Stability and Priority of Symptoms and Symptom Clusters Among Allogeneic HSCT Patients Within a 5-Year Longitudinal Study.

CONTEXT: Due to toxicity and invasiveness, allogeneic hematopoietic stem cell transplantation causes severe and longstanding symptom burden. Longitudinal studies on symptoms and symptom clusters (SC) would be helpful to optimize symptom control but are rare to date. OBJECTIVES: The objective of this study was to investigate stability of symptoms, extract time stable SC, and determine their priority in symptom management. METHODS: In this multicenter study, patients diagnosed with hematologic cancer were assessed before conditioning (T0) and three months (T1), one year (T2), and five years (T3) after transplantation. Symptoms were assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Symptoms were stable when rated as present at three consecutive time points. Applying factor analysis, stable SC were composed of symptoms loading on the same factor across all time points. Priority in symptom management was derived from a combination of severity and predictive power for quality of life (QoL). RESULTS: Two hundred thirty-nine patients participated at T0, 150 (63%) at T1, 102 (43%) at T2, and 45 (19%) at T3. We identified three stable SC, composed of rest-tired-weak-dyspnea-loss of appetite (exhausted), tense-worried-irritable-depressed (affective), and nausea-vomiting (gastrointestinal). Fatigue was most persistent and also most severe and predictive for QoL, both as symptom and in cluster (exhausted). CONCLUSION: Given its high stability, severity, and impact on QoL, fatigue should have priority in symptom management. The treatment of this symptom could be enhanced by also incorporating interventions addressing dyspnea and loss of appetite.

Molecular diagnostics, targeted therapy, and the indication for allogeneic stem cell transplantation in acute lymphoblastic leukemia.

In recent years, the panel of known molecular mutations in acute lymphoblastic leukemia (ALL) has been continuously increased. In Philadelphia-positive ALL, deletions of the IKZF1 gene were identified as prognostically adverse factors. These improved insights in the molecular background and the clinical heterogeneity of distinct cytogenetic subgroups may allow most differentiated therapeutic decisions, for example, with respect to the indication to allogeneic HSCT within genetically defined ALL subtypes. Quantitative real-time PCR allows highly sensitive monitoring of the minimal residual disease (MRD) load, either based on reciprocal gene fusions or immune gene rearrangements. Molecular diagnostics provided the basis for targeted therapy concepts, for example, combining the tyrosine kinase inhibitor imatinib with chemotherapy in patients with Philadelphia-positive ALL. Screening for BCR-ABL1 mutations in Philadelphia-positive ALL allows to identify patients who may benefit from second-generation tyrosine kinase inhibitors or from novel compounds targeting the T315I mutation. Considering the central role of the molecular techniques for the management of patients with ALL, efforts should be made to facilitate and harmonize immunophenotyping, cytogenetics, and molecular mutation screening. Furthermore, the potential of high-throughput sequencing should be evaluated for diagnosis and follow-up of patients with B-lineage ALL.

The Role of Allogeneic Stem Cell Transplantation in Relapsed/Refractory Hodgkin's Lymphoma Patients.

Despite the favorable prognosis of most patients with Hodgkin's Lymphoma (HL), 15-20% of patients remain refractory to chemoradiotherapy, and 20-40% experience relapses following autologous stem cell transplantation (SCT) being used as salvage approach in this situation. Long-term survival of only 20% was reported for patients who failed this option. As some authors suggested the presence of a graft versus HL effect, allogeneic SCT was introduced as a further option. Myeloablative strategies were reported to be able to achieve cure in some younger patients, but high nonrelapse mortality remains a problem. Reduced intensity conditioning, in turn, was found to be associated with high posttransplant relapse rates. As there is currently no standard in the management of HL patients who failed autologous SCT, we here review the literature on allogeneic stem cell transplantation in HL patients with a special focus on the outcomes and risk factors being reported in the largest studies.

Chimerism studies with quantitative real-time PCR in stem cell recipients with acute myeloid leukemia.

