Unrelated Cord Blood Transplantation with a Reduced-Intensity Conditioning Regimen following Autologous Transplantation for Multiple Myeloma

Two patients, 51- and 45-year-old men with stage III immunoglobulin G multiple myeloma, achieved partial and complete remissions, respectively, after conventional chemotherapy. They both received high-dose melphalan (200 mg/m2) with autologous stem cell transplantation (ASCT). Eighty-four and 78 days after ASCT, the patients underwent unrelated cord blood transplantation (CBT) following treatment with total-body irradiation (2 Gy), fludarabine (90 mg/m2), and melphalan (140 mg/m2). Neutrophil engraftment was attained on day +27 in patient 1 and day +15 in patient 2. Full donor chimerism of the marrow cells was confirmed. Regimen-related toxicity in both patients remained within grade I. Grades I and II acute graft-versus-host disease (GVHD) occurred in patients I and 2, respectively, but improved without steroid therapy. Both patients developed limited chronic GVHD of the skin but needed no treatment. The serum paraprotein level in patient 1 decreased further after ASCT and CBT but remained at minimally detectable levels. The serum and urine paraprotein levels in patient 2 remained below detectable limits. These results suggested that CBT with a reduced-intensity conditioning regimen after high-dose chemotherapy with ASCT is a new promising approach for the treatment of multiple myeloma.     

Unmanipulated Reduced-Intensity Stem Cell Transplantation from a Haploidentical Donor Mismatched at 3 HLA Antigens to a Patient with Leukemic Transformation of Myelodysplastic Syndrome: Successful Second Transplantation after Graft Rejection

We present the case of a patient with myelodysplastic syndrome who experienced leukemia transformation and subsequently underwent transplantation of unmanipulated peripheral blood stem cells from a haploidentical sibling mismatched at 3 HLA antigens, along with a reduced-intensity regimen (fludarabine, busulfan, and anti-T-lymphocyte globulin) and tacrolimus-containing graft-versus-host disease (GVHD) prophylaxis. The patient experienced graft rejection but successfully underwent a second transplantation from the same donor with a slightly intensified conditioning regimen. Although the patient developed life-threatening cytomegalovirus (CMV) pneumonia following the second transplantation, he recovered completely from the pneumonia with intensive supportive therapy. He is still in complete remission past day 1000 in the absence of GVHD. As far as we know, this report is the first to describe a successful second transplantation that was performed for graft rejection following HLA-haploidentical nonmyeloablative stem cell transplantation. Furthermore, we emphasize that patients should be carefully monitored for CMV infection when reduced-intensity conditioning is given repeatedly over a short period.     

Disseminated tuberculosis following second unrelated cord blood transplantation for acute myelogenous leukemia

Abstract: Here we report the case of a 43-year-old Japanese woman with acute myelogenous leukemia who underwent 2 unrelated cord blood transplantations (UCBT), terminating in fatal disseminated tuberculosis (TB). The patient did not achieve remission despite intensive chemotherapy, and subsequently underwent UCBT with a standard conditioning regimen. However, engraftment was not achieved. Fifty days after the first UCBT, the patient underwent a second UCBT with a reduced-intensity conditioning regimen. She developed a pre-engraftment immune reaction, which responded well to prednisolone, and engraftment was documented. However, 50 days after the second UCBT, the patient presented with high fever and developed pneumonia despite antibiotic and antifungal treatments. Thereafter, Mycobacterium tuberculosis was detected in blood cultures and specimens of bronchoalveolar lavage, thus indicating disseminated TB. Despite anti-tuberculous treatment, she died on day 85. TB should always be considered as a possible diagnosis when treating febrile immunocompromised patients.     

Salvage Cord Blood Transplantation Using a Short-term Reduced-intensity Conditioning Regimen for Graft Failure

Objective Graft failure (GF) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). A standardized conditioning regimen and an appropriate graft source of salvage HSCT for GF have not yet been established. Some case series have shown good hematopoietic recoveries after salvage HSCT using a short-term reduced-intensity preparative regimen consisting of fludarabine (30-90 mg/m²), cyclophosphamide (2 g/m²), and total-body irradiation (2 Gy). However, the dose of fludarabine has varied in these reports based on the clinical condition of the patients, resulting in very limited experiences with each dose of fludarabine. Methods We retrospectively analyzed 10 patients who developed GF after allogeneic HSCT and underwent salvage cord blood transplantation (CBT) using the above-mentioned conditioning regimen with a fixed dose (90 mg/m²) of fludarabine. Results Eight patients (80.0%) achieved neutrophil engraftment within 30 days from salvage HSCT with a median of 21 (range, 17-23) days. The 1-year overall survival (OS) rate after the salvage HSCT was 50.0%, and the median OS was 281 (range, 23-1,638) days. Cumulative incidences of non-relapse mortality and relapse at 1 year were 50.0% and 10.0%, respectively. Conclusion CBT using this short-term reduced-intensity conditioning regimen may be a promising salvage therapy for GF.     

