Unusual recurrence of chronic myelogenous leukemia following bone marrow transplantation

We report a patient who developed a bone and adjacent soft tissue malignancy 22 months after bone marrow transplantation (BMT) for Philadelphia chromosome positive chronic myelogenous leukemia (CML). Concomitant bone marrow was cytologically and cytogenetically normal. Cytogenetic study of tumoral tissue was unsuccessful but DNA analysis revealed BCR-AB1 rearrangement similar to that observed in hematopoietic cells prior to BMT. The present case demonstrates that molecular analysis is helpful in the diagnosis of unusual relapse of CML.     

Cytogenetic conversion following allogeneic bone marrow transplantation for advanced chronic myelogenous leukemia

We performed a pilot study to test the effectiveness of allogeneic bone marrow transplantation in the treatment of chronic myelogenous leukemia. Five patients in the advanced stages of chronic myelogenous leukemia (four in blast crisis, one in accelerated phase) with abnormal chromosomes underwent matched-sibling allogeneic bone marrow transplantation after preparation with busulfan, vincristine, cyclophosphamide, and fractionated total body irradiation. Engraftment and conversion to normal chromosome patterns after transplantation occurred in all five patients. None of the patients reverted to an abnormal chromosome pattern of demonstrated clinical or hematologic evidence of recurrent disease during the course of this study; however, longest survival from transplant was 248 days. Allogeneic bone marrow transplantation can eradicate the abnormal clone even in far advanced chronic myelogenous leukemia and can provide normal hematopoiesis. We suggest that clinical complications of chemotherapeutic toxicity and infection were responsible for the short survival in this group of patients, and that these complications could be decreased by performing transplantation in the chronic phase or early accelerated phase of the disease.     

Autologous bone marrow transplantation in chronic myelogenous leukemia

Introduction of interferon-alpha therapy to chronic myelogenous leukemia (CML) has improved the survival rate of CML patients compared with conventional busulfan therapy. There still, however, are some IFN-resistant cases. To improve the survival rate of these IFN-resistant cases, bone marrow transplantation (BMT) has been tried at the world wide level. In cases without any allogeneic donors, autologous BMT is another choice. We recently have proposed the flow chart therapy system to select the auto-BMT candidates in CML patients. This system, briefly, consists of (1) bone marrow collection as early stage of CML as possible, (2) IFN-alpha treatment with administration of weekly methotrexate or occasional use of hydroxyurea, (3) early detection of accelerated or blastic phase of CML by using scoring system, (4) conditioning regimens of auto-BMT for CML and (5) post-BMT follow-up with IFN-alpha. Following this system, we have initiated the treatment of CML cases. Our tentative results on one case favorable outcome including complete disappearance of Ph1 positive clone. However, there are several questions to be answered in the auto-BMT for CML, namely, (1) do we need to purge Ph1 progenitor cells or not, if yes, how? (2) does the long term use of IFN affect the bone marrow microenvironment resulting in graft failure? Although our preliminary results gave some answers on these questions, further clinical and basic studies are required to obtain higher survival rates in CML treatment.     

Unrelated donor bone marrow transplantation therapy for chronic myelogenous leukemia

Eight patients received allogeneic bone marrow transplantation (BMT) as therapy for chronic myelogenous leukemia (CML) using marrow from unrelated donors. In all cases donors and recipients were HLA DR identical and had low MLC reactivity. In three cases recipients received marrow that was identical at the HLA A,B loci. In five cases HLA identity differed for one HLA A locus antigen. The unrelated donor search interval ranged from 2 to 28 months (median, 3 months). All recipients were prepared with a combination of cyclophosphamide, 60 mg/kg/d administered intravenously (IV) (days -6,-5) and with total body irradiation administered in 165 cGy fractions twice daily for four days (days -4, -3, -2, -1). Engraftment occurred in all cases (range, 18 to 48 days; median, 35 days), and return to a complete Philadelphia chromosome (Ph') negative state was documented in six of eight cases. Moderate or severe acute graft v host disease (GVHD) occurred in seven of eight cases, and extensive chronic GVHD in four of six evaluable recipients. A B cell lymphoproliferative disorder developed in one patient. Four recipients have died within 2 to 4 months of transplant. Four of eight patients survive at 11+ to 24+ months following transplantation (median, 15+ months) with normal peripheral blood counts and without evidence of leukemia. Current Karnofsky activity assessments are 90% or 100% in all survivors. Curative therapy of CML has been available only to the minority of patients eligible for sibling donor BMT. Unrelated donor BMT can be effective in the treatment of CML and may be particularly useful in this disorder since the prolonged stable phase of disease offers an opportunity to locate suitable donors.     

