Nonmyeloablative Allogeneic Stem Cell Transplantation Research Articles

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 mug/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.

No recovery of T-cell receptor excision circles (TRECs) after non-myeloablative allogeneic hematopoietic stem cell transplantation is correlated with the onset of GvHD

Improper T-cell reconstitution with its consequences, graft-vs-host disease (GvHD) and outbreak of viral infections, is the major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). To determine the factors affecting reconstitution of naive T-cells after non-myeloablative HSCT (NM-HSCT), the T-cell receptor excision circle (TREC) content was measured on a weekly basis in 24 transplanted patients with various malignant diseases. We analysed correlations of the results with the development of GvHD. In addition, in 11 chronic myeloid leukaemia (CML) patients, we correlated TREC and BCR-ABL transcript numbers. After HSCT, in most patients (22/24) TRECs became undetectable. In 12 patients, TRECs reappeared 3-4 months after HSCT, in 1 patient TRECs reappeared 5 months after HSCT, and in 11 patients TRECs remained negative for more than a year. All 11 patients who remained TREC-negative, developed acute GvHD grade 2-3, while only 6 out of 13 patients who recovered TRECs developed GvHD. We show that after non-myeloablative HSCT, thymopoiesis takes place and is affected by GvHD. Our results indicate that no recovery of TRECs after NM-HSCT (which most likely reflect the expansion of host-reactive co-transplanted mature T-cells) correlates with the onset of GvHD.

Fludarabine-Based Nonmyeloablative Stem Cell Transplantation for Sickle Cell Disease with and without Renal Failure: Clinical Outcome and Pharmacokinetics

End-organ damage is common in patients with sickle cell disease (SCD) thereby limiting the use of allogeneic stem cell transplantation (SCT). We report the outcome of 2 adult SCD patients, 1 with end-stage renal disease (ESRD), who underwent fludarabine-based nonmyeloablative SCT from HLA-identical matched siblings. To prevent fludarabine toxicity, the patient with ESRD underwent aggressive dialysis following adjusted fludarabine dosing. Pharmacokinetics of the fludarabine metabolite F-Ara-A was studied on the patient with ESRD and 2 additional patients with normal renal function. Both patients with SCD achieved full donor erythroid chimerism, have normal blood counts, and are on no immunosuppressive medications. With a 20% dose reduction followed by daily dialysis, we achieved fludarabine drug exposure that is nearly identical to that achieved in patients with normal renal function. We conclude that fludarabine-based nonmyeloablative allogeneic SCT for adult patients with SCD is feasible, even in the setting of ESRD.

Non-Myeloablative Allogeneic Stem Cell Transplantation (NMT) Overcomes the Adverse Effects of Treatment Resistance and High Beta-2-Microglobulin in Patients with Mantle Cell Lymphoma (MCL): An Analysis of 123 Transplantations at the MD Anderson Cancer Center.

BACKGROUND: MCL remains incurable with cytotoxic therapy, but may be susceptible to immune-based modalities. Since the availability of NMT(1997) and rituximab(1999), we have employed the following risk-adapted strategy: patients (pts) in first remission after one chemotherapy (REM1) were offered autologous SCT (ASCT) with high-dose rituximab (R), and pts beyond REM1 were offered NMT if a donor was available, and ASCT+R if not. In order to assess the success of this strategy, we analyzed the results of 17 years of MCL transplantation at our center, including ASCT pts transplanted without R as historical controls.METHODS: 52 pts in REM1 (ASCT1) and 36 pts beyond REM1 (ASCT2) received ASCT with (43%) or without (57%) R, and 35 pts beyond REM1 received NMT with fludarabine, cyclophosphamide & R. ASCT1, ASCT2 and NMT pts were balanced for age, Ann-Arbor stage, B-symptoms, LDH and B2m, but NMT pts were more heavily pretreated (p=0.01) and were further from initial diagnosis (p=0.02) than ASCT2 pts.RESULTS {ASCT}: 96% & 91% of ASCT1 & ASCT2 pts were in CR following transplantation. Chemoresistance was an important determinant of ASCT outcome, with ASCT1 pts experiencing superior median PFS (42 v 27 months, p=0.009) and OS (94 v 52 months p=0.01) than ASCT2. B-symptoms and B2m≥3.0mg/L adversely affected OS in both ASCT groups. There was a trend to improved PFS for the 20 ASCT1 pts who received R, with no events in 10 pts followed between 24 to 94 months, compared with a continuous pattern of progression in non-R pts (p=0.06). {NMT}: 94% of pts were in CR after transplantation, and the 42 month current-PFS was 57%. In contrast to the ASCT pts, OS following NMT was not affected by high B2m, although B-symptoms remained significant (p=0.03). Despite all pts being transplanted beyond REM1, a plateau in survival was evident with no deaths occurring among 11 pts followed between 46 to 98 months (figure). Actuarial non-relapse mortality (NRM) at 90 days, 12 months and 2 years were 0%, 13% and 20% respectively. Neither the stem cell source (related 69% v unrelated 31%) nor a history of previous autologous transplantation (n=6) had a significant impact on NMT outcome (p>0.30 for PFS, OS and NRM).CONCLUSIONS: These results suggest that ASCT is most effective in pts transplanted in REM1, in whom the addition of R may have improved PFS. NMT is effective in overcoming the adverse impact of prior chemotherapy and high B2m, and remains the modality of choice for pts beyond first remission. [Display omitted]

