Transplant-related Toxicity Research Articles

Fludarabine, Cyclophosphamide and ATG Based, Reduced Intensity Conditioning for HLA-Match Sibling Donor Transplant in Severe Aplasic Anemia (SAA) - Case Report.

Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling is a curative form of therapy for patients with acquired severe aplastic anemia. Survival has significantly improved over the past 3 decades. The actuarial risk of rejection has been reduced to about 7%. Improved results with survival in excess of 90% have been reported. Current preparative therapies are associated with early and late sequelae such as acute and chronic graft-versus-host disease (aGvHD or chGvHD, respectively) and secondary tumors. Two patients (6 years and 11 years old) with SAA, who had an HLA-identical sibling donor could not proceed with myeloablative therapy at the time of transplant due to delay in results of chromosome stability and fragility in one patient and abnormal pulmonary function in the second. Both received reduced intensity preparative regimen with Fludarabine (30 mg/m2×4 doses) Cyclophosphamide (5 mg/kg×4 doses) and rabbit ATG (1.5 mg/kg×4 doses) followed by an unmanipulated allogeneic BMT from their HLA-identical sibling donors. Graft versus host disease prophylaxis consisted of Cyclosporine from day -1 and Methotrexate 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, +11 after transplant. Myeloid engraftment occurred on day +15 and day +28. The time to a platelet count >20,000 unsupported was +11 days and +29 days. No transplant-related toxicities, including mucositis or alopecia, were recorded. There were no signs for aGvHD or chGvHD. The patients continue with full donor chimerism 27 months and 130 days post transplant, respectively. This data suggests that a non-myeloablative, immunosuppressive regimen is sufficient to provide a stable engraftment in the patients with SAA. This approach may be associated with decreased transplant-related short- and long-term toxicities. A larger study is needed to fully evaluate the outcome and the toxicity associated with this conditioning.

Autologous Non-Myeloablative Hematopoietic Stem Cell Transplantation for Refractory Systemic Vasculitis.

BackgroundCurrent mortality rate in systemic vasculitis (SV) patients with the use of cytotoxic / immunosuppressive therapy is over 20 % at 5 years in some studies. For patients refractory to conventional therapy new strategies aimed at aggressive induction of remission and relapse prevention are being sought. We here report our single center experience in treating 4 patients with refractory SV employing non-myeloablative autologous hematopoietic stem cell transplantation (HSCT).Patients and MethodsFour patients with refractory SV (2 - with neurovascular Behcet's disease, 1 - with neurovascular Sjogren's syndrome, and 1 - with Wegener's granulomatosis) were involved in an IRB and FDA approved phase I clinical trial of high dose chemotherapy and autologous HSCT. Peripheral blood stem cells were mobilized with cyclophosphamide (Cy) 2g/m2 IV and granulocyte-colony stimulating factor 10 mcg/kg/day SQ and were CD34+ enriched. Conditioning regimen consisted of Cy 200 mg/kg and rabbit anti-thymocyte globulin 5.5 mg/kg IV. Disease activity and cumulative organ damage were assessed using Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI), respectively. Primary and secondary endpoints were transplant-related toxicity, survival and change in BVAS and VDI after the transplant.ResultsAll 4 patients tolerated HSCT well without transplant related mortality or any significant toxicity. At median follow up of 28 (range 22–35) months all patients are alive. Three patients (1 each with Behcet's, Sjogren's, and Wegener's) entered a sustained remission at 6, 6 and 24 months after the transplant. Both, BVAS and VDI, markedly decreased within 6 months post-transplant. In a patient with WG C-ANCA levels became undetectable at 24 month evaluation corresponding to clinical and radiological improvement. All 3 patients who achieved remission discontinued immunosuppressive therapy at the time of transplant and have not required since. Two patients with pre-transplant steroid dependency discontinued prednisone at 6 and 14 months after HSCT. One patient with BD who is positive HLA-B51, now 22 months since HSCT, has never achieved remission and is still requiring immunosuppressive therapy.ConclusionWe suggest autologous HSCT utilizing a non-myeloablative regimen is a safe and effective treatment for select patients with SV refractory to conventional immunosuppressive therapies. However, in patients with significant genetic predisposition, more aggressive approach such as allogeneic HSCT or cord blood transplantation might be considered.

Novel Tyrosine Kinase Inhibitor Therapy (NTKI) Prior to Allogeneic Stem Cell Transplantation (ASCT) in Patients with Chronic Myeloid Leukemia (CML): No Evidence for Increased Transplant-Related Toxicity.

