Recurrent graft failure following syngeneic bone marrow transplantation for aplastic anaemia

We present the case of a 60-year-old woman with drug-induced aplastic anaemia with a healthy monozygotic twin. Proof of monozygosity was confirmed by studies using the hypervariable minisatellite probe to obtain identical DNA fingerprints in donor and recipient. In vitro co-culture studies performed showed no evidence of a recipient-derived cellular or humoral inhibitor of donor haemopoiesis. Despite this, there was no engraftment following simple marrow infusion without preconditioning. A second syngeneic transplant following high dose cyclophosphamide therapy produced trilineage engraftment but severe thrombocytopenia developed at 3 months, followed later by pancytopenia with generalized marrow failure. Following a third syngeneic transplant with cyclophosphamide and total lymphoid irradiation there was good initial engraftment but graft failure occurred at 14 weeks. A fourth transplant using Campath 1G as preconditioning resulted in no engraftment and the patient died of septicaemia 8 weeks following her fourth transplant. We suggest that the cause of the recurrent aplastic anaemia in this case was a defect of marrow stroma as neither an inhibitor of donor haemopoiesis nor an intrinsic defect of donor stem cell growth could be demonstrated in vitro.     

Death related to albendazole-induced pancytopenia: case report and review

Albendazole is a benzimidazole with wide spectrum coverage as an antiparasitic drug. Reported side effects have been minimal. We report the case of a patient who died with severe prolonged pancytopenia beginning during the third week of therapy for a pulmonary echinococcal cyst. This case was a 68-year-old man who presented with a large cystic lung mass. His medical history was significant for Child-Pugh class B cirrhosis. A prolonged course of albendazole was initiated. Two weeks later, the patient presented in septic shock with severe pancytopenia. The patient was initially resuscitated, but died after 10 days with no marrow recovery. Autopsy was consistent with albendazole-induced pancytopenia. This is the third human case of pancytopenia and the first death reported in relation to albendazole-induced pancytopenia. Neutropenia seems to be related more to higher dosage and longer duration of use. Albendazole sulfoxide peak dose and half life are significantly prolonged by liver disease and concomitant administration of certain drugs. The severity and duration of albendazole-induced pancytopenia in this case was likely related to the underlying liver disease. Frequent serial monitoring of blood counts and cessation of medication with any evidence of marrow toxicity in such patients is warranted.     

Thalidomide for the treatment of histiocytic sarcoma after hematopoietic stem cell transplant

Histiocytic sarcoma (HS) is a rare neoplasm of uncertain etiology. Most recently, the diagnostic criteria for this entity have been revised with inclusion of diagnostic modalities such as immunohistochemical and cytogentic techniques. HS tends to have an aggressive clinical course and presents with systemic symptoms of fever, weight loss, adenopathy, hepatosplenomegly, rash, and pancytopenia. Thalidomide is a promising agent that may exert a therapeutic benefit in HS. We report a case of a 48-year-old female with HS who presented with fever, weight loss, fatigue, generalized anasarca, and pancytopenia. She underwent multi-agent chemotherapy followed by matched unrelated hematopoietic stem cell transplant. Her disease recurred and thalidomide therapy was started, with her overall disease burden significantly reduced as measured radiographically.     

Linezolid-Related Pancytopenia in Organ-Transplant Patients: Report of Two Cases

Abstract Linezolid is a recent oral antibiotic used in drug-resistant Gram-positive cocci infection. We herein report on the first two cases of linezolid-related pancytopenia in organ-transplant patients. Both patients had methicillineresistant Staphylococcus aureus infections. Pancytopenia, i.e. aregenerative anemia, neutropenia and thrombopenia, developed 3 weeks and 5 weeks after initiating linezolid therapy at a conventional dosage (600 mg bid). There were no other confounding causes of pancytopenia, which resolved promptly after withdrawing linezolid. Because of the potential hazards of pancytopenia in immunosuppressed organ-transplant patients, we advocate the cautious use of linezolid for transplant patients.     