OBJECTIVE: Chimerism is well-established for surveillance of acute myeloid leukemia (AML) patients after allogeneic hematopoietic stem cell transplantation (HSCT), but interpretation of the results and techniques is not standardized. MATERIALS AND METHODS: We correlated chimerism in 75 AML patients (38 male, 37 female) who underwent myeloablative (n = 36)/reduced (n = 39) allo-HSCT with the risk of relapse and survival. Chimerism was evaluated by quantitative real-time polymerase chain reaction for donor/recipient specific polymorphisms/Y-specific sequences. RESULTS: After HSCT, 40 patients (53%) achieved stable complete donor chimerism (≥ 99.0% of donor alleles), while 35 (47%) failed to achieve stable donor chimerism. Thirty-one patients (41%) showed decreasing donor alleles after having first achieved complete donor chimerism. To investigate the kinetics of mixed chimerism, patients were separated whether they showed subsequent increasing or decreasing donor alleles. Subsequent decrease of donor alleles was associated with relapses in 17 of 18 cases (94%), while no patient with subsequent increasing donor alleles relapsed (p < 0.001). Patients with mixed chimerism and increasing donor alleles had better 2-year disease-free survival (85%) than those with decreasing donor alleles (0%; p < 0.001). CONCLUSIONS: The kinetics of mixed chimerism as assessed by quantitative real-time polymerase chain reaction is an important prognostic predictor in the post-transplantation period of AML patients.

Allogenic hematopoietic stem-cell transplantation with reduced-intensity conditioning in patients with refractory and recurrent multiple myeloma: long-term follow-up.

BACKGROUND: Allogeneic stem cell transplantation (SCT) with myeloablative conditioning is potentially curative therapy for myeloma, but is reportedly associated with a high risk of nonrecurrence mortality (NRM). Reduced-intensity conditioning (RIC) allows for the reduction of NRM, but the recurrence rate is increased. The role and timing of allogeneic SCT in the disease course remains controversial. To the authors' knowledge, there are limited data regarding the long-term outcome of RIC in the recurrent/refractory setting. METHODS: A retrospective analysis was conducted of SCT outcomes in 50 patients who received RIC for recurrent/refractory myeloma between the years 2001 and 2004. All patients were given fludarabine-melphalan based conditioning and stem cell grafts from a related (n=27) or unrelated donor (n=23). RESULTS: The median age was 53 years. Forty-seven patients failed a prior autologous SCT. Thirty patients were in disease remission at the time of SCT and 20 had stable or progressive disease. With a median follow-up of 6.4 years (range, 5-7.9 years), the overall and progression-free survival (PFS) rates were 34% and 26%, respectively. The NRM rate was 26%. Adverse prognostic factors for survival included SCT not in remission, long duration of disease (>5 years from diagnosis), and transplantation from a female donor to a male recipient. The 7-year PFS in 19 patients with none of these adverse prognostic factors was 47%. Chronic graft versus host disease and the achievement of complete remission after SCT were associated with improved outcome. CONCLUSIONS: Allogeneic SCT can result in long-term PFS in a subset of myeloma patients who fail prior therapy and should be considered early after failure and after achieving remission.

Post-transplant immune reconstitution after unrelated allogeneic stem cell transplant in patients with acute myeloid leukemia.

We evaluated immune recovery in 67 patients with acute myeloid leukemia (AML) with a median age of 40 years (4-69) following allo-SCT after reduced (n = 35) or myeloablative (n = 32) conditioning. The following lymphocyte populations were determined on days +30, +90, +180, +270, and +365 by flow associated cell sorting: CD3+, CD3+CD4+, CD3+CD8+, CD3+CD4+/CD3+CD8+ ratio, CD3-CD56+, and CD19+ cells. Peripheral blast count >5% was related to lower number of CD3+CD4+ (day +30) and NK cells (day +180; p = 0.02). Intensity of conditioning did not have any significant impact on the kinetics of immune recovery. Patients with normal CD3+CD4+/CD3+CD8+ ratio (day +30) and NK cell count (day +90; p <0.05) experienced better survival than those with decreased parameters. Post-transplant sepsis/severe infections impaired CD3+CD8+ (day +90; p = 0.015) and CD19+ (day +90; p = 0.02) recovery. Relapse in patients following allo-SCT showed an association with decreased numbers of CD19+ (day +270) and NK cells (day +365). Acute GvHD (II-IV) was accompanied by reduced CD19+ and CD3+CD4+ cells. Thus, the evaluation of post-transplant immune reconstitution in patients with AML might improve risk stratification concerning either relapse or TRM and remains to be further explored.

Diagnostic tools in the indications for allogeneic stem cell transplantation in myelodysplastic syndromes.