Introduction: Patients undergoing ASCT for CML are increasingly likely to have received a NTKI after failing imatinib mesylate. It is unknown whether the use of these NTKIs prior to ASCT increases transplant-related toxicity. Methods: We retrospectively analyzed the outcome of 12 patients with CML (1 in chronic phase, 6 in accelerated phase, and 5 in blastic phase) who received dasatinib (n=2), nilotinib (n=7), or both (n=3) prior to ASCT. Results: Median age was 41 years (range, 18–59 years). The median time on treatment was 134 days (range, 30–285 days), and the median time from the end of NTKI therapy to ASCT was 34 days (range, 7–130 days). Preparative regimen was ablative in 8 patients and non-ablative in 4. Stem cell source was a matched related donor in 7 patients, a matched unrelated donor in 3, a haplo-identical donor in 1, and unrelated cord blood in 1. All patients engrafted within 13 days. There was no significant early transplant-related toxicity: gastro-intestinal toxicities of grade 3 were encountered in 2 patients. One patient had secondary graft failure 6 months after the first ASCT that required a second ASCT. Acute graft-versus-host disease (GVHD) of grade 2 was observed in 7 patients (58%) and chronic GVHD in 6 (50%). Nine patients achieved a molecular response: four complete and five major (Q-PCR< 0.05%). Three patients had disease progression by day 30 post ASCT. Two patients have relapsed after 6 and 18 months. After a median follow-up of 10 months (range, 3–22 months), 7 patients are alive in molecular response and 5 patients died, 4 of disease progression and one of extensive chronic GVHD. Conclusion: Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and larger number of patients will be necessary to confirm these observations.

Autologous Stem Cell Transplantation for Multiple Myeloma in Patients with Reduced Renal Function: A Matched Set Comparison.

Background: Renal insufficiency of varying severity including end stage renal disease requiring dialysis is often a presenting manifestation of multiple myeloma (MM). While many patients (pts) improve following initiation of therapy for MM, a considerable number of pts proceed to stem cell transplant with less than optimal renal function. It is not clear whether the outcome of their transplants differs from pts with normal renal function.Methods: The MM transplant database was searched to identify pts with a Creatinine clearance (Crcl) of less than 50 ml/min/m2 (study cohort). These pts were then matched to two pts each with a clearance of ≥ 50 ml/min/m2 (control cohort), based on cytogenetic abnormalities (normal vs. abnormal), circulating plasma cells (yes vs. no), age at transplant, % of plasma cells at transplant, plasma cell labeling index, time to transplant from diagnosis and the disease status at transplant, the factors used in that order of importance.Results: Eighty pts with a Crcl < 50 ml/min were identified and matched to 160 pts with Crcl ≥ 50 ml/min. The pts were matched for the above factors and the two groups were similar in terms of their other baseline features except CRP and B2M, both of which were lower in the control group. Pts with reduced renal function were more likely to receive dose reduced melphalan for conditioning (32.5%) compared to the control group (2%; P < 0.0001). The outcomes from the stem cell transplant were similar in both the groups. 96% of pts obtained an objective response to stem cell transplant in each of the groups with no difference in the time to response; and a complete response was seen in 38.5% and 36.6% of the study and control cohorts respectively (P=NS). The median post transplant progression free survival was 18.2 months and 18.4 mos respectively for the study cohort and the control group (P=0.4). However, the median overall survival from transplant was shorter for the study cohort (30.7 mos vs. 60 mos for the controls; P = 0.007; Figure). The time to platelet and neutrophil engraftment was not different between the groups. In terms of transplant related toxicity, the median days hospitalized was higher in the study group (5 days vs. 9.5 days; P=0.003) as was the incidence of grade 3 and 4 mucositis (8% vs. 23%; P= 0.0008). Six pts (7.5%) had treatment related deaths in the study group compared to 3 pts (2%) among the controls (P=0.03), the majority of the deaths being infection related.Conclusion: Here we demonstrate that pts with MM and reduced renal function derive disease free survival comparable to those with normal renal function, despite the increased use of reduced dose Melphalan for conditioning. The toxicity is clearly increased in the presence of abnormal renal function. Interestingly, the overall survival was inferior among the pts with reduced renal function. One possible explanation for this observation is the decreased availability of novel therapies for salvage among pts with reduced renal function as many of them would not be eligible for clinical trials due to reduced renal function. [Display omitted]

Haploidentical Peripheral Blood Stem Cell Transplantation for Relapsing/Refractory Neuroblastoma.