Donor‐transmitted parvovirus infection in a kidney transplant recipient presenting as pancytopenia and allograft dysfunction

Abstract: Parvovirus B19 is a nonenveloped single‐stranded DNA virus that commonly causes a benign childhood infection typically manifesting as a ‘slapped‐cheek’ rash. In immunodeficient hosts, this infection can cause persistent anemia and occasionally pancytopenia. Recently, direct renal involvement has been reported in renal transplant recipients leading to various forms of glomerulopathy and allograft dysfunction. Most cases are primary infections and are donor transmitted through the transplanted organ. Clinical and virological response to intravenous immunoglobulin (Ig) is usually excellent. We describe a case of donor‐transmitted parvovirus infection in a 23‐year‐old male who received his first cadaver renal transplant. The patient had an uncomplicated postoperative course with immediate graft function. Eight weeks after transplantation, he presented with fever, polyarthralgia, pancytopenia, and allograft dysfunction. Serological studies revealed elevated IgM titers against parvovirus B19. A renal biopsy was performed, which showed no evidence of acute rejection but with moderate degree of tubular damage. Parvovirus B19 viral DNA was detected in the renal tissue via polymerase chain reaction (PCR). The patient received a 10‐day course of intravenous Ig (400 mg/kg/day) with excellent response. His blood count normalized and the allograft improved to baseline function. The incidence of parvovirus infection in renal transplant patients is probably underestimated, because patients are not routinely screened for it and anemia and/or pancytopenia in these patients are often ascribed to immunosuppressive drugs. Because this infection is treatable, we conclude that parvovirus B19 infection should be actively considered in transplant patients presenting with pancytopenia and allograft dysfunction.     

Treatment of busulfan-induced pancytopenia.

A patient with busulfan-induced pancytopenia and recurrent, thrombocytopenic bleeding was treated prophylactically with random-donor platelet transfusions and later with HLA-matched platelets from a sibling. The pancytopenia remitted after five months. The course and alternative modes of therapy of busulfan-induced pancytopenia are discussed. This disorder may be reversible if the patient can be supported through an initial period of severe pancytopenia.     

Allogeneic bone marrow transplantation for Fanconi anemia.

Five patients (age range 7-14 years) received allogeneic bone marrow transplantation (BMT) for Fanconi anemia (FA). All patients showed progressive pancytopenia associated with congenital malformations. Diagnosis was confirmed by studies of cellular hypersensitivity to the clastogenic effect of the DNA crosslinking agent diepoxybutane. The conditioning regimen consisted of low dose cyclophosphamide (5 mg/kg x 4) and fractionated total body irradiation (167 cGy x 3). For graft-versus-host disease prophylaxis one patient was given cyclosporin alone while the remaining four patients received a combination of cyclosporin and two doses of methotrexate. Marrow was given unmanipulated from HLA-identical siblings. All patients are alive 18-67 months after grafting with Karnofsky scores of 100% and normal hemopoiesis of donor origin. Modifications in transplant protocols such as those here described have resulted in a decreased risk of severe transplant-related complications. These results confirm that BMT is a curative therapy in FA patients and should be considered as a first choice treatment if an HLA-identical donor is available.     

Human granulocytic ehrlichiosis in pancreas transplant recipients

Abstract: Human ehrlichioses are tick‐borne infections caused by bacteria in the genus Ehrlichia of the family Rickettsiaceae. To date there have been three cases of ehrlichiosis reported in the transplant population, a human monocytic ehrlichiosis (HME) infection in a liver transplant recipient and two cases of human granulocytic ehrlichiosis (HGE) in kidney transplant recipients. We report three pancreas transplant patients who developed HGE in the last two years at a single southeastern center in the United States. All three patients had clinical, laboratory, and pathophysiologic findings on bone marrow biopsy and peripheral blood smears consistent with HGE, and responded to doxycycline therapy. In the setting of potent immunosuppression, ehrlichiosis should be considered in the differential diagnosis of transplant patients presenting with persistent fever, pancytopenia, and abnormal liver function. Patients with ehrlichiosis infection may be at risk for developing other opportunistic infections or lymphoproliferative disease.     

