D Heim

The probability of identifying a 10/10 HLA allele-matched unrelated donor is highly predictable

Identification of an unrelated HLA allele-matched hematopoietic stem cell (HSC) donor is a costly and time-consuming procedure. To improve search logistics, we have limited the search period to 6 months and have introduced a probability estimate of the chances of identifying a 10/10 HLA allele-matched donor. Probabilities were classified as high (>95%), intermediate (50%) and low (<5% chance) based on allele and haplotype frequencies. By analyzing 350 consecutive searches between 2002 and 2005 (1719 donors tested), the probability estimates turned out to be correct for 96% (high), 88% (low) and 56% (intermediate) patients. For searches with a high probability of success, at least one of the 10 most frequent haplotypes in Caucasoids was found in 69% of the patients, but in only 11% of the patients with a low-probability estimate (P<0.00001). Survival probability at 3 years was significantly higher for HSCT patients classified with a high-probability estimate when compared to patients in the intermediate/low-probability groups (74 vs 51 and 54% respectively, P=0.01). The same difference in survival probabilities was observed when only 10/10 matched unrelated HSCT patients were analyzed. In the intermediate-/low-probability groups, patients with alternative (haploidentical, autologous) or mismatched unrelated donors had similar survival estimates. Probability prediction is therefore feasible in the search process for unrelated donors and can guide the therapeutic strategy.

Order of application and liver toxicity in patients given BU and CY containing conditioning regimens for allogeneic hematopoietic SCT

BU–CY is the established non-TBI-based myeloablative conditioning regimen for allogeneic hematopoietic SCT. However, liver toxicity and hepatic veno-occlusive disease (VOD) are frequent life-threatening complications. Pharmacological considerations suggest that BU can trigger toxicity of subsequent CY. Recent animal data confirmed this hypothesis. Less liver toxicity and better outcomes were observed when mice were treated with the reversed order of CY and BU. We analyzed in this study liver toxicity and outcome in patients receiving BU–CY (16 patients) or CY–BU (59 patients). Liver function differed significantly with higher levels of liver function tests between day +10 and +30, and a higher cumulative incidence of VOD in the BU–CY cohort (2/16 (12.5%) vs 0/59 (0%), P=0.006). TRM was significantly higher in patients receiving BU–CY (cumulative incidence BU–CY 45%, CY–BU 17%, P=0.02), without yet translating into a significant survival difference (incidence for survival: BU–CY 38%, CY–BU 63%; hazard ratio 1.19 for BU–CY, 95% confidence interval 0.29–4.82, P=0.80). Rates of engraftment and relapse were not different. These data support the concepts derived from animal models in favor of CY–BU compared with traditional BU–CY and form the basis for prospective controlled comparisons.

High stem cell dose will not compensate for T cell depletion in allogeneic non-myeloablative stem cell transplantation.

The best strategies for non-myeloablative stem cell transplants (NST) are not known. We hypothesized that a high stem cell dose and post-transplant donor lymphocyte infusions (DLI) in a T cell-depleted NST setting may result in stable engraftment without severe GvHD. We used conditioning with 200u2009mg/kg cyclophosphamide, and ATG, a high peripheral stem cell dose of >10u2009×u2009106 CD34+ cells/kg, T cell-depleted to <1u2009×u2009105 CD3+ cells/kg followed by incremental DLI. Ten patients, 53 (42–61) years of age with hematological malignancy (CML in 3, MDS in 2, myeloma in 3 and CLL in 2) were included. All patients achieved initial engraftment, at a median 13.5 (10–20) days. Three patients achieved complete chimerism, four achieved a complete hematologic remission. In seven patients the graft ultimately failed. Acute GvHD grade II was seen in three patients after DLI. At a median follow-up of 28 months (range 15–35), eight patients are alive, none died of treatment-related complications. NST with T cell depletion to prevent GVHD results in a high graft failure rate. High stem cell dose (⩾10u2009×u2009106 CD34+cells/kg) and post-transplant DLI will not compensate for the lack of T cells to ensure stable engraftment.