This study was aimed at evaluating the feasibility and safety of a novel therapeutic modality in children with neuroblastoma (NBL) refractory to treatment. In order to reduce the tumor burden, a single infusion of radionuclide (10000 MBq 131I-Meta-Iodobenzylguanidine; MIBG) was administered as tumor-targeting therapy followed by reduced intensity conditioning (RIC) and haploidentical HSCT. T cell graft depletion with post-transplant donor T cell add-backs were used to improve immunological reconstitution and mediate potential GVT.Piloting this concept 5 children (4 boys, 1 girl) of a median age of 7 (range 5–11) years entered the study. High-risk NBL was diagnosed at median age of 2 (1–7) years. Four had recurrent refractory, 1 primary therapy resistant NBL. All were heavily pretreated and 3 underwent auto-HSCT.G-CSF primed PBSC were harvested from haploidentical paternal donors. The graft consisted of CD34+ cells selected from the 1st apheresis and CD3-depleted cells from the 2nd one. RIC preparative regimen (Fludarabin 5×25 mg/m2, Thiotepa 2×5 mg/kg, Melphalan 2×60 mg/m2) was given 2 weeks after MIBG from day -8 to day -1 followed by a single dose Rituximab (Mabthera® 375 mg/m2) on day +1. GVHD prophylaxis with OKT3, steroids and Mycophenolate Mofetil was administered from day -8 to day +28. The median given dose of CD34+ cells was 12.5×106 (9.6–22.6) combined with CD3+ cells 0.96×105 (0.4–1.0) per kg. In order to reduce the risk of GvHD and facilitate engraftment donor-derived BM cultured mesenchymal stem cells were co-administered on day 0 at median dose 0.75×106/kg (0.3–1.0). Commencing immunosuppression cessation escalated donor T cells add-backs were initiated with a starting dose of 2.5×104 CD3+ cells/kg (up to 5.0×105/kg).All children engrafted with neurophils >500/μL on day +11 (10–13) and 4 out of 5 pts with platelets >50000/μL on day +11 (11–14). One patient rejected the graft on day +18 and was hematologically reconstituted with autologous back up, but died of progressive NBL five months later. GVHD did not occur before DLI was given. All 4 evaluable children developed aGVHD post DLI (grade I skin - 1 pt, grade II skin - 1 pt, grade III skin/gut -2 pts), which resolved without treatment (1 pt) or after short course of steroids ± CsA (3 pts). Three out 4 patients who engrafted received (preemptive) treatment for viral reactivation (AdV, CMV, BK/JC). One child relapsed 7 months post grafting and after local irradiation, the second high-dose MIBG with Melphalan was given with subsequent haplo-HSCT. The patient went into remission but died because of pulmonary toxicity.In August 2006 three children are alive and well (11, 10 and 9 months after haplo-HSCT) without any signs of NBL, one with active CNS disease before grafting has ongoing liposomal Ara-C (Depocyte®) intrathecal prophylaxis.High-dose MIBG and RIC followed by haplo-HSCT for treatment of high risk relapsed/refractory NBL is feasible with no major transplant related toxicity, however, evaluation of immune reconstitution and antitumor efficacy needs longer follow up. Viral reactivation and post-DLI GvHD remain a continuing challenge.

Establishment of Chimerism in Rhesus Macaques through Nonmyeloablative Hematopoietic Stem Cell Transplant and Costimulation Blockade-Based Immunosuppression.

We established a strategy for producing high level hematopoietic chimerism after non-myeloablative conditioning in the Rhesus macaque. This strategy relies on hematopoietic stem cell transplantation after induction with a non-myeloablative dose of busulfan and blockade of the IL2-receptor in the setting of mTOR inhibition with rapamycin and combined CD28/CD154 costimulation blockade. Hematopoietic stem cells derived from bone marrow and leukopheresis products both were found to be successful in inducing high level chimerism. Mean peripheral blood peak donor chimerism was 81% with a median chimerism duration of 145 days. This prolonged chimerism occurred in the setting of full MHC disparity in unrelated transplant donors and recipients. Additional immune modulation strategies such as pre-transplant CD8 depletion, donor-specific transfusion, recipient thymectomy or peri-transplant deoxyspergualin treatment did not improve the level or durability of chimerism. Recipient immunologic assessment suggested that chimerism occurred amidst donor-specific down-regulation of alloreactive T cells, and the reappearance of vigorous T-mediated alloreactivity accompanied rejection of the transplants. Furthermore, viral reactivation constituted a significant transplant-related toxicity and may have negatively impacted the ability to achieve indefinite survival of transplanted stem cells. Nevertheless, this T cell costimulation blockade-based chimerism-induction regimen induced the longest-lived stem cell chimerism reported to date for non-human primates and thus represents an important platform upon which to evaluate emerging tolerance-induction strategies. Future nonmyeloablative transplant strategies based on immunomodulation via T cell costimulation blockade may have significant clinical relevence for nonmalignant hematologic diseases such as sickle cell disease and beta-thalassemia.

Long-Term Outcome of Methotrexate-Free GVHD Prophylaxis Using Sirolimus and Tacrolimus in Matched Related (MRD) and Unrelated Donor (URD) Peripheral Blood Stem Cell Transplantation (PBSCT).