Non-Myeloablative Allogeneic Transplantation for Hodgkin's and Non-Hodgkin's Lymphoma: Evidence for a Graft-Versus-Lymphoma Effect and Relevance of Chimerism.

The role of non-myeloablative allogeneic stem cell transplantation (NST) in the treatment of patients with Hodgkin’s disease (HD) or non-Hodgkin’s lymphoma (NHL) is still undefined. We report the outcomes of 87 patients with lymphoma who underwent NST at our institution. Thirty-six patients had HD and 51 had NHL (13 indolent NHL (indNHL), 23 aggressive NHL (aggNHL), and 15 mantle cell lymphoma (MCL)). Median age was 46 (18–64). Patients had received a median of 4 prior lines of therapy; 94% of the HD patients had received a previous autograft, as had 49% of NHL patients. 28% of patients were transplanted in CR, 49% in PR, and 23% with stable or progressive disease. The conditioning regimen consisted of IV busulfan (0.8 mg/kg/d × 4) and fludarabine (30 mg/m2/d × 4). Donors were matched related (38%), matched unrelated (56%), or mismatched (6%). Most patients received GVHD prophylaxis with a calcineurin inhibitor plus sirolimus or methotrexate. All patients engrafted. The 3-year cumulative incidence of non-relapse mortality (NRM) was 23%, and of relapse was 50%. The cumulative incidence of grade 2–4 acute GVHD was 16%, and the 2-year incidence of chronic GVHD was 68%. With a median follow-up of 21 months for survivors, the projected 3-year overall survival (OS) was 59% for patients with HD, 79% for indNHL, 42% for aggNHL, and 36% for MCL. The corresponding figures for 3-year progression-free survival (PFS) were 17% for HD, 59% for indNHL, 21% for aggNHL, and 30% for MCL. Figure Figure Multivariate analysis identified elevated pre-transplantation LDH and more than 4 prior lines of therapy as adverse factors for PFS, while indolent NHL histology was a favorable factor. In time-dependent multivariable models, grade 3–4 acute GVHD was associated with increased NRM and relapse, and decreased PFS and OS. Chronic GVHD was associated with a lower risk of relapse and improved PFS, without a significant effect on OS. The protective effect of chronic GVHD on relapse applied to all histologies except for aggNHL. Forty-five percent of relapsed patients (13 pts with HD and 5 with aggNHL) received donor lymphocyte infusion (DLI). The overall response rate (ORR) was 15% (2/13) for patients with HD, with both patients remaining progression-free at last follow-up; ORR was 40% (2/5) for patients with aggNHL, but responses were transient. For all patients, median chimerism at day 20–50 was 97% (range 46–100). Low early donor chimerism was not predictive of relapse, PFS, or OS in univariate or multivariate analyses. Moreover, relapse was not associated with loss of chimerism. Finally, chimerism at the time of DLI had no apparent bearing on its outcome. Conclusions: NST results in high PFS for indolent NHL. There is evidence of a graft-versus-lymphoma effect. Chimerism is not at any point predictive of relapse or of outcome. Future research could be aimed at increasing specific anti-lymphoma immune activity to harness GVL without increasing the incidence of GVHD.

Effect of T Cell Recovery on Overall Survival (OS) Following Pentostatin Conditioning for Nonmyeloablative Allogeneic Stem Cell Transplantation (NST).

