficient for two marrow infusions was harvested (range 0.86-4.82 x 10(8) nucleated cells per kg). All 35 patients received half of the collected bone marrow 3 days after the last dose of chemotherapy; 23 responders received a second round of the same chemotherapy followed by infusion of the second half of the bone marrow. Eighteen patients could be compared for the two transplant episodes. The "rate of engraftment" was defined as the unweighted mean of four parameters: 1) the number of days until the absolute granulocyte count surpassed 0.2 x 10(9)/liter, 2) the number of days until the absolute granulocyte count surpassed 0.5 x 10(9)/liter, 3) the number of days until the last platelet transfusion, and 4) the number of days until the reticulocyte count surpassed 25 x 10(9)/liter. No significant correlation was found between rate of engraftment and such factors as the number of nucleated cells per kg infused, the dose of chemotherapy, extent of prior chemotherapy, tumor response to the high-dose chemotherapy, age of the patient, or the days of granulocytopenic fever (all p greater than 0.20). In contrast, a close correlation was found for the number of units of platelets (p = 0.005) and red blood cells (p = 0.006) transfused following each of the two transplants. There was no significant difference between rate of engraftment after first and second transplantation. Comparison of these data with the results obtained in reported ABMT with separate harvests suggests that the characteristics of the infused marrow determine the rate of engraftment after ABMT. This model of repeated transplantation could provide an important tool for assessing the therapeutic efficacy of hematopoietic growth factors.     

Fatal hepatitis B reactivation after autologous bone marrow transplantation

We report a fatal case of hepatitis B reactivation following autologous bone marrow transplantation for acute lymphocytic leukaemia. The presence of antibodies to HBs and HBc at presentation indicated previous infection with hepatitis B; these antibodies disappeared during the course of treatment for leukaemia. HBsAg was first detected in serum 5 weeks post-transplant; liver function tests began to deteriorate 8 weeks later, when HBeAg was first detected. The hepatitis followed a fulminant course, and the patient died 10 days later, in the 15th week following transplant.     

Allogeneic bone marrow transplantation in children failing prior autologous bone marrow transplantation

Twenty-three children with de novo acute myelogenous leukemia (AML) (n = 20), secondary AML (n = 1), or non-Hodgkin's lymphoma (NHL) (n = 2) underwent allogeneic bone marrow transplantation (alloBMT) for graft failure (n = 1) or recurrent malignancy (n = 22) between February 1992 and August 1999 following autologous BMT (ABMT). Induction chemotherapy was given to 14 patients and nine patients went directly to alloBMT. Five received marrow from matched siblings, 14 from matched unrelated donors and four from mismatched family members. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Nine patients are alive disease-free between 627 and 2433 days (1.7-6.7 years) post BMT resulting in a 4-year DFS of 39%. Eight patients relapsed at a median of 206 days (range, 35-669 days) post alloBMT and all eventually died. Eight patients (two of whom also relapsed) died of RRT. Although RRT and relapse remain significant problems, a significant percentage of pediatric patients failing ABMT may be cured with alloBMT.     

Impaired erythropoietin response to anemia after bone marrow transplantation.

Delayed erythroid recovery is common after bone marrow transplantation (BMT), with some patients continuing to require red blood cell (RBC) transfusion support for as long as 1 year. While the etiology is multifactorial, inadequate stimulation of erythroid progenitors by the erythroid growth factor, erythropoietin, may play a role. In this study, the erythropoietin response to anemia of 70 consecutive patients undergoing BMT at the Johns Hopkins Oncology Center was compared with the erythropoietin response in uncomplicated iron deficiency anemia. Erythropoietin levels were elevated for the degree of anemia early after BMT; however, at the time of marrow recovery, erythropoietin levels were significantly suppressed in both allogeneic and autologous BMT patients compared with the iron-deficient patients. Patients with acute graft-versus-host disease (GVHD) had a more marked suppression of the erythropoietin response to anemia. In the patients who remained anemic for extended periods of time (up to 12 months after BMT), an inadequate erythropoietin response to anemia persisted. Delayed erythroid recovery after BMT is associated with inadequate erythropoietin levels. Therefore, recombinant human erythropoietin may be useful in the treatment of the anemia associated with both autologous and allogeneic BMT.     