Methotrexate (Mtx) is an antiproliferative agent associated with toxicity and delayed engraftment after transplantation. Sirolimus is an immunosuppressive mTOR inhibitor that acts synergistically when administered with tacrolimus. We assessed the combination of sirolimus and tacrolimus without Mtx after MRD and URD PBSCT in concurrent trials. Methods Eligible subjects had HLA-A, B, C and DRβ1 matched MRD and URD donors. Conditioning consisted of cytoxan (1800 mg/m2 x 2 days) and TBI (14 Gy, 7 fractions with lung shielding). Tacrolimus (serum conc. 5–10 ng/mL) and sirolimus (serum conc. 3–12 ng/mL) were given as GVHD prophylaxis. No Mtx was given. G-CSF (5 μg/kg/day) was administered from day+12 until neutrophil engraftment as needed. PCP, VZV, and HSV prophylaxis was used, and CMV was treated pre-emptively. No routine anti-fungal prophylaxis was given. Results 53 MRD and 30 URD recipients were enrolled between 7/2002 and 8/2005. The median number of stem cells infused was lower in MRD recipients (7.6 x106 CD34+ cells/kg vs. 10.2 x106 CD34+ cells/kg, p<0.001). Neutrophil engraftment was similar in MRD and URD patients (14 vs. 13.5 days, p=0.2). Platelet engraftment to 20 x106/ml (12 vs. 12 days, p=0.13) and to 100 x106/ml (17.5 vs. 17 days, p=0.32) were similar in the two cohorts. The median time to hospital discharge was 19 days in both groups (p=0.95), with only 2 deaths prior to discharge. Acute lung injury (IPS/DAH) occurred in only 1 subject and was not fatal. 7 (8.4%) subjects developed hepatic veno-occlusive disease (VOD) and was the cause of death in 4. Thrombotic microangiopathy (TMA) was noted in 6 subjects (MRD 5, URD 1; combined incidence 7.3%) and resolved with the elimination of tacrolimus. Renal function recovered in all individuals and TMA did not contribute to the cause of death in any subject. The cumulative incidence of grade II–IV acute GVHD was 20.5%, and was not different between cohorts (18.9 vs. 23.3%, p=0.78). There were only 3 cases of grade III–IV acute GVHD (2 MRD, 1 URD). In a competing risk model (relapse/death as competing risk) the cumulative incidence of chronic GVHD was 52.4% and was not different between groups (50.9 vs. 53.3%, p=0.67). The median follow-up of all surviving patients is 29.5 months from transplantation. Non-relapse and relapse-related mortality at 30 days was 0%. At 100 days they were 4.8% and 1.2% respectively (overall 100 day mortality 6%), without differences in cohorts. Relapse-free survival for the entire group was 72.3% and 68.1% at 1 and 2 years (MRD 71.7% and 66.0%; URD 73.3% at both times points, log rank p=0.6). Overall survival at 1 and 2 years is 77.1% and 71.7% (MRD 77.4% and 69.8%; URD 76.7% at both time points, log-rank p=0.67). The causes of death (n=24) include relapse(13), VOD(4), late pulmonary disease(3), GVHD(2), infection and organ failure(2). Conclusions Sirolimus in lieu of Mtx in a tacrolimus-based GVHD prophylactic regimen is associated with lower transplant-related toxicity, lower rates of acute GVHD and excellent outcomes than would be expected with a Mtx-based regimen. Moreover, MRD and URD outcomes appear to be equivalent, suggesting that the historical disparity in outcomes between MRD and URD transplantation can be abrogated with effective GVHD prophylaxis. This regimen is worthy of further study and broader use in MRD and URD PBSCT.

Optimization of allogeneic transplant conditioning: not the time for dogma

Numerous reduced-intensity conditioning regimens for allogeneic hematopoietic cell transplantation are currently being explored, primarily in older patients and in individuals with comorbid conditions who are not eligible for conventional myeloablative conditioning regimens. There is agreement that these approaches have reduced early transplant-related (non-relapse) toxicity and mortality. It is unclear, however, whether these strategies improve long-term survival. Furthermore, as most trials with reduced-intensity regimens have enrolled older patients and patients with comorbid conditions, it is not appropriate to compare the results of these trials to those obtained with more conventional approaches. It remains to be determined whether younger patients, and patients without comorbid conditions, will derive significant long-term benefits from reduced-intensity regimens when compared to conventional strategies. It may be that the different approaches are complementary and in the end will preferentially serve specific patient populations based on age, comorbid conditions and malignancy type. To determine the role of reduced-intensity approaches, controlled prospective trials are needed, with enrolled patients being stratified according to comorbid conditions, disease characteristics, pre-transplant therapy and source of stem cells, at a minimum.

The clinical outcome and toxicity of high‐dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British society of blood and marrow transplantation study

The outcome of high-dose chemotherapy (HDT) was evaluated retrospectively in 27 patients with myeloma and four patients with AL amyloidosis with severe renal impairment. Twenty-three patients were receiving dialysis and the rest had a creatinine clearance of <20 ml/min. The median melphalan dose was 140 mg/m2 (range: 60-200 mg/m2), but 10 patients (37%) received 200 mg/m2. Myeloid and platelet engraftment were similar to that seen in patients without renal failure. Five of 27 patients died of transplant-related toxicity before the day 100. Twenty of 27 patients had a response (70%). The median time to disease progression was 32 months (range: 6-54 months) and the median time to best response was 6.5 months. Four of 17 evaluable patients (24%) became dialysis-independent at a median of 5 months post-HDT/stem cell transplantation. At a median follow-up of 70 months, 7/23 patients with myeloma were alive but three of these seven patients had progressive disease. Two of the four patients with amyloidosis have survived. HDT is feasible in these patients and results in 5-year survival in about one-third of patients.

Allogeneic hematopoietic cell transplantation after reduced intense conditioning as adoptive cell therapy in resistant metastatic colorectal carcinoma. The European experience