Allogeneic bone marrow transplantation as treatment for accelerating chronic myelogenous leukemia

Sixteen patients with chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation (BMT) when they presented with or developed objective signs suggesting acceleration of disease. Patients have been followed for a median of 515 days (range 216-806 days). Seven patients are alive from 319 to 732 days (median 538 days). Four patients are in complete remission 501-732 days after BMT. Three patients have developed cytogenetic evidence of relapse after BMT; however, these patients are alive and not dependent on therapy and have normal activity levels at 319, 515, and 550 days following BMT. Three additional patients have developed cytogenetic and hematologic evidence of relapse after BMT, progressed to blast crisis, and died. Six patients have died of other causes. Allogeneic BMT can eradicate the abnormal clone and provide normal hematopoiesis when performed during the accelerated phase of CML; however, this approach is associated with relapse and with relatively high mortality. The long-term efficacy of this approach and the relative efficacy of transplant during acceleration rather than during the chronic phase of CML have yet to be established.     

Allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic or accelerated phase

Eight patients with Ph1-positive chronic myelogenous leukemia (CML) in chronic or accelerated phase received high-dose cyclophosphamide, total body irradiation, and bone marrow transplantation from an HLA-identical sibling donor. All patients had prompt engraftment and achieved complete hematologic remission. Six patients remain alive and in continuous remission with a normal bone marrow karyotype 3-20+ mo posttransplant. One patient died from cytomegalovirus interstitial pneumonitis. Only one patient who was transplanted in accelerated phase relapsed 6.5 mo posttransplant and died in blast crisis. High-dose combined modality therapy is capable of producing sustained complete remissions in patients with CML treated during chronic or accelerated phase.     

Isolated pericardial relapse following allogeneic bone marrow transplantation for acute myelogenous leukemia

A 34-year-old male patient developed an isolated pericardial relapse of an acute myelogenous leukemia (M3) 11 months after marrow grafting from his HLA-identical brother. Alloenzyme pattern analysis revealed recipient type of the myeloblasts obtained from the pericardial effusion. Recurrence of the original leukemia was preceded by a reactivation of latent cytomegalovirus (CMV) infection which, in spite of a systemic humoral immune response to the virus, persisted in the pericardium as shown by dot-blot hybridization using CMV-specific DNA fragments. Activated T cells propagated with IL-2 from the pericardial effusion did not reveal any cytotoxic or restimulation capacity on the original or relapse myeloblasts, nor on other donor, recipient or NK target cells. Local coincidence of virus persistence and leukemic relapse suggested CMV-mediated modulation of the immune response in the pericardium with consequent induction of a proliferation of the original malignant cell clone. After local chemotherapy and one course of systemic treatment the patient is still in complete remission--longer than after the marrow grafting.     

Transient nephrotic syndrome after allogeneic bone marrow transplantation for chronic myelogenous leukemia

A 42-year-old man with chronic myelogenous leukemia underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor in January 1998. About 100 days later, he developed skin eruption and a diagnosis of chronic graft-versus-host disease (cGVHD) was made by skin biopsy. The eruption improved with steroid therapy, and the dose of steroid was gradually tapered. On day 151, the patient developed nephrotic syndrome with proteinuria up to 20 g/day. A renal biopsy carried out on day 160 showed minimal change in the glomeruli. The proteinuria disappeared 19 days after the onset of nephrotic syndrome without any additional therapy, and no recurrence was observed upon re-tapering of the steroid. In this case, cGVHD might have been related to development of the nephrotic syndrome. Nephrotic syndrome after allo-HSCT is a rare complication, and only ten cases have been reported. The histological findings were mainly membranous nephropathy, and immunosuppressive therapy was effective. As seen in this case, transient nephrotic syndrome with cGVHD may occur after allo-HSCT, and care is necessary to ensure that treatment of cGVHD is sufficient.     