NST provides graft-versus-leukemia (GVL) activity with reduced regimen related toxicity. We used a conditioning regimen consisting of Pentostatin 4 mg/m2 daily × 3 days and 200 cGy TBI 24 hrs prior to stem cell infusion in patients (pts) with high-risk/relapsed/refractory hematologic malignancies. The importance of the timing of stem cell infusion relative to Pentostatin administration was examined in a comparison of two sequential protocols. In cohort 1 (n=39) Pentostatin was given on days -21, -20, and -19. In cohort 2 (n=39) Pentostatin was given on days -10, -9, and -8. The median age of the day -21 cohort was 52 years (range 22–70) and the day -10 cohort was 59.5 years (range 36–70). The median number of prior therapies in the day -21 cohort was 4 (range 0–8), including prior autologous SCT in 22 pts, while in the day -10 cohort, the median number of prior therapies was 6 (range 0–18), including prior autologous SCT in 9 pts. Post-grafting immunosuppression was cyclosporine (CsA)/mycophenolate mofetil (MMF). In both protocols, CsA 2.0 mg/kg IV q12 hrs was administered on days -1, 0, and +1, and then converted to oral 5 mg/kg PO BID with a taper beginning on day +70. In the second protocol, pts with unrelated donor transplants tapered CsA starting at day +100. MMF at 15 mg/kg PO BID was administered on days 0–27 for related donor transplants in both protocols and in the second protocol this was extended until day +40 for the unrelated donor transplants. In the day -21 protocol, SCTs were obtained from matched related (n=14) or unrelated (n=25) donors. The cumulative incidence of all grades of acute GVHD at day 100 was 40% and was more common in unrelated donor (60%) vs. related donors (15%) transplants. In the day -10 protocol, SCT was performed with products from matched related (n=15) or unrelated (n=21) donors. The cumulative incidence of grade II–IV acute GVHD was approximately 35% (30% in related versus 40% in unrelated donors). In both protocols, the median chimerism values for CD3+ cells and white blood cells at day 28 were >80% and 90% donor cells, respectively. T, B and natural killer (NK) lymphocyte frequency and numbers were identical at protocol entry. One day following TBI conditioning, there was a 57% depression in CD3+ cells in the day -21 protocol that was retained on day 28 post transplant (55%). In the day -10 protocol, there was a significant depression (47%) in the frequency of CD3+ cells one day following TBI, which was depressed further (68%) on day 28 post transplant. The dendritic cells (DCs), both CD123+ and CD11c+, were not suppressed by the conditioning regimen. Separation of pts on day 28 into cohorts with an absolute number of CD3+ cells >0.25×106/ml revealed that those pts with a higher CD3+ cell count had a median OS time of 36.7 weeks, which was significantly longer than pts whose absolute number of CD3+ cells <0.25×106 (median OS of 21 weeks). This differential effect on OS was not observed when pts were separated on the basis of either CD4+ or CD8+ cells. In conclusion, there is a lower incidence of acute GVHD in the day -10 protocol, which can be associated with a significant reduction in the frequency and absolute number of circulating T cells. The significant reduction in T cells, observed one day following TBI and 28 days post transplant, is associated with the timing of transplant relative to Pentostatin conditioning and a significant prolongation of OS.

A Large Cohort Analysis of CMV Viral Load and Ganciclovir-Related Neutropenia in Nonmyeloablative (NM-HCT) and Myeloablative (M-HCT) Allogeneic Hematopoietic Cell Transplant Recipients.

Background. The “true” nonmyeloablative allogeneic stem cell transplantation (NM-HCT) allows initial establishment of mixed T-cell chimerism for up to 6 months. The prolonged presence of host memory immune response after NM-HCT may play a role in protection against CMV infection especially early after NM-HCT. Furthermore, we previously reported that the incidence and poor outcome of ganciclovir-related neutropenia (GCV-N) is strongly associated with myelotoxic conditioning. Therefore, non-myeloablative HCT may also contribute to a lower risk of GCV-N. In this to date largest cohort we examined the risk of CMV infection and GCV-N after NM conditioning.Methods. We retrospectively analyzed 537 NM-HCT recipients (median age 54.2 yrs) and 2489 M-HCT recipients (median age 39.8 yrs) transplanted between 1/1995 and 12/2005. The conditionings for NM-HCT mostly consisted of 2 Gy TBI with/without fludarabine. Post-grafting immunosuppression consisted of most commonly mycophenolate mofetil and cyclosporine (CSP) for NM-HCT recipients and methotrexate/CSP for M-HCT recipients. CMV surveillance was performed weekly by antigenemia (AG) or plasma PCR testing. GCV/VGCV was given for CMV AG/PCR positivity. We evaluated1.any AG/DNA detection by day 100,2.AG >10/200,000 PBL or PCR> 1000 copies/ml (high-grade CMV AG/DNA) by day 100 and3.GCV-N defined as non-relapse-related neutropenia (ANC<500 μL) after AG/PCR positivity with ANC>1000 μL at time of viremia using multivariable Cox regression.In addition, post-engraftment neutropenia, defined as ANC<500 μL occurring after day 28 post HCT among relapse-free patients.Results. There was no significant difference in the incidence of CMV AG/DNA at any level between NM-HCT and M-HCT (39% vs.37%, HR 1.1, P=0.42). However, there was less high-grade CMV infection in NM-HCT compared to M-HCT patients (9% vs. 14%, adj. HR 0.6, P < 0.01). Risk factors for high-grade CMV infection other than M-HCT were advanced recipient age, CMV serostatus, transplantation year and acute GVHD. The incidence of GCV-N was similar between NM-HCT and M-HCT recipients (28% vs. 20%, adj. HR 1.3, P=0.27). Risk factors for GCV-N were advanced recipient age and acute GVHD. On the other hand, the incidence of post-engraftment neutropenia was higher in NM-HCT (29% vs. 13%, adj. HR 2.1, P<0.0001). Other risk factors for post-engraftment neutropenia included advanced recipient or donor age, cord blood, HLA mismatched/unrelated donor, female donor to male recipient, acute GVHD, recipient CMV seropositivity and CMV infection.Conclusion. Our results suggest that the risk of CMV reactivation is not affected by NM conditioning but that progression to higher levels of viral load is reduced. This may be due to residual host memory immunity after NM-HCT. Despite less toxic conditioning, the incidence of GCV-N in NM-HCT was similar to that in M-HCT. Notably, the incidence of post-engraftment neutropenia was more frequent in NM-HCT compared to M-HCT recipients. This may be due to higher recipient and/or donor age, lower capacity to metabolize drugs, or the use of myelotoxic co-medication such as MMF or TMP-SMX.