3596 Background: Allogeneic reduced intense conditioning regimens decreased morbidity and mortality related to hematopoietic stem cell transplantation (HCT), retaining a powerful graft versus tumor effect (GVT). On this basis, it became possible to explore the existence of alloreactivity in solid tumors. A GVT effect was described in metastatic colorectal cancer (CRC). Methods: We report the data on 35 patients with CRC treated with non-myeloablative allogeneic HCT in Europe. Median time from the diagnosis of metastatic disease to transplant was 16 (4–47) months; 25 patients (67%) received at least 2 lines of therapy before transplant. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (14%) and partial response (PR) in 2 (6%). Patients were treated according to different nonmyeloablative regimens. All but one patient received allogeneic peripheral hematopoietic cells [median CD 34+ cells/kg was 6.7 × 106 (2,5–55), median CD3 + cells/kg was 4.9 × 108 (0,11–33)] from HLA identical familiar donors. GVHD prophylaxis consisted of cyclosporine A (CyA) + Mycophenolate Mofetil in 24 (68%), of CyA + methotrexate in 6 (25%) and other CyA regimens in the others (18%). Results: Myelosuppression was mild and all patients engrafted with a median donor chimerism of 90% (45–99) on CD 3 cells on day +60. Transplant-related toxicities were limited. Grades II-IV acute GVHD occurred in 18 patients (51%) and chronic GVHD in 6 patients (25%). Transplant-related mortality was the cause of death in 4 patients (11%). As best tumor response we observed: 1 complete response (3%), 8 PRs (20%) and 9 SDs (29). Overall median survival from the date of transplant was 198 days (6–1020); median overall survival for the responding patients was 353 days (113–1020). Conclusions: Allogeneic HCT after RIC is safe and feasible in metastatic CRC. The results obtained compared favorably with those observed in patients with hematologic malignancies or metastatic CRC beyond second line in terms of transplant-related complications and tumor response respectively. Thus a study of allogeneic cell therapy in a less advanced patient cohort is warranted. No significant financial relationships to disclose.

Novel tyrosine kinase inhibitor therapy (NTKI) prior to allogeneic stem cell transplantation (ASCT) in patients (pts) with chronic myeloid leukemia (CML): No evidence for increased transplant-related toxicity

16515 Background: Patients undergoing ASCT for CML are increasingly likely to have received a NTKI after failing imatinib mesylate. It is unknown whether the use of these NTKIs prior to ASCT increases transplant-related toxicity. Methods: We retrospectively analyzed the outcome of 8 patients with CML (1 chronic, 4 accelerated, and 3 in blastic) who received dasatinib (n = 2) or AMN-107 (n = 6) prior to ASCT. Results: The median time on treatment was 85 days, and the median time from the end of NTKI therapy to HSCT was 37 days. Preparative regimen was ablative in 5 patients and non-ablative in 3. All patients engrafted within 13 days. There was no significant early transplant-related toxicity. Five patients achieved a molecular response after a median follow-up of 8 months; three complete and two major (Q-PCR &lt; 0.05%). Three patients relapsed within 3 months. Two patients died of disease progression, and extensive GVHD, respectively. Conclusions: Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and larger number of patients will be necessary to confirm these observations. No significant financial relationships to disclose.

Tandem high-dose therapy with autologous stem cell support for small-cell lung cancer (SCLC)

17033 Background: We evaluated the therapeutic efficacy of tandem high-dose chemotherapy followed by autologous peripheral stem-cell transplantation (PBSCT) in patients with newly diagnosed SCLC in complete remission or very good partial response after induction chemotherapy. Methods: Between 1996 and 2000, 19 patients with newly diagnosed SCLC in CR or very good PR after two cycles of induction chemotherapy (cisplatin 90 mg/m2 day 1, etoposide 120 mg/m2 day 1–3, ifosfamide 1500 mg/m2 day 1–4) received a tandem high-dose chemotherapy (cyclophosfamide 2000 mg/m2 day 1 and 2, etoposide 700 mg/m2 day 1–3, carboplatin 1200 mg/m2 day 1) followed by PBSCT. Following transplantation, patients received concurrent chest and cranial radiotherapy to a total dose of 45 Gy and 30 Gy, respectively. Results: Of 19 patients with SCLC, 18 had stage III and one stage IV disease. The median age was 50.7 years. Median time to leukocyte-recovery above 1000/μl and platelet-recovery above 20.000/μl was 12 days and 9 days, respectively. The median follow-up was 6.38 years (range 5.11–7.23) for surviving patients. There were no transplant-related deaths and toxicity was moderate. Using the Kaplan-Meier method, the 2- and 5-year survival rates after high-dose therapy were 42% and 32% respectively. Median time to relapse was 0.7 years (range 0.2–4.6). The mean survival was 36.8 months. This outcome compared favourably to a group of 77 patients who did not receive high-dose therapy but responded to conventional chemotherapy (mean survival 11.4 months). Using the Cox regression model, among all patients response to induction, normal LDH and PBSCT were associated with favourable outcome. Conclusions: Our findings suggest that patients with or near complete response after conventional therapy might benefit from tandem high-dose therapy with PBSCT with tolerable toxicicity. No significant financial relationships to disclose.