Chimerism and T-cell receptor repertoire analysis after unrelated cord blood transplantation with a reduced-intensity conditioning regimen following autologous stem cell transplantation for multiple myeloma

A 65-year-old Japanese male was diagnosed as multiple myeloma with Bence Jones kappa type, clinical stage IIIA. His disease status reached partial remission after chemotherapy. Thereafter, he received tandem transplantation, consisting of high-dose chemotherapy with autologous stem cell transplantation (ASCT), followed by unrelated cord blood transplantation (U-CBT). U-CBT with a reduced-intensity conditioning regimen (RI-CBT) was performed in August 2003. HLA mismatch between the patient and the CBT donor was present at two serological loci (B and DR). A total nucleated CBT cell dose of 2.45 x 10(7)/kg body weight was infused on day 0. Graft-vs.-host disease (GVHD) prophylaxis consisted of cyclosporine A and short-term methotrexate. Neutrophil engraftment (>0.5 x 10(9)/l) was obtained on day 46. He developed positive cytomegalovirus antigenemia, grade II acute GVHD involving skin and liver, varicella-zoster virus infection, septic shock, hemorrhagic cystitis caused by adenovirus and acute hepatitis B virus infection after U-CBT. We retrospectively analyzed T-cell receptor (TCR) repertoire diversity and found that TCR repertoire diversity decreased continuously after U-CBT. Therefore, low-TCR repertoire diversity in this patient appears to be associated with various infections caused by immunodeficiency.     

Successful cord blood transplantation for mycosis fungoides

A 26-year-old female diagnosed as mycosis fungoides (MF, clinical stage IV) was treated with single-agent chemotherapy, multi-drug chemotherapy and unrelated bone marrow transplantation with reduced-intensity conditioning (engraftment failure), resulting in failure. Unrelated cord blood transplantation (CBT) as second transplantation following myeloablative conditioning brought complete remission (CR), but relapse of MF occurred 3 months after transplantation. However, discontinuation of immune suppressant led to the regression of MF regions and to second CR that continued for more than 23 months. This is the first report of successful CBT for MF, suggesting the graft-versus-MF effect in a setting of CBT.     

Salvage Cord Blood Transplantation for Sustained Remission of Acute Megakaryoblastic Leukemia That Relapsed Early after Myeloablative Transplantation

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia accompanied by an aggressive clinical course and dismal prognosis. We herein report a case of AMKL preceded by mediastinal germ cell tumor that relapsed early after allogeneic hematopoietic stem cell transplantation with myeloablative conditioning but was successfully treated using salvage cord blood transplantation (CBT) with reduced-intensity conditioning. Although several serious complications developed, sustained remission with a favorable general condition was ultimately achieved. Although an optimal therapeutic strategy remains to be established, the graft-versus-leukemia effect of CBT may be promising, even for the treatment of refractory AMKL.     

Cord blood transplantation with a reduced-intensity conditioning regimen for patients with relapsed aggressive multiple myeloma after cytoreduction with bortezomib

Two multiple myeloma patients relapsed after autologous stem cell transplantation (ASCT). Conventional chemotherapy, including thalidomide, showed very little effect, but both patients responded well to a standard dose of bortezomib. One patient was treated with two additional cycles of bortezomib, but his clinical course suddenly deteriorated. Unrelated cord blood transplantation (CBT) with reduced-intensity conditioning regimen (RIC) was performed in refractory disease. After CBT, the clinical course was aggravated by tumor lysis syndrome and other conditions, thus resulting in patient death on day 34. Thereafter, we administered CBT with RIC on the second patient after just one course of bortezomib therapy since she was in partial remission. The second patient developed acute and chronic GVHD, and both responded to the steroid therapy. She has been in complete remission for more than 48 months after CBT. These results suggested that the timing of CBT with RIC may be very important, and cytoreduction with not only ASCT but also bortezomib could give a promising chance for a successful CBT.     