Non-Myeloablative Allogeneic Stem Cell Transplantation in 154 Patients (pts) with Chronic Myeloid Leukaemia (CML).

Background: Allogeneic stem cell transplantation using a reduced intensity or nonmyeloablative conditioning (NSCT) represents an attractive treatment modality in CML. The rationale behind such approach is to decrease toxicity while inducing the graft-versus-leukemia (GVL) effect. Because of its significantly lower cost in comparison to Imatinib mesylate, NSCT may be considered an early treatment option in countries where limited resources.Material and Methods: Between April 2001 and December 2006, we treated 154 CML patients (131 in first chronic phase, 23 in accelerated phase) with NSCT from an HLA-identical family donor. The majority of pts has a Gratwohl score <2 prior to NSCT (n=115; 74,6%). The conditioning regimen included Fludarabine 150 mg/m2 and oral Busulfan 8 mg /kg (139 pts). GVHD prophylaxis consisted of association ciclosporine (CSA)-Mycophenolate (MMF). 15 pts received an additional prophylaxis with antithymocyte globulin (ATG). Median age was 35 (range, 18–55) years, and the sex-ratio (M/F) 0,87. The median time from diagnosis to NSCT was 11 (range, 4–50) months. All pts received G-CSF mobilised peripheral blood stem cells, median CD34+ cells count: 7,02.106/kg (range, 1,28–44,9).Results: Leucopenia is found almost at 71 pts (46,1%). The median time to achieve ANC >500. 109/l granulocytes was 14 (range, 7–24) days, and median time of aplasia was 7 (range, 2–19) days. Transfusion requirements were significantly reduced, only 3 pts (1,9%) required red blood cells transfusions. Only 15 pts (9,7%) needed platelets transfusions. Acute GVHD was seen in 65 cases (43,6%) including 26 (17,4%) cases of grade III–IV and 32 cases (21%) of late onset acute GVHD occurring after day 100 post-NSCT. 93 pts (67,3%) had chronic GVHD, of whom 58 with an extensive form. 23 pts (15,4%) had CMV reactivation. 24 pts (16,1%) relapsed (15 in chronic phase, 7 in blast crisis and 2 with a molecular relapse), but 11 pts could be salvaged and are currently in remission (7 after immunosupression discontinuation, one after DLI and 3 after a second conventional allograft). The chimerism of donor origin (STR-PCR method) of patients in remission was at an average of 74% at day 30, 80% at d100, 93% at 6 months, 97% at 1 year, and 99% at 2 years. Fifty pts (33,5%) have died, of whom 39 (22,1%) from GVHD and 10 (6,7%) from disease relapse. Transplant Related Mortality (TRM) at 100 days was 6%, but rose to 31,5% at 3 years. At last follow-up (median, 32 (range 6–68) months), 99 pts (66,4%) are still alive, 97 (65,1%) pts in hematologic remission; of whom 76 (78,3%) in complete molecular remission evaluated by RT-PCR. Overall survival and progression-free survival at 5 years are 61% and 51,6% respectively.Conclusion. The study demonstrates a relatively low rate of short-term toxicities after NSCT. However, long-term TRM is still high because of the GVHD. The GVL effect is well admited. The relapse can be often controled by immunomodulation (stoppage of immunosuppression, DLI) and eventually by second myeloablative allograft.