Hematopoietic Stem Cell Transplantation in Hemophagocytic Lymphohistiocytosis: A Single-Center Report of 48 Patients

Familial hemophagocytic lymphohistiocytosis (FHLH) is a genetically determined disorder characterized by the early onset of fever, hepatosplenomegaly, central nervous system disease, thrombocytopenia, coagulation disorders, and hemophagocytosis. It is caused by genetic defects that impair T cell-mediated and natural cytotoxicity. Chemotherapy- or immunotherapy-based treatments can achieve remission. Hematopoietic stem cell transplantation (HSCT), however, is the only curative option, but optimal modalities and long-term outcome are not yet well known. We retrospectively analyzed the outcome of HSCT that was performed in 48 consecutive patients who had FHLH and were treated in a single center between 1982 and 2004. The overall survival was 58.5% with a median follow-up of 5.8 years and extending to 20 years. A combination of active disease and haploidentical HSCT had a poor prognosis because in this situation, HLH disease is more frequently associated with graft failure. Twelve patients received 2 transplants because of graft failure (n = 7) or secondary graft loss that led to HLH relapse (n = 5). Transplant-related toxicity essentially consisted in veno-occlusive disease, which occurred in 28% of transplants and was associated with young age, haploidentical transplantation, and the use of antithymocyte globulin (ATG) in the conditioning regimen. A sustained remission was achieved in all patients with a donor chimerism > or = 20% of leukocytes. Long-term sequelae were limited, because only 2 (7%) of 28 patients experienced a mild neurologic disorder. This survey demonstrates the long-term efficacy of HSCT as a cure of FHLH. HSCT preserves quality of life. It shows that HSCT should be performed as early as a complete remission has been achieved. Additional studies are required to improve the procedure and reduce its toxic effects.

Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents – a Berlin–Frankfurt–Münster group report

Patients with refractory or early relapsed anaplastic large cell lymphoma (ALCL) have a poor chance of survival. We report 20 children and adolescents with high-risk relapsed or refractory ALCL who underwent allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively analysed 20 patients who relapsed between December 1991 and April 2003 during (six patients) or soon after first-line Berlin-Frankfurt-Münster-type chemotherapy (14 patients) and underwent allogeneic HSCT. Nine patients received allogeneic HSCT after the first relapse and 11 after multiple relapses. Eight patients received their transplants from matched sibling donors, eight from unrelated donors and four from haploidentical family donors. The conditioning regimen was based on total body irradiation in 15 patients. Two patients relapsed after allogeneic HSCT and died. Three patients died of transplant-related toxicity. Event-free survival at 3 years after allogeneic transplant was 75 +/- 10%. There was no influence of donor type or conditioning regimen on outcome. Two of six patients with progressive disease during frontline therapy survived compared with 13/14 patients with a first relapse after frontline therapy. Two of three patients who were transplanted with active lymphoma and all five patients who received allogeneic HSCT for relapse following autologous HSCT survived disease-free. Allogeneic HSCT is effective and has acceptable toxicity as rescue therapy for high-risk ALCL relapse. It even offers cure for patients refractory to chemotherapy, suggesting a graft-versus-ALCL effect.

Acute renal failure in hematopoietic cell transplantation

Hematopoietic cell transplantation is a common procedure for the treatment of malignancies and some non-malignant hematologic disorders. In addition to other transplant-related organ toxicities, acute renal failure is a common complication following transplantation. This review discusses the incidence, timing, etiologies, risk factors, and prognosis of renal failure associated with three commonly used transplantation procedures - myeloablative autologous, myeloablative allogeneic, and non-myeloablative allogeneic transplantation. It is important to note that the epidemiology and prognosis of renal failure are distinct with these three transplantation procedures. However, the common theme is that mortality increases with worsening renal failure with all three procedures. Moreover, mortality is >80% for patients with renal failure requiring dialysis. It also appears that surviving patients have an increased risk of chronic kidney disease after renal failure. The reduction of acute renal failure will have several advantages, including reducing mortality and the burden of chronic kidney disease following transplantation.

High-Dose Idarubicin, Busulphan and Melphalan for Autologous Stem Cell Transplantation in Multiple Myeloma Responsive to DAV Chemotherapy: Comparison with a Historical Control

Since 1997, 32 newly diagnosed multiple myeloma patients responsive to DAV chemotherapy were autografted with idarubicin-intensified busulphan-melphalan (ida-bu-mel). Main endpoints of the study were transplant-related toxicity, overall survival (OS) and progression-free survival (PFS). The results were compared with a historical control group of 38 patients treated with the ‘standard’ bu-mel regimen. Concerning time to engraftment, no significant difference was observed between the two groups, while toxicity was significantly higher in the intensive conditioning group, regarding grade IV mucositis, duration of profound neutropenia, incidence of infections and platelet requirement. Five-year OS and PFS are 73 versus 78% and 37 versus 48% for the intensive and standard regimen, respectively (p value not significant). The ida-bu-mel schedule appears to be a feasible and effective regimen for newly diagnosed multiple myeloma patients; nevertheless, no apparent benefit in OS and PFS arises from the comparison with a historical control treated with standard bu-mel, which is better tolerated and at least equally effective.

Nonmyeloablative Allogeneic Stem-Cell Transplantation for Metastatic Renal Cell Cancer: A Review and Update

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy and radiotherapy. However, immunotherapy appears to be effective in 15—20% of cases, with interleukin-2 becoming the standard therapy for this disease. As a consequence of the immune susceptibility of RCC, other avenues of immunotherapy are being explored, such as nonmyeloablative allogeneic stem cell transplantation (NST). A number of trials have shown NST to be effective in varying degrees, causing partial or complete regression. Although nonmyeloablative conditioning is safer than myeloablative conditioning, its role has yet to be clearly proven as many studies have shown variable effect. Alongside this limitation, transplant-related toxicity also forms obstacles. Regardless of the limitation of NST, further refinement of the technique, with appropriate patient selection, may lead to this being an effective therapeutic choice for a significant number of individuals.

