Tatjana Zabelina

Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m(2))-based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P = .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P = .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio = 2.70; P = .02) and human leukocyte antigen-mismatched donor (hazard ratio = 3.04; P = .006) remained significant factors for survival. The study was registered at www.clinicaltrials.gov as #NCT 00599547.

Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis

A prospective pilot study was performed to evaluate the effect of reduced‐intensity conditioning with busulphan (10 mg/kg), fludarabine (180 mg/qm) and anti‐thymocyte globulin followed by allogeneic stem cell transplantation from related (n = 8) and unrelated donors (n = 13) in 21 patients with myelofibrosis. The median age of the patients was 53 years (range, 32–63). No primary graft failure occurred. The median time until leucocyte (>1·0 × 109/l) and platelet (>20 × 109/l) engraftment was 16 (range, 11–26) and 23 d (range, 9–139) respectively. Complete donor chimaerism on day 100 was seen in 20 patients (95%). Acute graft‐versus‐host disease (GvHD) grades II–IV and III/IV occurred in 48% and 19% of cases and 55% of the patients had chronic GvHD. Treatment‐related mortality was 0% at day 100 and 16% [95% confidence interval (CI): 0–32%] at 1 year. Haematological response was seen in 100% and complete histopathological remission was observed in 75% of the patients and 25% of the patients showed partial histopathological remission with a continuing decline in the grade of fibrosis. After a median follow‐up of 22 months (range, 4–59), the 3‐year estimated overall and disease‐free survival was 84% (95% CI: 67–100%).

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.

Hematopoietic stem-cell transplantation from unrelated donors in elderly patients (age>55 years) with hematologic malignancies: older age is no longer a contraindication when using reduced intensity conditioning

Allogeneic stem cell transplantation (SCT) is a potentially curative approach for patients with hematological malignancies. Reduced-intensity conditioning regimens allow SCT in elderly patients; however, there are only limited data on the feasibility and outcomes of unrelated donor SCT in these patients. In this study, we analyzed, retrospectively, data of 36 patients with various hematological malignancies and median age 58 years (range, 55–66), who were given unrelated donor SCT after reduced-intensity conditioning. The preparative regimen consisted of fludarabine combined with oral busulfan (8 mg/kg, n=8), intravenous busulfan (6.4 mg/kg, n=11), treosulfan (30 g/m2, n=5) or melphalan (100–150 mg/m2, n=12). Patients were also given serotherapy, ATG (n=32), or alemtuzumab (n=4). The probabilities of overall survival, disease-free survival, and nonrelapse mortality at 1 year after SCT were 52, 43, and 39%, respectively. Acute graft-versus-host disease (GVHD) grade II–IV and chronic GVHD occurred in 31 and 45%, respectively. Multivariable analysis determined that survival rates were higher in patients with chemosensitive disease (HR 4.5), and patients conditioned with intravenous busulfan or treosulfan (HR 3.9). Unrelated donor SCT is feasible in elderly patients, with outcomes that are similar to younger patients. Favorable outcome was observed in patients with myeloid malignancies, and those transplanted in remission and early in the course of disease. Age alone should not be considered a contraindication to unrelated donor SCT.

Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis

Allogeneic stem cell transplantation (ASCT) after reduced-intensity conditioning has become a reasonable treatment option for patients with advanced myelofibrosis. The role of characteristic molecular genetic abnormalities, such as JAK2V617F on outcome of ASCT, is not yet elucidated. In 139 of 162 myelofibrosis patients with known JAK2V617F mutation status who received ASCT after reduced-intensity conditioning, the impact of JAK2 genotype, JAK2V617F allele burden, and clearance of mutation after ASCT was evaluated. Overall survival was significantly reduced in multivariate analysis in patients harboring JAK2 wild-type (hazard ratio = 2.14, P = .01) compared with JAK2 mutated patients. No significant influence on outcome was noted for the mutated allele burden analyzed either as continuous variable or after dividing into quartiles. Achievement of JAK2V617F negativity after ASCT was significantly associated with a decreased incidence of relapse (hazard ratio = 0.22, P = .04). In a landmark analysis, patients who cleared JAK2 mutation level in peripheral blood 6 months after ASCT had a significant lower risk of relapse (5% vs 35%, P = .03). We conclude that JAK2V617F-mutated status, but not allele frequency, resulted in an improved survival and rapid clearance after allografting reduces the risk of relapse.

Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation

We report the results of 84 patients with ALL after related (n=46) or unrelated (n=38) allogeneic SCT. Mean recipient age was 23 years (range: 1–60) and median follow-up was 18 months (range: 1–133). Forty-three patients were transplanted in CR1; 25 in CR2 or CR3; four were primary refractory; four in PR; eight in relapse. The conditioning regimen consisted of TBI/VP16/CY (n=76), TBI/VP16 (n=2), TBI/CY (n=2), Bu/VP16/CY (n=4). The OS at 3 years was 45% (44% unrelated, 46% related). Univariate analysis showed a significantly better OS for patients <18 years (P=0.03), mismatched sex-combination (P=0.03), both with a stronger effect on increasing OS after unrelated SCT. Factors decreasing TRM were patient age <18 years (P=0.004), patient CMV-seronegativity (P=0.014), female recipient (P=0.04). There was no significant difference in TRM and the relapse rate was similar in both donor type groups. Multivariate analysis showed that factors for increased OS which remained significant were mismatched sex-combination (RR: 0.70,95% CI: 0.51–0.93, P=0.015), patient age < 18 years (RR: 0.66, 95% CI: 0.47–0.93, P=0.016). A decreased TRM was found for female patients (RR: 0.56, 95% CI: 0.33–0.98, P=0.042), negative CMV status of the patient (RR: 0.57, 95% CI: 0.36–0.90, P=0.015). Unrelated stem cell transplantation for high-risk ALL patients with no HLA-compatible family donor is justifiable.

Post-transplant immunotherapy with donor-lymphocyte infusion and novel agents to upgrade partial into complete and molecular remission in allografted patients with multiple myeloma.

OBJECTIVE To investigate post-transplant immunotherapy with escalating donor-lymphocyte infusions (DLI) and novel agents (thalidomide, bortezomib, and lenalidomide) to target complete remission (CR). MATERIALS AND METHODS Thirty-two patients with multiple myeloma who achieved only partial remission after allogeneic stem cell transplantation were treated with DLI. If no CR was achieved, one of the novel agents was added to target CR. RESULTS CR defined either by European Group for Blood and Marrow Transplantation criteria, flow cytometry, or molecular methods as assessed by patient-specific immunoglobulin H-polymerase chain reaction or plasma cell chimerism polymerase chain reaction was accomplished in 59%, 63%, and 50% of patients, respectively. Achievement of CR resulted in improved 5-year progressive-free and overall survival, according to European Group for Blood and Marrow Transplantation criteria (53% vs 35%; p=0.03 and 90% vs 62%; p=0.06), flow cytometry (74% vs 15%; p=0.001 and 100% vs 52%; p=0.1), or molecular methods (84% vs 38%; p=0.001 and 100% vs 71%; p=0.03). CONCLUSIONS Our finding demonstrates the clinical relevance of posttransplantation therapies to upgrade remission, and of remissions depth for long-term survival in myeloma patients.