Bacterial Bloodstream Infection in Neutropenic Adult Patients after Myeloablative Cord Blood Transplantation: Experience of a Single Institution in Japan

Bacterial infection is one of the most important causes of morbidity and mortality after unrelated cord blood transplantation (CBT). In the present study, we studied 101 adult patients with respect to the incidence, outcome, and risk factors for bacterial bloodstream infection (BSI) within 30 days after CBT using a myeloablative conditioning regimen. Bacterial BSI occurred in 12 patients within 30 days after CBT. The cumulative incidence of bacterial BSI was 12%. The median time of onset was day +6 (range, day -1 to day +13) after CBT. In all patients, the neutrophil count was 0/microL at the onset of bacterial BSI. Eight (67%) and 4 (33%) of the isolates were Gram-positive and Gram-negative bacteria, respectively. Only 2 (17%) of the 12 patients who had bacterial BSI died within 100 days after CBT. No risk factors for the occurrence of bacterial BSI within 30 days after CBT were identified. The low mortality rate for bacterial BSI in the neutropenic period appeared to be associated with the low incidence (6%) of transplantation-related death at day +100 in our study patients. Early diagnosis of bacterial BSI and prompt treatment with effective antibiotics are necessary for neutropenic adult patients after myeloablative CBT.     

Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen

The optimal approach to stem cell transplantation in children with immunodeficiency who lack a matched family donor is controversial. Unrelated donor stem cell transplantation gives equivalent outcome to mismatched family donor stem cell transplantation in severe combined immunodeficiency, whereas unrelated donors may be preferable in non-severe combined immunodeficiency children. However, unrelated donor stem cell transplantation with conventional conditioning regimens has been associated with significant treatment-related toxicity, particularly in non-severe combined immunodeficiency patients with preexisting organ dysfunction. We report the outcome of a series of 33 consecutive unrelated donor transplantations performed at our center in children with primary immunodeficiency using a reduced-intensity conditioning regimen between 1998 and 2001. We have compared these outcomes with a retrospective control cohort of 19 patients who underwent transplantation with myeloablative conditioning between 1994 and 1998. All children in both groups had primary engraftment. There was no statistical difference in the speed of immune reconstitution or incidence of graft-versus-host disease between the 2 groups. Overall survival was significantly better in the reduced-intensity conditioning group: 31 (94%) of 33 patients survived, compared with 10 (53%) of 19 in the myeloablative conditioning group (P = .014). We conclude that the reduced-intensity conditioning regimen results in improved survival and reduced transplantation-related mortality compared with myeloablative conditioning in high-risk patients undergoing unrelated donor transplantation.     

Successful treatment with low-dose etoposide for hemophagocytic syndrome following reduced-intensity conditioning for cord blood transplantation in a patient with acute myelgenous leukemia

A 56-year-old man was diagnosed with acute myeloid leukemia with myelodysplasia-related changes. Chromosomal analysis showed a complex karyotype. Complete remission could not be achieved even after several induction chemotherapy regimens, and the patient suffered from invasive pulmonary aspergillosis. He was transferred to our hospital and underwent reduced-intensity conditioning cord blood transplantation (RIC-CBT) in a non-remission state. The conditioning regimen involved fludarabine 125 mg/m2 combined with melphalan 140 mg/m2 and total body irradiation (4 Gy). GVHD prophylaxis was tacrolimus alone at relatively low concentrations (app. 5 ng/ml). On days 6 and 9 after CBT, he experienced a pre-engraftment immune reaction and hemophagocytic syndrome (HPS). We started steroid pulse therapy, but this failed to resolve the symptoms. We then administered low-dose etoposide (50 mg/m2). The symptoms gradually resolved after three administrations of etoposide and engraftment was achieved on day 35. Satisfactory hematological recovery was noted on day 300 after CBT and the patient has maintained complete remission to date. HPS is one of the most serious complications following CBT and often results in engraftment failure. This case suggests that repeated administration of etoposide may safely and effectively overcome this serious complication in some cases.     

Successful treatment of chronic granulomatous disease with fludarabine-based reduced-intensity conditioning and unrelated bone marrow transplantation

Allogeneic hematopoietic stem-cell transplantation (HSCT) for chronic granulomatous disease (CGD) with a reduced-intensity conditioning regimen can be expected to lead to less therapy-related mortality and late-onset impairment, whereas it has also been reported to increase the risk of unsustained mixed donor chimerism and late rejection after transplantation. Herein, we report a 4-year-old boy with CGD who was successfully treated with unrelated bone marrow transplantation with a reduced-intensity conditioning regimen (RIC). Fludarabine-based RIC, 4 Gy of total body irradiation, 120 mg/kg of cyclophosphamide, and 125 mg/m² of fludarabine, was adopted for transplantation, followed with 8.9 × 10⁸/kg mononucleated donor cells infused without T-cell depletion. Although hematopoietic engraftment was rapidly obtained by day +17, he developed unstable donor chimerism. After tacrolimus withdrawal, the patient showed grade III acute graft-versus-host disease (GVHD), and subsequently reached full donor chimerism by day +61. Twelve months post-transplant, the patient has remained well with stable and durable engraftment, 100% donor chimerism, and normal superoxide production, without the requirement of donor lymphocyte infusions (DLI).     