Successful treatment of Epstein–Barr Virus-associated haemophagocytic syndrome arising after living donor liver transplantation

A 6-year-old girl received an orthotopic liver transplant secondary to liver failure of unknown etiology. Several days after liver transplantation, she developed pancytopenia and Epstein –Barr Virus (EBV)-positive seroconvert after transplant. Taking of medical history to provide evidence of pancytopenia correlated with EBV infection after transplant. Bone-marrow biopsy was carry out to confirm haemophagocytic syndrome (HPS). Laboratory investigations, including blood routine count, microscopic blood film examination, serum ferritin concentration, and liver function tests were carried out starting from the first day of suspected HPS infection, continuing until 15 weeks post-infection. Liver transplantation followed with a combination of cyclosporin A, corticosteroids, VP-16, and supportive strategies.     

Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis

Objective. To assess the frequency of methotrexate (MTX)-induced pancytopenia in rheumatoid arthritis (RA). Methods. A MEDLINE literature search was conducted to identify articles published during the last 15 years (1980–1995) that presented data on MTX-associated pancytopenia. Two case reports of our own experience are also presented. In addition, articles that examined risk factors associated with MTX-related pancytopenia were identified. Results. A total of 70 patients with pancytopenia related to MTX therapy were identified (68 reported in the literature, 2 from our own experience). Sixty-one of the patients were described in published case reports, 7 patients were from 5 long-term prospective studies. In many of these cases, predisposing factors for the development of pancytopenia were described. The 5 long-term prospective studies reported toxicity data on patients who had been treated with MTX for at least 13 weeks. A total of 511 patients were included in the prospective trials, yielding an overall incidence of pancytopenia of 1.4% (7 of 511). Of the 70 cases reported, 12 patients died (17%). Most of them had impaired renal function, hypoalbuminemia, concurrent infection, and/or concomitant medication with more than 5 drugs. The minimal cumulative MTX dose leading to fatal pancytopenia was 10 mg, observed in one of our patients. Conclusion. Pancytopenia is not an uncommon side effect of low-dose pulse MTX therapy in RA. It can lead to serious complications, including death.     

Hemophagocytic syndrome in kidney transplant recipients: report of four cases from a single center

BACKGROUND: The prognosis of hemophagocytic syndrome (HPS) in kidney transplant recipients is reported to be poor, however the optimal therapeutic approach is still unclear. PATIENTS AND METHODS: The clinical and follow-up data of the 4 patients with HPS (3 male, 1 female; age 39.7 +/- 11.3 years) among 368 kidney transplant recipients during a 5-year period were retrospectively analyzed. RESULTS: HPS developed 35-61 days in the post-transplant period. All 4 patients presented with fever. Hepatosplenomegaly and lymphadenopathy were observed only in the first patient. Laboratory tests revealed pancytopenia and hyperferritinemia in all patients, but elevated liver enzymes were observed in 3. Two patients had cytomegalovirus infection, and 1 had Epstein-Barr virus infection. Three patients died despite aggressive supportive therapy, however the fourth case survived after graft nephrectomy. CONCLUSION: HPS pathogenesis in kidney transplants appears to be related with the graft itself. Graft nephrectomy may be the preferable therapeutic approach for kidney transplant recipients with HPS resistant to standard supportive therapy.     

Low dose methotrexate therapy for rheumatoid arthritis complicated by pancytopenia and Pneumocystis carinii pneumonia

In a patient with rheumatoid arthritis pancytopenia and Pneumocystis carinii pneumonia occurred during low dose methotrexate therapy. This case emphasizes the potential development of opportunistic infections even with low dose methotrexate. Pneumocystis carinii pneumonia resembles methotrexate induced pneumonitis. Therefore opportunistic infections should be considered before a definite diagnosis of methotrexate induced pneumonitis is made.     

Parvovirus B19-related anaemia after renal transplantation

We describe here the case of a renal transplant recipient treated by sirolimus based immunosuppresive therapy, who developed severe and unusual pancytopenia 2 months after renal transplantation. Parvovirus B19 primo-infection was diagnosed. The first course of intravenous immunoglobulin failed. Bone marrow aspiration confirmed megaloblastic anaemia associated with parvovirus B19. Finally, this infection was succesfully treated by the reduction of immunosuppression combined with a second course of intravenous immunoglobulin.     