The rates of allogeneic stem cell transplantation (SCT) to treat the myelodysplastic syndromes (MDS) is continually increasing. However, given the growing arsenal of therapeutic options in parallel to deeper insight into the heterogeneity of this disorder, determining the indications for SCT in MDS remains a difficult task. The International Prognostic Scoring System (IPSS) serves as a guideline for therapeutic decisions, but many aspects (eg, interpretation of rare cytogenetic abnormalities, combinations of chromosomal alterations and/or molecular markers, variant clinical courses within distinct biological subgroups) remain the subject of continuous investigation. In an effort to achieve a more well-differentiated risk categorization, attempts have been made to perform a more detailed cytogenetic categorization, and the use of various fluorescein in situ hybridization (FISH) techniques has improved the description of aberrations. Multicenter initiatives have standardized multiparameter flow cytometry techniques for diagnosis of MDS. In advanced MDS, screening for molecular mutations can identify cases with a high transformation risk. Finally, the new World Health Organization classification system provides a more homogenous morphological categorization of MDS compared with the former French-American-British system. Consequently, in the near future, risk stratification in MDS might incorporate additional diagnostic tools and categorization systems aimed at improving the timing and indication for SCT in this complex disorder.

Current status and perspectives of tyrosine kinase inhibitor treatment in the posttransplant period in patients with chronic myelogenous leukemia (CML).

Following the introduction of tyrosine kinase inhibitors (TKIs) in chronic myelogenous leukemia (CML), allogeneic stem cell transplantation (SCT) took a shift toward high-risk patients. Considering the high relapse rates posttransplant in these selected patients, several studies evaluated posttransplant use of the TKI imatinib. Although the number of studies are still limited, and data have to be confirmed by additional studies, safety of imatinib even within the first months after SCT seems to be acceptable. Imatinib was shown to be effective in patients with molecular or hematologic relapse of chronic or accelerated phase posttransplant (CP, AP), whereas outcomes in blast phase were more unfavorable. The compound further seemed beneficial for prophylactic use in patients who achieved complete remission posttransplant. The combination of imatinib with donor lymphocytes did not result in increased toxicity or graft-versus-host disease (GVHD). First studies suggest that second-generation TKIs such as dasatinib or nilotinib are manageable posttransplant with acceptable toxicity as well. In conclusion, TKIs of the first- and second-generation are promising options for the posttransplant period of patients with CML, but algorithms for dosage, intervals from SCT, duration of application, and the combination with donor lymphocytes still have to be developed.

Bone marrow mesenchymal stromal cells remain of recipient origin after allogeneic SCT and do not harbor the JAK2V617F mutation in patients with myelofibrosis.

The close association of the myeloproliferative neoplasms with the activating non-receptor tyrosine kinase JAK2V617F mutation is well established. To further clarify the pathomechanisms of this mutation in patients with myelofibrosis, we performed screening with quantitative real-time PCR for the respective mutation in in vitro expanded bone marrow (BM) mesenchymal stromal cells (MSCs) and compared the results with BM/peripheral blood (PB). Eight patients with primary/secondary myelofibrosis were investigated before (n = 4) or after allogeneic stem cell transplantation (n = 4). All patients had systemic evidence of the JAK2V617F mutation in BM/PB (mutation ratios 0.2-23.5) at the time of investigation in contrast to negative results in the MSCs (n = 7) or a very low (0.004) mutation ratio (n = 1) which was probably due to hematopoietic contamination. The four patients post-transplant had systemic donor chimerism between 96.5 and 100% in BM/PB, while MSCs showed no evidence of donor-specific alleles. In conclusion, in myelofibrosis, the JAK2V617F mutation is restricted to hematopoietic cells, and cannot explain the stromal alterations being observed in this disorder. Further, the MSCs remain of recipient origin after allogeneic SCT, which might contribute to the increased risk of graft dysfunction or failure in myelofibrosis patients after allogeneic transplantation.

Second allogeneic stem cell transplantation in myeloid malignancies.

For patients with myeloid malignancies who relapse after allogeneic stem cell transplantation (allo-SCT), one salvage option is a second SCT. We retrospectively analyzed outcomes of the second allo-SCT in 25 patients who received at least 2 allografts from related/unrelated donors due to relapse of acute myeloid leukemia, myelodysplastic syndrome or myelofibrosis after the first SCT. A minority of the acute myeloid leukemia/myelodysplastic syndrome patients had reached complete hematological remission before the second SCT (6/25, 24%). Reduced conditioning strategies were performed in the majority (n = 23). Complete remission was achieved in all 21 cases with available data after the second SCT, but relapse was seen in 11/25 patients (44%). After a median follow-up of 18 months (range 6-47), 8/25 patients (32%) were still alive, and of those, 6 (24%) were in stable remission. In 9 cases mortality was associated to relapse and in 8 cases to transplant-related causes (treatment-related mortality; 8/25, 32%). In conclusion, a second SCT offers the chance of stable remission for some patients relapsing with a myeloid malignancy after a first allo-SCT, although high treatment-related mortality and relapse rates remain a problem. Efforts should concentrate on an optimization of conditioning strategies, immunosuppression and post-transplant surveillance for this specific situation.