Improvement in Hemolytic Parameters and Tricuspid Regurgitant Jet Velocity (TRV) Following Non-Myeloablative Allogeneic Stem Cell Transplantation (allo-SCT) in Adults with Severe Sickle Cell Disease (SCD).

Although SCD has a variable clinical course, many individuals develop end-organ complications that are associated with significant morbidity and early mortality. SCD-related pulmonary hypertension is a frequently recognized complication (up to 30%), is associated with significant mortality, and is resistant to hydroxyurea or chronic exchange transfusions. Currently myeloablative allo-SCT in children under age 16 is curative in the majority, preventing or ameliorating many of the complications of the disease. However, it is unclear whether reduced intensity allo-SCT in adults that allows mixed hematopoietic chimerism could offer the same benefit. Furthermore, reversal of pulmonary hypertension has not been previously demonstrated in either setting. Beginning in 2003, we initiated an IRB approved clinical trial testing a nonmyeloablative approach in adults with severe SCD. Protocol entry criteria include end-organ complications, (stroke, pulmonary hypertension TRV≥ 2.5 m/s, or frequent vaso-occlusive crises or acute chest syndrome not ameliorated by hydroxyurea. Conditioning was achieved with low dose radiation, alemtuzumab, and sirolimus (rapamycin). All patients receive unmanipulated G-CSF mobilized peripheral blood progenitors obtained from an HLA-matched sibling. Assessment of donor chimerism is measured by microsatellite PCR of CD3 and CD14/15 positive white cells. Hemolysis is monitored by serial measurements of total bilirubin, lactate dehydrogenase, hemoglobin and absolute reticulocyte counts. Transthoracic echocardiography is performed in all patients, and serially in those with TRV ≥ 2.5 m/s. Transmitral flow, Doppler determinations of valvular regurgitant velocity, and left ventricular stroke volume are assessed and graded. A total of 8 patients have accrued. 4 of 8 patients met criteria for pulmonary hypertension. Post transplant follow-up for these 4 patients ranged from 7 to 36 months and stable donor lymphoid (13–39%) and myeloid (53–100%) chimerism was observed in all 4. This pattern of mixed chimerism was sufficient for full donor erythroid engraftment as all demonstrated normal hemoglobin, allowing for therapeutic phlebotomy to correct transfusional iron overload. Improvement in TRV and hemolytic parameters were observed (see table) as early as 3 months post transplant. The average pre- and post allo-SCT values were: TRV 3.1 → 2.5 m/s (p=0.13, Wilcoxon rank sum), total bilirubin 4.0 → 0.6 (p=0.1), lactate dehydrogenase 487 →178 units/L (p=0.2), hemoglobin (hgb) 8.6 → 12.6 g/dL (p=0.002), and reticulocyte (retic) count 326 → 68 k/uL (p=0.01). Our results indicate that reduced intensity allo-SCT in adults patients with SCD allows for full donor erythroid engraftment, normalization of blood counts, reversal of hemolysis, and improvement in TRV.TRV and hemolytic parametersPatient 1Patient 2Patient 3Patient 4AverageTRVPre3.72.63.42.63.08(m/s)BMT2.62.42.52.32.45T biliPre8.34.01.91.94.0(0.1–1.1 mg/dL)BMT0.80.50.50.40.6LDHPre1065330338215487113–226 units/L)BMT23417820990178HgbPre8.18.58.88.98.6(g/dL)BMT12.913.911.911.612.6ReticPre344213417331326(31–105 k/uL)BMT7632768768

Outcomes of a second non-myeloablative allogeneic stem cell transplantation following graft rejection

Following initial graft rejection, a second attempt at allogeneic immunotherapy is often contemplated, but data on the success is limited. We therefore report on 11 patients with hematologic malignancies, renal cell cancer or marrow failure who underwent a second reduced-intensity regimen for primary or secondary graft failure. Nine of the 11 patients initially engrafted with the second attempt including two of four who used the same donor. One of the patients engrafted after the third attempt using a different donor and conditioning regimen. There were two treatment-related deaths. Four patients died from progressive disease 1-9 months after the second transplant. Two patients are still in recovery phase less than 1 year from the second transplant. Long-term remission is possible and three patients are alive in complete remission.