Clodronate in myelofibrosis: a case report

A 59-year-old man had well-documented agnogenic myeloid metaplasia (AMM) with pancytopenia. Frequent blood transfusions were required over a 10-month period. Androgen therapy was not beneficial and treatment with interferon resulted in severe thrombocytopenia with no decrease in transfusion requirements. Treatment with clodronate at a daily oral dose of 30 mg/kg resulted in a marked decrease in bone marrow fibrosis, and gradual normalization of blood counts over an 8-month period. He has been transfusion independent for the last 33 months. We support the findings of a previous case report that oral bisphosphonate therapy may be of value in patients with AMM.     

Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma

Single‐agent post‐autologous transplant maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma. The tolerability and effectiveness of combination post‐transplant maintenance therapy is unknown, so we investigated lenalidomide and vorinostat (suberoylanilide hydroxamic acid) in this setting, hypothesizing that the regimen would be well tolerated and associated with an improved post‐transplant response. This trial followed a standard 3 × 3 dose escalation phase 1 design. Vorinostat was administered beginning day +90 post‐haematopoietic stem cell transplantation for days 1–7 and 15–21, and lenalidomide was started at 10 mg days 1–21, both on a 28‐d cycle. The primary endpoint was maximum tolerated dose and dose limiting toxicities were assessed during the first cycle. Treatment was well tolerated in 16 enrolled patients. During Cycle 1, the most common toxicities included cytopenias, gastrointestinal complaints and fatigue. Seven patients improved their transplant response after starting combination therapy. The median follow‐up was 38·4 months, and the median progression‐free survival and overall survival have yet to be reached. This oral post‐transplant maintenance regimen was well tolerated. This is the first trial to publish results on the use of a histone deacetylase inhibitor in the maintenance setting, and it provides rationale for the ongoing randomized trial in maintenance (ISRCTN 49407852). Trial Registration: NCT00729118     

Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis

A multicenter prospective randomized trial of four versus six weeks of amphotericin B, 0.3 mg/kg per day, plus flucytosine, 150 mg/kg per day, was performed with 194 patients with cryptococcal meningitis. One or more toxic drug reactions developed in 103 patients: azotemia (51), renal tubular acidosis (two), leukopenia (30), thrombocytopenia (22), diarrhea (26), nausea/vomiting (10), and hepatitis (13). The four- and six-week regimens were complicated by toxicity in 44 percent and 43 percent of cases, respectively. Toxicity appeared during the first two weeks of therapy in 56 percent and during the first four weeks in 87 percent. Azotemia did not occur more frequently in renal transplant recipients or diabetic patients. Cytopenias did not appear more often in patients with hematologic malignancies or those receiving immunosuppressive therapies. Toxic reactions that contributed to death developed in five patients (two with azotemia, one with pancytopenia, one with hepatitis, one with ileus). Amphotericin B-induced azotemia was not a significant risk factor for the subsequent development of bone marrow, gastrointestinal, or hepatic toxicity attributable to flucytosine. Flucytosine toxicity was associated with peak serum flucytosine levels of 100 micrograms/ml or more during two or more weeks of therapy (p = 0.005). Peak 5-fluorouracil levels were not predictive of toxicity. An initial dose of flucytosine is recommended based on the creatinine clearance: 150 mg/kg per day at a creatinine clearance above 50 ml/minute, 75 mg/kg per day at a creatinine clearance of 26 to 50 ml/minute, and 37 mg/kg per day at a creatinine clearance of 13 to 25 ml/minute. The serum creatinine level should be monitored twice weekly and the creatinine clearance weekly during therapy in order to anticipate changes in serum flucytosine concentration. In addition, it is recommended that the serum flucytosine level be determined two hours after an oral dose once a week, and that the dose be adjusted to maintain a level of 50 to 100 micrograms/ml.     