Patient cytomegalovirus seropositivity with or without reactivation is the most important prognostic factor for survival and treatment‐related mortality in stem cell transplantation from unrelated donors using pretransplant in vivo T‐cell depletion with anti‐thymocyte globulin

We evaluated the cytomegalovirus (CMV) serostatus as a risk factor for survival and treatment‐related mortality (TRM) in 125 patients allografted from an unrelated donor between 1994 and 1999. All patients received pretransplant in vivo T‐cell depletion using rabbit anti‐thymocyte globulin (ATG). Only one patient had primary graft failure and severe grade III/IV graft‐versus‐host disease occurred in 14% of the patients. The overall survival (OS) at 3 years was 70% for CMV‐negative patients (n = 76) and 29% in the seropositive cohort (n = 49) (P > 0·001). In multivariate analyses, CMV seropositivity remained an independent negative prognostic factor for OS (RR: 2·1; CI: 1·2–3·8; P = 0·014), apart from age > 20 years (RR: 2·74; CI: 1·2–3·8; P = 0·004) and late leucocyte engraftment (RR: 2·4; CI: 1·2–4·9; P = 0·015). The TRM for all patients was 27%. Despite monitoring for CMV antigenaemia and preemptive therapy with ganciclovir when reactivation occurred, seropositive patients had a three times higher risk of fatal treatment‐related complications than seronegative patients. In multivariate analyses, CMV seropositivity remained the strongest independent negative factor for TRM (RR: 5·3; CI: 1·9–14·6; P = 0·002), followed by age > 20 years (RR: 4·8; CI: 1·3–18·1; P = 0·02) and delayed leucocyte engraftment (RR: 3·6; CI: 1·2–11; P = 0·02). The TRM was identical in seropositive patients with (n = 27) or without (n = 22) CMV reactivation (44% versus 50%). We conclude that CMV seropositivity, despite preemptive ganciclovir therapy and even without reactivation, is a major negative prognostic factor for survival as well as for TRM in unrelated stem cell transplantation using pretransplant in vivo T‐cell depletion with ATG.

Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS)

We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation (SCT) in 26 patients with secondary AML or MDS. Twenty patients were transplanted from matched or mismatched unrelated donors and six from HLA-identical sibling donors. The median age of the patients was 60 years (range, 44–70). None of the patients was eligible for a standard myeloablative preparative regimen. No graft-failure was observed, and leukocyte and platelet engraftment were observed after a median of 16 and 17 days, respectively. Acute graft-versus-host disease (GvHD) grade II–IV was seen in 23% and severe grade III GvHD in 12% of the patients. No patients experienced grade IV acute GvHD. Chronic GvHD was noted in 36% of the patients, which was extensive disease in 18%. The 2-year cumulative incidence of relapse was 21%. The relapse rate was higher in patients beyond CR1 or with intermediate two or high risk MDS (P=0.02). The treatment-related mortality at day 100 was 28%. The 2-year estimated overall and disease-free survival was 36–34%, respectively. No difference in survival was seen between unrelated and related SCT.

Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

Summary. We report the results of 50 allogeneic transplantations from related (n = 43) or unrelated (n = 7) donors, performed for chronic myelomonocytic leukaemia (CMML) in 43 European centres. The median age at transplant was 44 years (range 19–61). Eighteen patients had excess blasts ranging from 5% to 30% at the time of transplantation. Two graft failures were observed (4%). Neutrophil (> 0·5 × 109/l) and platelet engraftment (> 50 × 109/l) was reached after a median of 17 d (range 11–38) and 27 d (range 11–48) respectively. Acute graft‐versus‐host disease (GvHD grade II–IV was seen in 35% of patients, while 20% developed severe‐acute GvHD grade III/IV. Twenty‐six patients (52%) died of treatment‐related causes. After a median follow‐up of 40 months (range 11–110), the 5‐year‐estimated overall survival was 21% (95% CI: 15–27%) and the 5‐year‐estimated disease‐free survival (DFS) was 18% (95% CI: 13–23%). Earlier transplantation in the course of disease, male donor, use of unmanipulated grafts, allogeneic transplantation and occurrence of acute GvHD favoured better DFS, but did not reach statistical significance. The 5‐year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute GvHD grade II–IV (24% vs 54%; P = 0·07), and for a higher relapse rate in patients with T cell‐depleted grafts (62% vs 45%), suggesting a ‘graft‐versus‐CMML effect’.