Comparison of Myeloablative and Nonmyeloablative Hematopoietic Stem Cell Transplantation for Treatment of Chronic Myeloid Leukemia

This retrospective study compared outcomes for 81 chronic myeloid leukemia patients who underwent myeloablative or nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT). Sixty-five patients received myeloablative HSCT, and 16 patients received fludarabine (Fd), low-dose busulfan (Bu), and antithymocyte globulin (ATG) in nonmyeloablative HSCT. We determined overall survival (OS) and disease-free survival (DFS), as well as the occurrence of acute and chronic graft-versus-host disease (GVHD). The incidences of acute GVHD of grades II to IV were 14.0% and 18.7% for the myeloablative and nonmyeloablative groups, respectively. The incidence of chronic GVHD was significantly higher in the nonmyeloablative group (80% versus 66%). Five-year OS and DFS rates were significantly higher in nonmyeloablative group (70% for both), compared with 56% and 54%, respectively, for the myeloablative group. A univariate analysis, however, revealed a strong but statistically insignificant trend for enhanced overall OS and DFS in the nonmyeloablative group (P = .1 and .07, respectively). A multivariate analysis with the factors of treatment, age, sex, acute and chronic GVHD, and disease status at the time of transplantation revealed that both OS and DFS were significantly higher in the nonmyeloablative group than in the myeloablative group. These findings suggest that nonmyeloablative Fd/Bu/ATG treatment is at least not inferior (and quite probably superior) in terms of patient outcome compared with standard myeloablative therapy. Further larger-scale randomized clinical trials are warranted to clarify the efficacy of this treatment regimen.

A Case Report of Thrombotic Thrombocytopenic Purpura and Severe Acute Renal Failure Post Non‐myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation Treated With Plasma Exchange and Hemodialysis

A 59-year-old-woman received related non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) subsequent to autologous PBSCT in our hospital five years after she was diagnosed as oligo-secretory myeloma. She was admitted to our hospital because of vomiting and grayish diarrhea 4 months after non-myeloablative allogeneic PBSCT (mini-alloPBSCT). Although her initial symptoms improved after admission, she gradually showed thrombocytopenia, anemia, and oliguria during the 2 weeks after admission. Our diagnosis was thrombotic thrombocytopenic purpura (TTP) and acute renal failure (ARF) secondary to mini-alloPBSCT. After cessation of cyclosporine administration, we began to treat her with plasma exchange (PE) and hemodialysis. During the three and a half months after we started PE, the TTP gradually improved. Although PE had been reported to be ineffective for TTP post bone marrow transplantation, we could finally discontinue PE. In contrast, since her anuria continued, she was managed with hemodialysis. One month after PE was started, her activity of von Willebrand factor-cleaving protease was 41% (normal range, >50%) and the ultrasonographic investigation of both kidneys was normal. She could be discharged after four and a half months hospitalization and lived well as an outpatient for a further two months. She died shortly after readmission from multiple organ failure without the relapse of TTP. The patient's clinical course would suggest that TTP post mini-alloPBSCT could be treated with PE in some cases, despite the development of dialysis-requiring severe ARF being a poor prognostic factor.

The Role of High-Dose Chemotherapy Supported by Hematopoietic Stem Cell Transplantation in Patients With Multiple Myeloma: Implications for Nursing

Multiple myeloma (MM), a neoplastic proliferation of plasma cells originating from the B-cell line, is associated with deleterious complications and poor outcomes. The failure of conventional combination chemotherapies to improve the overall survival of patients with MM has led to the use of high-dose chemotherapy supported by stem cell transplantation (SCT). Although several novel therapies have emerged since the late 1990s, their survival benefits are undetermined. High-dose chemotherapy with SCT provides better response rates compared to conventional chemotherapy and yields a trend toward greater survival benefits, especially with the use of a tandem (two successive) transplantation strategy. This article discusses standard SCT in patients with MM and some of the new transplantation strategies, including tandem autologous SCTs and reduced-intensity nonmyeloablative allogeneic SCT, and their implications for nursing.

Mitochondrial DNA Sequence Heterogeneity of Single CD34+ Cells After Nonmyeloablative Allogeneic Stem Cell Transplantation

We applied a single-cell method to detect mitochondrial DNA (mtDNA) mutations to evaluate the reconstitution of hematopoietic stem cells (HSCs) and committed progenitor cells after nonmyeloablative allogeneic stem cell transplantation in humans. In a total of 1,958 single CD34(+) cells from six human leukocyte antigen-matched sibling donor and recipient pairs, individual CD34(+) clones were recognized based on the observed donor- or recipient-specific mtDNA sequence somatic alteration. There was no overall reduction of mtDNA heterogeneity among CD34(+) cells from the recipient after transplantation. Samples collected from two donors over time showed the persistence of certain CD34(+) clones marked by specific mutations. Our results demonstrate the feasibility of distinguishing donor and recipient individual CD34(+) clones based on mtDNA mutations during engraftment. HSCs were not limited in number, and similar mtDNA heterogeneity levels suggested representation of the total stem cell compartment during rapid hematopoietic reconstitution in the recipient. Disclosure of potential conflicts of interest is found at the end of this article.