Influence of Comorbidities on Outcomes of Autologous and Allogeneic Stem Cell Transplantation (SCT).

Centers that perform stem cell transplants have patient selection criteria for treatment, typically including patient performance status, acceptable cardiopulmonary function, normal renal function, absence of active infection, and underlying disease likely to respond to treatment. Despite these selection criteria, transplant-related morbidity and mortality are high, particularly in allogeneic transplants. We sought to find a method to better predict outcome after SCT. The Charlson Comorbidity Index (CCI) is a tool to assess comorbidities and outcome in a varitety of diseases, but its utility in SCT is unclear. This retrospective study used chart review from 187 procedures (109 autologous and 78 allogeneic; 43 myeloablative and 35 non-myeloablative) performed between 2002 and 2004 to assign CCI scores. Transplant outcomes, including 100-day and 1-year survival and transplant related toxicity, were grouped according to CCI and analyzed using regression analysis, T-test, Fisher Exact and ANOVA. Median age at transplant was 55 years for autologous and 48 years for allogeneic (41 years for myeloablative and 55 years for non-myeloablative). The CCI was not predictive of survival or toxicity in autologous transplant patients. In allogeneic transplants, the CCI was predictive of only long-term survival when a score of zero was compared to all other scores, but was not clinically useful since 76% of patients had a CCI score of zero and values over one had similar outcomes. We thus sought a better tool to predict outcomes and modified the CCI using clinical parameters that were anticipated to impact outcome. These included pre-transplant lab values (AST, ALT, creatinine and bilirubin), scores for prior organ dysfunction (CNS, cardiovascular, diabetes, lung, liver and kidney), pulmonary function, alcohol use and smoking history. This new SCT Comorbidity Index, SCI, was used to evaluate outcomes using the same methodology. The modification of the original CCI expanded the range of comorbidities to 27 from the 19 medical conditions assessed in the original CCI. By this expansion, a new maximum score of 38 was created with an individual patient high SCI score of 8. The autologous and allogeneic SCT populations had comparable comorbidity scores, while non-myeloablative patients had higher comorbidity scores, on average, than myeloablative. For short term 100-day survival, the SCI proved to be a better predictor than the original CCI only in autologous SCTs (99% survival with SCI scores of 0 or 1 vs. 83% survival with other SCI scores p=0.004). Long-term survival 100 days to 1 year was opposite of anticipated in autologous SCTs (67% survival with SCI score of 0 vs. 91% survival with other SCI scores p=0.007) but appeared to be predictive in allogenic transplants (87% survival with SCI score 0–2 vs. 50% for higher SCI scores p=.002). The SCI did not predict long-term survival in the non-myeloablative allogeneic SCT subset of patients. In addition, neither index predicted overall toxicity (d0 to d30), and neither predicted grade III–IV toxicity (d0 to d30) in any patient population. Thus neither the Charlson Comorbidity Index nor a modified index was found to be a helpful in the consistent prediction of stem cell transplant outcomes. This likely reflects the selection criteria used for determining candidacy that limits the degree of comorbidity.

Autologous Bone Marrow Transplant after Failed Peripheral Blood Stem Cell Mobilization Does Not Adversely Affect Engraftment or Transplant Related Toxicity.

Introduction: Chemotherapy and G-CSF are widely used to collect adequate numbers of peripheral blood stem cells (PBSC) prior to autologous transplant. However, 10–30% of patients (pts) will not mobilize adequately. Alternatives include use of stem cell factor (SCF) and bone marrow (BM) harvest. Limited information is available on the hematopoietic reconstitution and clinical outcome of intensively treated pts who fail to mobilize sufficient numbers of PBSC and receive BM grafts. We sought to determine whether BM is an acceptable source of stem cells in these pts.Methods: We conducted a retrospective analysis of toxicity, engraftment parameters, transfusion requirements and outcome in pts who failed mobilization and underwent unprimed BM harvest at our institution.Results: Between 02/97 and 07/05, 47 heavily pre-treated pts (male/female 22/27; median age 49, range 22–66) who failed mobilization underwent an autologous BM transplant. Diagnoses included non-Hodgkin's lymphoma (n=37: 17 low grade and 20 intermediate grade), Hodgkin's lymphoma (n=6), and multiple myeloma (n=4). Median number of chemotherapy cycles prior to harvest was 11 (range 5–20); 17 pts (36%) had previously received radiotherapy. 42 pts had 1 mobilization attempt and 5 pts had 2 attempts. Mobilization regimens included chemotherapy(C) + G-CSF (n=27), C + G-CSF + SCF (n=20), G-CSF + SCF (n=4) and C + GM-CSF (n=1). G-CSF was given at a minimum dose of 10μg/kg/day. Pts were defined as poor mobilizers if the peak value of CD34+ cells during mobilization was lower than 10 cells/μL (n=33) or in the case of stem cell collection, if less than 1 x 106 CD34+ cells/kg were obtained (n=14). Conditioning regimens included: BEAC (n=38), Cy-TBI (n=5), high dose Melphalan (n=3), and BEAM (n=1). Infused median numbers of nucleated BM cells, CFU-GM and CD34+ cells per kilogram were 3.5×108 (range 1.0–21.6), 7.33×104 (range 0.3–52.7), and 1.1×106 (range 0.3–2.3), respectively. 34 pts received G-CSF during their hospitalization (median 12 days; range 2–38). Following transplant, median times to achieve an ANC > 0.5×109/L and platelet count >20×109/L were 19 (range 10–42) and 24 days (range 9–233), respectively; median time to RBC transfusion independence was 33 days (range 1–425). Median time to hospital discharge was 25 days (range 14–64). With a median follow-up of 36 months (range 1–97), Kaplan-Meier estimates of overall and disease-free survival at 3 years are 67% and 44%, respectively. The Kaplan-Meier estimates of transfusion independence for platelets and RBC at 3 months are 86% and 84%, and at 1 year 97% and 95%, respectively. 2 pts (4.3%) experienced procedure related deaths prior to day +100, one of cardiac insufficiency on day +3 and one of septic shock on day +90. Cumulative incidences of non relapse mortality at 1, 3 and 5 years were 4.3%, 10.6% and 14.9%, respectively. The incidence of post transplant MDS/AML was 10.6%.Conclusion: Autologous transplant with unprimed BM graft after failed PBSC mobilization does not adversely affect engraftment or transplant related toxicity significantly. Thus, hard to mobilize patients should not be excluded from a potentially curative treatment.