Large Granular Lymphocyte Expansion after Allogeneic Hematopoietic Stem Cell Transplant Is Associated with a Cytomegalovirus Reactivation and Shows an Indolent Outcome

Expansions of CD3+ large granular lymphocytes (LGLs) after allogeneic hematopoietic stem cell transplantation (HSCT) have been described. We sought to evaluate incidence, characteristics, and clinical significance of persistent T cell (T-)LGL after HSCT. Fourteen of 215 recipients (7%) were diagnosed with LGL expansions. Thirteen showed a CD3+/CD8+ immunophenotype, 5 of them with clonal TCR-γ rearrangement. The lymphocytes appeared at a median of 16 months (range, 3-58 months) after HSCT and lasted for a median time of 31 months (range, 2-179 months). Cytomegalovirus (CMV) reactivation (P =xa0.001) and acute graft-versus-host disease (aGVHD) were associated with LGL expansion (P =xa0.02). In the multivariate analysis, only CMV reactivation showed a significant association with T-LGL expansion (relative risk [RR]: 5.063; 95% confidence interval [CI]: 1.586-16.160; P = .006). The observed posttransplantation LGL expansions, even if monoclonal, showed a chronic, indolent course. Our data indicate that such expansions may be considered as an expression of chronic stimulation, triggered by CMV reactivation rather than a malignant transformation.

Combination therapy for multidrug-resistant cytomegalovirus disease.

Multidrug‐resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV‐seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV‐seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re‐transplantation from a CMV‐seropositive donor supported by adoptive transfer of pp65‐specific T cells and maribavir was followed by lasting suppression. This case illustrates that successful MDR CMV therapy may require individualized multidisciplinary approaches.

Cyclosporine levels and rate of graft rejection following non-myeloablative conditioning for allogeneic hematopoietic SCT.

Hematopoietic SCT (HSCT) after non-myeloablative conditioning is associated with reduced TRM, and increased risk of graft rejection. Although preclinical data have shown the importance of post transplant immunosuppression in achieving engraftment, little is known about the role of CSA in the clinical setting of non-myeloablative transplantation. In a retrospective analysis of patients treated with allogeneic HSCT after fludarabine and 2u2009Gy TBI, 15 of 77 evaluable patients (20%) experienced primary (n=2) or secondary graft rejection at a median of 66 days post transplant. Mean day 1–28 CSA trough levels were inversely associated with day 28 chimerism (median 99, 85 and 70% for mean CSA <300, 300–600 and >600u2009ng/mL, respectively; P=0.003). A similar association was observed for the cumulative incidence of graft rejection, which occurred in 8% (<300u2009ng/mL), 26% (300–600u2009ng/mL) and 50% (>600u2009ng/mL, P=0.005) of patients. The detrimental effect of high CSA levels on engraftment was confirmed in multivariable models and was found to operate comparably in sibling and unrelated donor transplants. Impairment of donor T-cell function by high serum levels of CSA might account for this finding, which should be verified in a larger patient group to better understand the role of CSA in non-myeloablative transplantation.

Sideroblastic changes of the bone marrow can be predicted by the erythrogram of peripheral blood

The diagnosis of sideroblastic anemia is based on bone marrow aspiration, and the detection of ring sideroblasts (RS) in iron staining. The finding of laboratory parameters to approach this diagnosis still remains a great challenge. In this study, we analyzed the value of a specific erythrogram pattern from peripheral blood, produced by the ADVIA®120 cell counter, to predict sideroblastic changes in the bone marrow. In a two step‐design study, we first showed that 32/38 consecutive patients reporting ≥15% RS had such a pattern in the erythrogram. In the second step, we prospectively identified over a period of 32u2003months 21 patients with this typical erythrogram; 20/21 had ≥15% RS in the bone marrow. Hence, by this validation, we confirm that the erythrogram is highly predictive of RS in the bone marrow. The interpretation of the erythrogram should become daily practice in hematology to improve the efficacy to detect sideroblastic changes.