T cell regeneration after allogeneic and autologous bone marrow transplantation

Venous blood T cell phenotypes were analysed with monoclonal antibodies after 11 allogeneic and 17 autologous bone marrow transplants. In seven cases studied in the early regenerative period, cells with a thymocyte phenotype were present in the blood. In the large majority of patients treated with both allografts and autografts there was an imbalance of phenotypic 'helper' and 'suppressor' T cell subsets with initially a relative and later an absolute increase of 'suppressor' T cells. This imbalance was still present at over 250 d in eight out nine cases. Suppressor T cells bearing HLA-Dr antigens were abundant in one case of fatal GVHD but not in another, and were also increased following two autografts. It is concluded that T cell phenotyping is not of diagnostic value in sick patients following bone marrow transplantation when graft-versus-host disease is suspected.     

GM-CSF therapy for delayed engraftment after autologous bone marrow transplantation

Based on previous observations that granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes granulocyte recovery following chemotherapy, we evaluated the effect of recombinant human GM-CSF on hematopoietic progenitors and clinical outcome in six patients with delayed engraftment (greater than 55 days) after high-dose therapy and autologous bone marrow transplantation (ABMT). Three patients responded to a 14-day course of GM-CSF (10 micrograms/kg body weight/day) with at least a sevenfold rise in circulating granulocytes and a corresponding increase in granulopoietic activity in the bone marrow. A fourth patient died of infection on the 8th day of GM-CSF therapy with no evidence of response, and the remaining two, one of whom received a lower dose of GM-CSF (5 micrograms/kg/day), did not respond. There was no change in platelet or red cell transfusion requirements in any patient during the treatment. In two of the three responders, the granulocyte counts returned to pretreatment levels by 4 and 7 weeks after stopping the drug, respectively. We observed a marked increase in marrow-derived as well as in circulating granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) by the end of the 14-day course of GM-CSF in the three responders. There was no change in the frequency of circulating or marrow-derived erythroid (erythroid burst-forming units, BFU-E) or multilineage (multilineage colony-forming units, CFU-GEMM) progenitors. The results indicate that GM-CSF therapy in patients with markedly delayed engraftment after ABMT may stimulate granulopoiesis, but the effect is transient in some patients.     

Varicella-zoster virus infections after autologous bone marrow transplantation in children

We report a retrospective analysis of children who underwent autologous bone marrow transplantation (ABMT) and subsequently developed a varicella-zoster virus (VZV) infection. Among 236 patients transplanted between January 1979 and December 1987, 54 (23%) aged 2 to 18.5 years (mean 7.2) developed 60 VZV infections (25%); there were 10 cases of chicken-pox in 10 patients, 43 zoster infections in 41 patients and seven disseminated zoster infections in seven patients. Eighty-seven percent of VZV infections occurred within the first 6 months after bone marrow transplantation, with a mean interval of 89 days. No significant risk factors for the development of zoster infections were identified. The incidence of VZV infections following ABMT was similar to that observed after allogeneic bone marrow transplant but the onset was earlier after ABMT (3 vs 5 months) and there were fewer complications (2 vs 18%). Acyclovir and/or adenine arabinoside were administered to 46 patients. One child who had had chicken-pox died of interstitial pneumonitis due to VZV despite antiviral therapy. No other symptomatic visceral dissemination was observed.     

Cyclosporin for thrombotic thrombocytopenic purpura after autologous bone marrow transplantation

Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT) is a serious complication that, in contrast to classic TTP, is generally not responsive to therapeutic plasma exchange. We describe the remission of TTP after autologous BMT by administration of cyclosporin in four patients, either after failure of plasmapheresis (two patients) or as primary treatment modality (two patients). Cyclosporin may be an attractive drug for post autologous BMT-TTP.