Nonmyeloablative allogeneic stem cell transplantation in elderly patients with hematological malignancies: Results from the GITMO (Gruppo Italiano Trapianto Midollo Osseo) multicenter prospective clinical trial

This study aimed to evaluate the efficacy of a nonmyeloablative conditioning consisting of fludarabine and TBI in patients aged > or =60 years.A total of 32 patients (median age 62 years; range 60-70) with hematological malignancies were treated with fludarabine (30 mg/m(2) x 3-5 days) and 200 cCy TBI followed by allogeneic hematopoietic stem cell transplantation (HSCT) from a matched-sibling donor. GVHD prophylaxis consisted of cyclosporine and mycophenolate. Neutrophil recovery occurred in all patients at a median time of 16 days (range 9-34). Six patients did not become granulocytopenic. On day +30, 10 patients had >95% donor chimerism and 19 patients had mixed chimerism. The cumulative probabilities of Grade II-IV acute GVHD and chronic GVHD were 48 and 83%, respectively. Transplant-related mortality at 100 days and 1 year was 6 and 10%, respectively. The probabilities of 2-year overall (OS) and progression-free survival (PFS) were 39 and 35%, respectively. The estimated 2-year probability of OS and PFS for patients in early disease stages were 77 and 64%, respectively, which were significantly higher than the survival and PFS estimates of 0% obtained in patients with advanced disease stages at the time of transplant. Our analysis would suggest that for patients older than 60, this regimen is well tolerated and associated with a low incidence of transplant-related mortality. The leukemic burden at time of transplant has proven to be the most important risk factor for the outcome.

Reduced Intensity Transplantation for Metastatic Renal Cell Cancer With 2-year Follow-up

Metastatic renal cell carcinoma (RCC) is a disease that is resistant to conventional systemic therapy. Nonmyeloablative allogeneic stem cell transplant has activity in patients with metastatic RCC. This approach has been used in related donor transplantation but there are limited data on outcomes in the setting of unrelated donor (URD) transplantation. This phase II trial assessed the efficacy, safety, and responses in 16 patients, 10 related and 6 URD transplants after a reduced intensity conditioning regimen and stem cell transplant as a treatment for metastatic RCC. Sixteen patients received a conditioning consisting of either fludarabine, cyclophosphamide (n=11) or fludarabine, total body irradiation (n=5) followed by transplantation from an HLA-matched sibling donor or a unrelated HLA-donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients were monitored for engraftment by short tandem repeat for myeloid and lymphoid lineages and clinical response was assessed by serial imaging. All patients achieved donor chimerism, 7 patients developed acute, grades 2 to 3, graft-versus-host disease. Chronic graft-versus-host disease occurred in 6 patients and transplant-related mortality was 12%. Of the 10 related donors, 1 obtained a complete response, 3 had a partial response, and 3 had stable disease. In the 6 patients who underwent URD transplant, 1 obtained a complete response and 1 patient had stable disease. These results suggest that similar outcomes are possible where either related or URD were used as the stem cell source in reduced intensity stem cell transplant for metastatic RCC.

Early Renal Injury after Nonmyeloablative Allogeneic Peripheral Blood Stem Cell Transplantation in Patients with Chronic Myelocytic Leukemia