Porphyria cutanea tarda after allogeneic bone marrow transplantation for chronic myelogenous leukemia

A case of porphyria cutanea tarda (PCT) occurring after bone marrow transplantation (BMT) is reported. A 43-year-old male with chronic myelogenous leukemia received an human leukocyte antigen (HLA)-identical allogeneic transplantation with T-cell depleted marrow. Because of graft rejection, a second transplant was performed 4 months later. A grade II acute graft- vs.-host disease and a cytomegalovirus (CMV) infection were subsequently observed. Two years after the second transplant, cutaneous symptoms of PCT with typical biochemical abnormalities developed. Liver biopsy revealed signs of hepatitis with iron overload. CMV was isolated from liver tissue. The possible roles of underlying disease, BMT, and CMV liver disease are discussed in view of the recently reported cases of PCT in patients with AIDS or hematological disorders.     

Long-term remission of T-lymphoid extramedullary blast crisis of chronic myelogenous leukemia following allogeneic bone marrow transplantation

Extramedullary blast crisis (EBC) with T-lymphoid phenotype has been reported rarely and generally associated with extremely poor prognosis. We describe a case of T-lymphoid EBC in which long-lasting remission was observed following intensive chemotherapy and allogeneic bone marrow transplantation (BMT). Characterization of bone marrow (BM) and lymph node (LN) cells was performed by means of morpho-cytochemical, cytogenetic, immunophenotypic and molecular analyses. These showed, together with a marrow picture consistent with typical Ph'+ chronic myelogenous leukemia, the expansion of an early T-lymphoid (CD7+/TdT+) LN cell population exhibiting the same bcr rearranged pattern and an additional Ph' chromosome. At the present time, 33 months after BMT, the patient is alive and well, with persistent clinical, hematological, cytogenetic and molecular evidence of complete remission.     

Acute myelogenous leukemia with mediastinal and subcutaneous emphysema following chronic GVHD after allogeneic bone marrow transplantation

A 38-year-old man was diagnosed as having acute myelogenous leukemia in December 2001. He achieved a complete remission after undergoing three courses of induction chemotherapy. As the patient's prognosis was considered to be poor, he was then treated with a bone marrow transplant from his HLA 1 antigen mismatched sister in May 2002. Grade 2 skin graft-versus-host-disease (GVHD) developed on day 14 but reduced with methylprednisolone (mPSL). Prednisolone (PSL) was discontinued on day 104, and the patient was discharged on day 112. There was no evidence of clinical chronic GVHD, the serum creatinine level remained high, and cyclosporine (CsA) was gradually tapered off and discontinued on day 165. However chronic GVHD of the skin appeared on day 179, and CsA (100 mg/day) was restarted. On day 186 he was admitted to our hospital complaining of fever. A CT scan of the chest demonstrated bilateral interstitial infiltrates, which were considered as lung GVHD lesions and PSL was started, following which chronic GVHD of the skin and liver improved. The lung GVHD worsened, however, subcutaneous and mediastinal emphysema developed and the patient died on day 206. Interstitial pneumonia had progressively worsened as the manifestation of the chronic lung GVHD. We concluded that this clinical course was rare.     

Allogeneic marrow transplantation for children with juvenile chronic myelogenous leukemia

Fourteen children between the ages of 2 and 5 years with juvenile chronic myelogenous leukemia were given cyclophosphamide, total-body irradiation, and marrow transplants. Unmodified marrow was given to six patients who received marrow from HLA-identical siblings and eight patients who received marrow from family members HLA identical for one haplotype but mismatched for one to three loci on the nonshared haplotype. Five patients died of transplant-related complications, and three relapsed at 48, 81, and 1,670 days posttransplant and died of leukemia. Six patients survive in continuous remission from 0.5 to 11.5 years posttransplant.