Feasibility of reduced-intensity conditioning followed by unrelated cord blood transplantation for primary hemophagocytic lymphohistiocytosis: a nationwide retrospective analysis in Japan

A nationwide retrospective analysis was performed on patients who received allogeneic hematopoietic stem cell transplantation for primary or familial hemophagocytic lymphohistiocytosis (HLH) in Japan. The present analysis investigated whether reduced-intensity conditioning (RIC) followed by cord blood transplantation (CBT) (RIC–CBT) is feasible, compared to the outcomes of myeloablative conditioning and bone marrow transplantation. Based on the JSHCT data, 53 patients were analyzed. The overall survival rate (OS) was 65.4 ± 6.6 %. RIC–CBT (n = 13) was not inferior to other methods. Patients with a performance status of PS 4 (ECOG scale) with HLH-associated severe organ dysfunction during the initiation of conditioning had extremely poor outcomes. The OS rate in the RIC–CBT patients, excluding those with a performance status 4, was 80.0 ± 12.6 %. RIC may reduce treatment-related mortality; in addition, patients with engraftment failure, which is the main adverse event following RIC–CBT, were successfully rescued with secondary CBT. Unrelated cord blood may represent an alternative source if a patient has no related donor. As a RIC regimen for CBT, 140 mg/m² melphalan with fludarabine and anti-lymphocyte globulin or anti-thymocyte globulin may be feasible, but further dosage optimization should be performed in controlled clinical trials.     

Cord blood transplantation using minimum conditioning regimens for patients with hematologic malignancies complicated by severe infections

Patients with severe infections are thought to be ineligible for cord blood stem cell transplantation (CBT) because the conventional 5–6 day-conditioning regimens potentially makes them susceptible to fatal infections by the time neutrophil engraftment occurs. Two patients were treated with minimum conditioning regimens consisting of 30 mg/m² fludarabin (Flu) and 2 g/m² cyclophosphamide (CY) on day-1 and total body irradiation (TBI) of 2 or 4 Gy on day −1 or 0 followed by single unit CBT. The reasons for adopting such weak regimen were febrile neutropenia due to the rejection of the first cord blood (CB) graft given to a patient with follicular lymphoma resistant to chemotherapy and pulmonary aspergillosis in another patient with AML who relapsed after CBT. The AML patient received 40 mg/m² of melphalan on day-2 to reduce the leukemia burden. Both patients achieved 100% donor chimerism by day 19 and day 20 after CBT without an apparent exacerbation of the infections and remained in remission at 23 and 18 months after the CBT. These findings suggest that the 1–2 day regimens excluding antihuman thymocyte globulin may be sufficiently potent to ensure engraftment of CB in immunocompromised patients and safely administered even when patients are complicated by active infections. An erratum to this article can be found at     

Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens

Allogeneic haematopoietic stem cell transplantation remains the only curative treatment of myelofibrosis with myeloid metaplasia (MMM). Previous reports have indicated significant treatment-related mortality (TRM) for patients transplanted after myeloablative conditioning but superior survival has been reported after reduced-intensity conditioning (RIC). We report the results of a survey of all allogeneic transplantations for MMM performed in Sweden at six transplant units between 1982 and 2004. Twenty-seven patients were transplanted; 17 with a myeloablative conditioning regimen and 10 with RIC. The median age was 50 years (5-63 years) at transplantation. After a median follow up of 55 months, 20 patients are alive. TRM was 10% in the RIC group and 30% in the myeloablative group. There was no difference in survival for high or low-risk patients according to Cervantes score or between sibling and unrelated donor transplantations.     

Successful unrelated donor bone marrow transplantation for shwachman-diamond syndrome with leukemia

Shwachman-Diamond syndrome (SDS) is a rare congenital disorder featuring exocrine pancreatic insufficiency, growth retardation, and bone marrow dysfunction. Reports suggest that nearly 25% of all cases are complicated with leukemia. Although stem cell transplantation is the sole option for these patients, successful results are rarely obtained. Poor outcomes are often related to graft failure and cardiac and other organ toxicities. We describe in this report successful unrelated donor bone marrow transplantation for a patient with SDS who progressed to acute myelogenous leukemia. The patient received attenuated intensified chemotherapy because of his intolerance to ordinary chemotherapy and went into remission. Sustained unrelated donor bone marrow engraftment was accomplished after treatment with a reduced amount of cyclophosphamide and antithymocyte globulin with 12 Gy of total body irradiation as a conditioning regimen. To the best of our knowledge, this report is the first to describe unrelated donor bone marrow transplantation with complete engraftment for an SDS patient with myelogenous leukemia.     