Safety of conditioning agents for allogeneic haematopoietic transplantation.

Allogeneic stem cell transplantation (allo-SCT) for haematological malignancies became a safer approach in recent years, for example, owing to improved supportive strategies. However, despite the efficacy of the procedure, morbidity and mortality mainly caused by infections and organ toxicity remain serious problems. Due to the variety of conditioning regimens being applied before allo-SCT, one important aspect is represented by the toxicity profiles of the specific compounds, which are being applied for the reduction of the leukaemia cell load and for immunosuppression. This is being illustrated by the hepatotoxic profile of busulfan with its high rate of veno-occlusive disease. However, recent advances in our understanding of drug metabolism, progress in the measurement of drug concentration, and the invention of some new drugs and therapeutic approaches in the conditioning period are promising steps in achieving more safety for patients undergoing allo-SCT. Reduced-intensity conditioning concepts allow the inclusion of heavily pretreated patients or patients with severe co-morbidities in transplantation concepts. New prophylactic regimens, including poly- or monoclonal antibodies, result in reduced rates of graft-versus-host disease, and some 'new' drugs such as treosulfan or clofarabine widen the range of available conditioning regimens for specific situations.

Characterisation of extramedullary relapse in patients with chronic myeloid leukemia in advanced disease after allogeneic stem cell transplantation.

Recently, higher extramedullary relapse rates following allogeneic stem cell transplantation (SCT) in myeloid malignancies were reported e.g. because of selection of poor-risk patients. We analysed five consecutive patients with post-transplant extramedullary relapse of chronic myeloid leukemia (CML) out of a total of 24 patients (21%) undergoing allo-SCT. All five patients with extramedullary relapse had clonal evolution and a history of blast phase (BP). In particular, 56% of the patients in BP had extramedullary relapse with no extramedullary relapse in patients with chronic/accelerated phase. Most frequent manifestation sites were the skeletal system, the muscles/subcutaneous tissue and the central nervous system. In one case chloroma was mimicking myositis of the lower limbs. Combined approaches were performed including irradiation (n = 4), chemotherapy (n = 2), IM (n = 2), dasatinib (n = 4), nilotinib (n = 1), a novel aurora-kinase-inhibitor (n = 1), donor lymphocytes (n = 2) or a second allo-SCT (n = 2). Transient response was achieved in one case, stable partial remissions in two cases, whereas two cases were refractory. Research should focus on prospective studies aiming to improve treatment of extramedullary relapse in stem cell recipients with CML with a special focus on the role of second generation tyrosine kinase inhibitors.

Quantitative monitoring of NPM1 mutations provides a valid minimal residual disease parameter following allogeneic stem cell transplantation.

BACKGROUND: Minimal residual disease (MRD) diagnostics in acute myeloid leukemia (AML) gain increasing importance after allogeneic stem cell transplantation (SCT). Nucleophosmin (NPM1) mutations, with their high frequency in AML, were suggested to represent suitable MRD markers, but so far no study has evaluated their usefulness in the posttransplantation period. MATERIALS AND METHODS: We evaluated the validity of this MRD marker in the posttransplantation period in a cohort of 13 patients with an NPM1A mutation (NPM1Amut). For this most frequent NPM1A subtype, quantitative real-time polymerase chain reaction (qPCR) was retrospectively performed on bone marrow/peripheral blood samples that had been taken before and after SCT. RESULTS: NPM1Amut was retrospectively followed up in 13 patients who received 14 transplantations. One-hundred and thirty-nine qPCR analyses were performed (median: 7 time points; median follow-up: 216 days; range, 35-1825 days). After SCT, 10 of 14 NPM1Amut cases (71%) became PCR-negative, of which four achieved stable remissions. All four patients (29%) who remained NPM1Amut-positive after SCT relapsed. In all nine relapse cases, increases of NPM1Amut were seen that preceded morphological relapse and the decrease of molecular chimerism with mean intervals of 24 days (range, 12-38 days) and 15 days (range, 1-36 days), respectively. CONCLUSIONS: Quantitative assessment of NPM1Amut seems to provide a reliable MRD marker in the posttransplantation period, predicting relapse earlier than morphology or molecular chimerism, which should be confirmed in larger studies.

Allogeneic stem cell transplantation in acute myeloid leukemia: establishment of indications on the basis of individual risk stratification.