Efficacy of Fludarabine and Cytarabine Combination for Salvage Treatment of Refractory/Relapsed Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Promising Results from a Single Center Experience.

Background: response of refractory or relapsed MDS/AML to current standard chemotherapy (CHT) is unsatisfactory; high dose CHT without hematopoietic stem cell support is often unsuccessful because of its high toxicity. As the only curative chance for these patients (pts) is to receive an allogeneic stem cell transplantation (AlloSCT) in a complete remission (CR) or in a minimal residual disease status, a salvage treatment with the highest efficacy and lowest toxicity is warranted; if no donor is available, consolidation with intensified-dose CHT and autologous stem cell transplantation (ASCT) is the preferable alternative. Fludarabine+cytarabine (FLA) containing regimens have shown promising results in CR induction of poor prognosis MDS/AML at diagnosis. Fludarabine has no direct activity on myeloid malignancies but improves cytotoxicity of cytarabine by increasing intracellular concentration of its toxic metabolite, ara-CTP, in leukemic blasts; priming of myeloid precursors with G-CSF increases the sensibility of leukemic blasts to cytarabine by committing them to phase S of the cell-cycle.Aim: we retrospectively evaluated the efficacy and toxicity of FLA regimens in pts with refractory or relapsed MDS/AML, treated at our Center.Patients and Methods: 25 pts in the period 6/1999–6/2005; median age 55 (18–72), 11 pts > 60 years. Diagnosis (FAB): AML 20, sAML 4, AREB 1 (IPSS: INT-2), no therapy-related AML/MDS. Cytogenetics: normal 15, poor 3, good 1, intermediate 6. Eight pts (32%) had refractory disease to standard induction CHT and 17 pts (68%) had relapsed disease after a median of 3 CHT cycles (range 1–4); 11 of them relapsed after ASCT. Median CR duration (17 pts): 10 months (range 1–59). Salvage treatment: 20 FLAG-Ida regimen, 4 FLAG, 1 FLAG+liposomal dauno.Results: overall response rate (RR) was 68%: 15 CR (60%), 2 PR (8%), 7 NR (28%); 1 pt not evaluable for prolonged marrow hypoplasia. RR for refractory and relapsed disease was 37.5% (CR 25%) and 88.2% (CR 82.3%) respectively. RR for <60 and ≥60 years-old pts was 67.4% (CR 57.1%) and 63.6% (CR 63.6%), respectively. RR for AML and sAML was 76% (CR 65%) and 80% (CR 80%), respectively. Toxicities: no treatment related deaths; FUO/sepsis 96% (24 pts); invasive fungal infections 8% (2 pts). No further major toxicities. Nine patients received further CHT after salvage with FLA, 8 for CR consolidation, 1 for reinduction: 5 FLAG, 3 high dose cytarabine, 1 gentuzumab-ozogamicine. Fourteen patients (56%) received a SCT: 2 ASCT, 12 AlloSCT. At transplant 10 pts (71%) were in CR, 3 (21%) had overt disease, 1 had an hypoplastic marrow. Relapses in pts who obtained a CR were 5 (33%), 2 before transplant and 3 after transplant (1 ASCT, 2 AlloSCT). After a median follow-up of 7 months (range 2–72) from the beginning of rescue treatment, 16 pts have died (64%), 12 with progressive/refractory disease, 4 in CR (1 sepsis after CHT, 2 transplant related toxicity, 1 Guillain-Barrè syndrome); 9 patients (36%) are alive, all in CR; six of them after SCT (1 ASCT, 5 AlloSCT). Median OS is 209 days (44–1993) 7 months (range 2–72), median DFS is 163 days (13–922) 5 months (range 1–30).Conclusions: FLA regimens induced a significant rate of responses in relapsed pts, with tolerable toxicity, also in the elderly subgroup. Consolidation with high dose CHT and ASCT or with AlloSCT could induce prolonged OS and DFS. Response and outcome of refractory diseases seem to have a worse trend.