Background: Renal insufficiency is a common complication early after hematopoietic stem cell transplantation (HSCT). Over the past several years, significant advancement has been achieved in HSCT, especially in nonmyeloablative stem cell transplantation. Compared with traditional HSCT, nonmyeloablative HSCT employs significantly lower doses of chemoradiotherapy and lower toxicity. The current study evaluated renal insufficiency during the first 100 days in patients with chronic myelocytic leukemia (CML) who underwent nonmyeloablative allogeneic peripheral blood stem cell transplantation (allo-PBSCT) in a single center. Methods: A total of 26 consecutive patients with CML received nonmyeloablative allo-PBSCT from 2002 to 2005 in Zhong Da Hospital. The average age of the patients was 40.2 ± 8.2 years. Renal function was measured by serum creatinine concentration and estimated glomerular filtration rate (GFR) during the first 100 days after nonmyeloablative allo-PBSCT. Renal dysfunction was classified as follows: grade 0 (<25% decline in GFR), grade 1 (≧25% decrese in GFR but <twofold rising in serum creatinine), grade 2 (≧twofold increase in serum creatinine but no need for dialysis) and grade 3 (≧twofold increase in serum creatinine and need for dialysis). Acute renal failure (ARF) was defined as a doubling of baseline serum creatinine, grade 2 and grade 3. Results: All the patients were successfully engrafted. Of the 26 patients, 10 (38%) patients had some degree of renal dysfunction (grade 1, 5 patients; grade 2, 4 patients; grade 3, 1 patient). They developed ARF at an average of 32.8 ± 4.0 days after transplantation. No significant difference was observed in terms of age, baseline serum creatinine, albumin and hemoglobin between the patients with ARF and without ARF. Renal dysfunction was associated with significantly higher frequencies of sepsis and hepatic veno-occlusive disease (VOD, p < 0.01, respectively). The overall mortality rate at the end of 100 days was 19% (5/26). The mortality rate for patients with ARF was significantly higher than those without ARF (p < 0.001). Conclusion: During the first 100 days following nonmyeloablative allo-PBSCT in patients with CML, a 38% incidence of renal dysfunction and a 19% of ARF were found, which were much less than previous studies. Sepsis and VOD were significantly correlated with the development of renal dysfunction. Severe nephrotoxicity was associated with the increase in mortality.

The First 2 Years of Clinical Experience With Peripheral Blood Stem Cell Transplantation for Various Hematological Malignancies: Results From a Single Baskent University Center

Autologous stem cell transplantation is the current standard approach for patients with multiple myeloma and relapsed or refractory lymphoma. Nonmyeloablative allogeneic stem cell transplantation has been applied worldwide. We analyzed the results of transplantation activity from 2004 to 2006. Seven evaluable patients younger than 65 years old with stage II/III multiple myeloma were treated with high-dose melphalan therapy (140 mg/m 2) plus autologous peripheral blood stem cell transplantation. Complete responses or tumor reductions of more than 75% were obtained in all patients. At a median follow-up of 10 months, all patients remained disease-free. Four patients with acute myeloblastic leukemia underwent nonmyeloablative allogeneic peripheral stem cell transplantation. Their median age was 30 years. One patient was refractory and the others were in hematological remission. The patients received fludarabine-based preparative regimens. All patients received fully matched blood from a related donor 2 days after chemotherapy in conjuction with graft-versus-host disease prophylaxis. One refractory patient with >90% engraftment had late autologous reconstitution at 3 months with evidence of relapse. All other patients in remission remained with >90% donor cell engraftment. These patients are disease-free at 13, 10, and 2 months. Toxicity was minimal. These results showed promise due to the minimal toxicity observed with the conditioning regimens which indicated the feasibility of these procedures.

A Novel Method to Quantify and Characterize Leukemia-Reactive Natural Killer Cells in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation following Conventional or Reduced-Dose Conditioning

The antitumor activity of natural killer (NK) cells has recently been shown to be assessable at a single-cell level via flow cytometric detection of CD107a. We used this novel method to prospectively quantify and characterize tumor-reactive NK cells in patients undergoing myeloablative or nonmyeloablative conditioning and allogeneic hematopoietic stem cell transplantation (HSCT). Degranulation of NK cells in the peripheral blood of 34 patients after HSCT (day +30, day +90) was determined by evaluating CD107a expression after coincubation of the cells with tumor targets. The percentage of degranulating NK cells was higher after nonmyeloablative conditioning than after myeloablative conditioning (P<.001), indicating a higher activation state and increased antitumor activity of NK cells after nonmyeloablative conditioning. We were able to analyze NK cell subsets separately and found that CD56bright NK cells following HSCT are functionally different from CD56bright NK cells in healthy donors, as indicated by a high percentage of degranulating NK cells in response to tumor targets in patients after HSCT. The CD107a assay is a new and feasible method to quantify and characterize tumor-reactive NK cells after HSCT. Using this method, we found that NK cells had high antitumor cytotoxic activity after nonmyeloablative conditioning, which may contribute to the effectiveness of nonmyeloablative conditioning.

Ethmoidal sinusitis caused by Exserohilum rostratum in a patient with malignant lymphoma after non‐myeloablative allogeneic peripheral blood stem cell transplantation

We describe a patient with aggressive lymphoma who contracted an ethmoidal sinus infection due to Exserohilum rostratum after non-myeloablative allogeneic peripheral blood stem cell transplantation. E. rostratum is an extremely rare causative pathogen of invasive fungal infection. Phylogenetic tree analysis of the D1/D2 domains within the LSU rDNA identified the molecular structure of isolates. We believe this is the first description of E. rostratum infection in a patient who underwent hematopoietic stem cell transplantation.