INTRODUCTION: Acute myeloid leukemia (AML) is a heterogeneous disorder with subtypes that differ considerably in morphology and in their underlying chromosomal and molecular aberrations, which, in turn, determine their prognosis. The establishment of the indications for allogeneic stem cell transplantation (SCT) therefore requires individualized risk stratification based on a combination of multiple diagnostic methods, including cytogenetic and molecular genetic studies, and immunophenotyping, as well as the sensitivity of the disease to chemotherapy. METHODS: This article surveys the current strategies for establishing the indications for SCT in AML on the basis of a selective review of the relevant literature in the Medline database. RESULTS: In patients with a high risk constellation-e.g., chromosome 7 anomalies, complex aberrations, or FLT3-length mutations-there is an indication for SCT in first remission. The balanced translocations t(15;17) and t(8;21), and the inversion inv(16) are prognostically favorable and are thus not considered an indication for SCT in first remission. The establishment of indications for stem cell transplantation also depends on the residual leukemic cell burden (minimal residual disease, MRD) as determined by the quantitative polymerase chain reaction or by flow cytometry, as well as an insufficient response to induction chemotherapy. Reduced-dose conditioning, a new technique that lessens acute toxicity, has been found to be associated with a 30% to over 50% two-year survival rate when used in the treatment of chemotherapeutically unresponsive or relapsing AML. DISCUSSION: The indications for allogeneic SCT in AML should be further refined by more investigation in large studies.

Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma.

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0.001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0.001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0.03) and platelets (P = 0.02) and in a lower incidence of acute graft versus host disease (GvHD) grades II-IV (24% vs. 47%, P = 0.06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0.001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12-37%] for ATG vs. 28% (95% CI = 15-55%) for alemtuzumab, P = 0.7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39-75%) vs. 45% (95% CI: 28-73%) and 30% (95% CI: 16-55%) vs. 36% (95% CI: 20-62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2.37; P = 0.05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0.0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma.

Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose-reduced allogeneic stem cell transplantation in patients with multiple myeloma.

We evaluated prognostic factors of melphalan/fludarabine-based dose-reduced allografts in patients with multiple myeloma. From 1998 to 2002, 120 patients with multiple myeloma were treated with melphalan/fludarabine followed by allogeneic stem cell transplantation. The cumulative risk at 1 year for treatment-related mortality (TRM) was 18% (95% confidence interval [CI], 12%-28%). In a multivariate analysis, relapse after prior high-dose chemotherapy was the most significant risk factor for TRM (hazard ratio [HR], 2.80; 95% CI, 1.16-6.74; P =.02), relapse (HR, 4.14; 95% CI, 2.04-8.38; P <.001), event-free survival (HR, 3.11; 95% CI, 1.77-5.46; P <.001), and overall survival (HR, 2.69; 95% CI, 1.35-5.35; P =.005). In addition, relapse was also significantly diminished by chronic graft-versus-host disease (GVHD) in a time-dependent Cox model (HR, 0.37; 95% CI, 0.16-0.87; P =.02). At transplantation, 8% of the patients were in complete remission, whereas 27% had progressive disease. After allografting, 49% achieved complete remission, and 38% achieved partial remission. In a subgroup of patients with chemosensitivity at transplantation and no relapse after prior high-dose chemotherapy who underwent transplantation with peripheral blood stem cells (n = 46), the cumulative risk of TRM at 1 year was only 8% (95% CI, 1%-54%). The 2-year estimated event-free and overall survival was 60% (95% CI, 42%-78%) and 75% (95% CI, 59%-91%), respectively, for related donors (n = 34) and was 81% (95% CI, 59%-100%) and 92% (95% CI, 76%-100%), respectively, for unrelated donors (n = 12).

Dose-reduced conditioning regimen followed by allogeneic stem cell transplantation in patients with myelofibrosis with myeloid metaplasia.

Three patients with myelofibrosis received allogeneic stem cell transplantation after a dose-reduced conditioning regimen of busulphan (8 mg/kg), fludarabine (180 mg/m2) and antithymocyte globulin (4 x 10 mg/kg). The median age at transplantation was 51 years (range 44-58). All patients engrafted with a leucocyte count > 1.0 x 10(9)/l after a median of 18 d (range 16-20). Grade II acute skin graft-versus-host disease (GvHD) occurred in one patient. One limited and one extensive chronic GvHD was observed. All patients achieved complete haematological remission. In one patient the fibrosis resolved completely 180 d post transplant. All patients are alive 126, 466 and 764 d after transplantation.