Double allogeneic hematopoietic SCT as a rescue therapy for poor-risk hematological malignancies

The prognosis of patients with poor-risk or relapsed hematological malignancies is dismal. The dose intensification necessary to achieve subsequent CR is limited by the toxicity of chemotherapy. Treatment intensification with double allogeneic HSCT (dHSCT) may enhance the antileukemic effect and reduces treatment-related toxicity associated with prolonged aplasia during reinduction. We evaluated this approach in 23 patients, nine with primary refractory disease or relapse after conventional chemotherapy (group I) and 14 with relapses after allogeneic HSCT (group II). Double HSCT was feasible in all patients. At the end of the observation period, 6 of 23 (26%) patients were still alive and in remission with a median observation time of 60 months (1–153). The overall survival probability at 1 year was 41% (95% confidence interval (CI), 21–62%), transplant-related mortality (TRM) 28% (9–47%) and the incidence of relapse 42% (18–66%). The TRM in groups I and II were 22 and 36% and the relapse rate 33 and 50%, respectively. In conclusion, we have shown the feasibility of dHSCT with an acceptable TRM, irrespective of a previous allogeneic HSCT. Whether this approach offers a survival benefit for patients with poor-risk leukemias has to be tested in larger prospective trials.

High-dose melphalan with or without stem cell support before myeloablative allo-SCT for remission induction in patients with advanced relapsed or refractory AML.

Treatment strategies for relapsed/refractory AML are limited and disappointing. Recently, high-dose melphalan (HDM) chemotherapy and autologous hematopoietic SCT (HSCT) has been proposed for AML re-induction. We investigated the impact of HDM remission induction in highly advanced relapsed/refractory AML patients planned for allogeneic HSCT. A total of 23 patients with relapsed/refractory AML were prospectively scheduled for HDM with or without stem cell support followed by myeloablative allogeneic HSCT. Patients included nine individuals with a history of previous HSCT (seven allogeneic, two autologous). A total of 18 patients (78%) achieved a leukemia-free state and an additional four had substantial reduction of the initial leukemia burden warranting treatment continuation. There were no differences between patients with or without immediate stem cell support regarding mucositis or other organ toxicity. A total of 20 patients proceeded to myeloablative allogeneic HSCT. Outcome of allogeneic HSCT was poor: 11 patients (55%) relapsed, 7 patients (35%) died from TRM and only 2 patients (10%) were alive at the last follow-up. Our study shows that HDM is effective in inducing a leukemia-free state in patients with highly advanced relapsed/refractory AML. Leukemia burden reduction with HDM, however, did not translate into improved OS.

Inability to work and need for disability pension among long-term survivors of hematopoietic stem cell transplantation

Return to work is critical goal following HSCT. However, late effects may impede return to normal activity after HSCT. In the case of inability to work, patients may need a work disability pension to ensure a reasonable livelihood. This study evaluated inability to work and need for disability pension among long-term survivors and analyzed possible determinants of need for social support. This retrospective, single-center study included all HSCT patients surviving ⩾5 years seen at the outpatient clinic between January 2013 and August 2015. There were 203 patients, median age at HSCT 35 years, and 50 years at time of study; median time between HSCT and study control was 12 years; 178 had allo-HSCT, 187 had a malignant disease. At time of study, 156 (77%) were working full or part-time, 47 (23%) were not working. In total, 76 (37%) survivors were receiving a work disability pension compared to 3.17% of the Swiss working population. Patients with a disability pension were significantly older at HSCT, were more often living alone, had more active physical and mental late effects, and higher score of fatigue compared to patients without. These findings underline the importance of screening for employment and the social consequences of non-employment in long-term survivors after HSCT.