Correction of Severe Myelofibrosis,Impaired Platelet Functions and Abnormalities in a Patient with Gray Platelet Syndrome Successfully Treated by Stem Cell Transplantation

Abstract

Gray platelet syndrome (GPS) is an inherited disorder. Patients harboring GPS have thrombocytopenia with large platelets lacking α-granules. A long-term complication is myelofibrosis with pancytopenia. Hematopoietic stem cell transplant (HSCT) could be a curative treatment. We report a male GPS patient with severe pancytopenia, splenomegaly and a secondary myelofibrosis needing red blood cells transfusion. He received an HSCT from a 10/10 matched HLA-unrelated donor after a myeloablative conditioning regimen. Transfusion independence occurred at day+21, with a documented neutrophil engraftment. At day+ 180, we added ruxolitinib to cyclosporine and steroids for a moderate chronic graft versus host disease (GVHD) and persistent splenomegaly. At day+240 GVHD was controlled and splenomegaly reduced. Complete donor chimesrism was documented in blood and marrow and platelets functions and morphology normalized. At day+ 720, the spleen size normalized and there was no evidence of marrow fibrosis on the biopsy. In GPS, HSCT may be a curative treatment in selected patients with pancytopenia and myelofibrosis.     

Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis

Low dose pulse MTX was associated with the development of pancytopenia in six patients with RA. Two patients died. Factors implicated in the occurrence of this complication were renal impairment in five patients, medication errors by two patients, preexisting marrow injury from occult alcoholism in one patient, and an apparent idiosyncratic reaction to the drug in another. Medication errors were associated with the use of five or more medications, and the unusual schedule of administration of low dose MTX may also have been contributory. From a consideration of the clinical pharmacokinetics of MTX, we suggest other factors that may predispose to the occurrence of marrow toxicity: the presence of hypoalbuminemia, interactions between MTX and other protein bound or weakly acidic drugs, and the repetitive dosing schedule of low dose MTX. Based on our experience, patients with impaired renal function (creatinine greater than or equal to 2.0 mg/dL) should not receive MTX. Renal function should be monitored regularly during treatment with MTX, and blood counts should be observed carefully if a new drug is added or substituted. A 5 mg test dose of MTX before initiating weekly therapy may identify patients with severe hypersensitivity to the drug. The potential risks of using MTX in a patient unwilling to accept blood products should be acknowledged and discussed with the patient. Furthermore, we recommend the use of leucovorin if pancytopenia occurs, even if low or undetectable serum levels of MTX are present.     

Bone marrow hypoplasia complicating tacrolimus (FK506) therapy

Tacrolimus (FK506)-induced hematological toxicity, which has rarely been reported in transplant recipients, may result in anemia episodes, reported mainly in kidney and heart transplant recipients, sporadic cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, red cell aplasia (4 reported cases), and generalized bone marrow suppression (only 1 reported case). We describe a case of a liver transplant recipient with pancytopenia that appeared during immunosuppressive therapy with tacrolimus. This patient suffered from progressive anemia, leukopenia with severe neutropenia, and mild thrombocytopenia; bone marrow biopsy showed hypoplasia (20% of cellularity) without dysplasia. Bone marrow recovery was made possible by suspending tacrolimus and changing to immunosuppression with cyclosporine A, despite the two drugs being very similar in their mechanism of immunosuppression. Contrary to previously reported cases (pure red cell aplasia and bone marrow hypoplasia), the recovery of hemoglobin and neutrophil values was slow after tacrolimus suspension, even though in the first month transfusions were no longer necessary.     

Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma

Although autologous stem cell transplant is an effective therapy for patients with multiple myeloma and extends progression-free survival (PFS) and overall survival (OS), patients show a continued pattern of recurrent disease. Twenty-nine patients were enrolled in a phase II study investigating the tolerability and efficacy of maintenance thalidomide following single autologous peripheral blood stem cell transplant. Six to eight weeks after transplant, patients were started on maintenance thalidomide at 50 mg a day. The dose was gradually escalated to a target dose of 400 mg a day and continued until disease progression or 6 months after achieving complete remission (CR) for a maximum total duration of 18 months. At 6 months, 13 patients (45%) achieved CR or near complete remission (positive immunofixation without any evidence of disease). The estimated 2-year OS was 83% and PFS was 49%. Median tolerated dose of thalidomide was 200 mg a day. In conclusion, thalidomide as maintenance therapy is feasible and may improve outcome after single autologous stem cell transplant.