Long-term follow-up of allogeneic bone marrow transplantation after reduced-intensity conditioning in patients with chronic myelogenous leukemia in the chronic phase

Although allogeneic transplantation is a curative therapy for chronic myelogenous leukemia (CML), treatment-related mortality is still a major cause of death after transplantation, especially in older patients. We investigated the safety and efficacy of reduced-intensity conditioning consisting of low-dose (600 cGy) total body irradiation and cytosine arabinoside (1 g/m2) together with a continuous infusion of granulocyte colony-stimulating factor and cyclophosphamide (120 mg/kg) in patients with CML in the chronic phase. Fractionated splenic irradiation (5 Gy) was also administered as part of the conditioning treatment. Eight patients older than 40 years underwent allogeneic bone marrow transplantation from an HLA-matched sibling following this conditioning. Regimen-related toxicities (equal to or greater than grade III) were not observed. Rapid restoration of 100% donor chimerism was confirmed by fluorescence in situ hybridization methods in 5 sex-mismatched transplant recipients. One patient died from severe acute graft-versus-host disease and another from Pneumocystis carinii pneumonia early in the course of transplantation. A sustained engraftment was achieved in 5 long-term survivors; in 1 case, the graft was rejected but the Philadelphia chromosome and BCR/ABL-negative autologous hemopoiesis were restored. After a minimum follow-up period of 60 months, 6 patients, including the patient with restored autologous hemopoiesis, were still alive and in remission with 100% donor chimerism. Six years after the transplantation, 1 patient experienced a cytogenetic relapse, which was successfully treated with donor lymphocyte infusions. In summary, this reduced-intensity conditioning resulted in a cure with markedly reduced regimen-related toxicities in this relatively older cohort of patients with CML.     

Successful sustained engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with severe aplastic anemia

We retrospectively analyzed 12 consecutive adult severe aplastic anemia patients who received unrelated umbilical cord blood transplantation after a reduced-intensity conditioning regimen (RI-UCBT). The conditioning regimen consisted of 125 mg/m2 fludarabine, 80 mg/m2 melphalan, and 4 Gy of total body irradiation. The median infused total nucleated cell number and CD34(+) cell number were 2.50 × 10?/kg and 0.76 × 10?/kg, respectively. Eleven of the 12 patients achieved primary neutrophil and platelet engraftment. All patients who achieved engraftment had complete hematologic recovery with complete donor chimerism, except for one patient who developed late graft failure 3 years after RI-UCBT. Two of the 12 patients died of idiopathic pneumonia syndrome, and the remaining 10 patients are alive, having survived for a median of 36 months. Our encouraging results indicate that RI-UCBT may become a viable therapeutic option for adult severe aplastic anemia patients who lack suitable human leukocyte antigen-matched donors and fail immunosuppressive therapy.     

Clearance of the Janus kinase 2 (JAK2) V617F mutation after allogeneic stem cell transplantation in a patient with myelofibrosis with myeloid metaplasia

A patient with myelofibrosis with myeloid metaplasia displaying the V617F mutation of the JAK2 gene was given an allogeneic stem cell transplantation using a reduced-intensity conditioning regimen. The patient engrafted, and as he became a chimera, the expression of the V617F mutation of the JAK2 gene decreased progressively until its disappearance. Accordingly, the concept of "molecular remission" of the myelofibrosis with myeloid metaplasia could be entertained and added to the categories of response to treatment which have been recently described.     

Allogeneic transplantation following nonmyeloablative conditioning for aggressive lymphoma

Allogeneic hematopoietic SCT following myeloablative conditioning is associated with a high nonrelapse mortality and usually reserved for young, medically fit patients. The use of allogeneic stem cells is associated with a less risk of relapse, but is also associated with the risk of GVHD. The increased antitumor activity is due to graft-vs-tumor immune responses. The newer use of nonmyeloablative or reduced-intensity conditioning has decreased the toxicity of this approach and allows the treatment of older patients or those with medical comorbidities that preclude the use of a myeloablative regimen. A nonmyeloablative regimen using fludarabine and 2 Gy TBI was developed in Seattle that reliably allows allogeneic engraftment from either matched related or unrelated donor stem cell sources. Here we describe our results using this regimen in multicenter studies for the treatment of aggressive non-Hodgkin's lymphoma (NHL) and mantle cell NHL.