Leukemia In First Chronic Phase Research Articles

De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial

All studies of treatment-free remission (TFR) in patients with chronic myeloid leukaemia have discontinued tyrosine kinase inhibitor (TKI) treatment abruptly and have focussed on patients with stable MR4 (BCR-ABL to ABL ratio ≤0·01%). We aimed to examine the effects of gradual treatment withdrawal and whether TFR is feasible for patients with less deep but stable remission. The De-Escalation and Stopping Treatment with Imatinib, Nilotinib, or sprYcel (DESTINY) study is a non-randomised, phase 2 trial undertaken at 20 UK hospitals. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase, who had received TKI therapy for 3 years or more, with three or more BCR-ABL quantitative PCR transcript measurements (BCR-ABL to ABL1 ratio) less than 0·1% (major molecular response [MMR]) in the 12 months before entry. Patients with all PCR measurements less than 0·01% were assigned to the MR4 group. Patients with results between 0·1% and 0·01% were allocated to the MMR group. TKI treatment was de-escalated to half the standard dose for 12 months, then stopped for a further 24 months, with frequent PCR monitoring. Recurrence was defined as the first of two consecutive samples with PCR measurement greater than 0·1%, which required treatment recommencement at full dose. The primary endpoint was the proportion of patients who could first de-escalate their treatment for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. Treatment at entry was imatinib (n=148), nilotinib (n=16), or dasatinib (n=10), for a median of 6·9 years (IQR 4·8-10·2). Between Dec 16, 2013, and May 6, 2015, we enrolled 49 patients into the MMR group and 125 into the MR4 group. In the MR4 group, 84 (67%) patients reached the 36-month trial completion point and recurrence-free survival was 72% (95% CI 64-80). In the MMR group, 16 (33%) entrants completed the study and recurrence-free survival was 36% (25-53). No disease progression was seen and two deaths occurred due to unrelated causes. All recurrences regained MMR within 5 months of treatment resumption. Initial de-escalation before discontinuation might improve the success of TFR protocols, although the mechanism of its benefit is not yet clear. The findings also suggest that TFR merits further study in patients with stable MMR. Newcastle University and Bloodwise.

Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents.

The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year progression-free survival rate was 92% (95% CI: 87%–94%) and the 5-year survival accounting for chronic myeloid leukemia deaths was 97% (95% CI: 94%–99%). Of the 309 patients allocated to low (n=199), intermediate (n=68) and high (n=42) risk groups by the EUTOS Long-Term Survival score, events (progression and/or death) occurred in 6.0%, 8.8% and 26.2%, respectively. Estimates of the 5-year progression-free survival rates according to these three risk groups were 96% (95% CI: 92%–98%), 88% (95% CI: 76%–95%) and 67% (95% CI: 48%–81%), respectively. Differences in progression-free survival according to these risk groups were highly significant (P<0.0001, overall). The EUTOS Long-Term Survival score showed better differentiation of progression-free survival than the Sokal (<45 years), Euro and EUTOS scores in children and adolescents with chronic myeloid leukemia and should be considered in therapeutic algorithms. (Trial registered at: www.clinicaltrials.gov NCT01281735)

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial

Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4. We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio <0·01%; MR4 cohort) or in stable MMR (BCR-ABL1:ABL1 ratio consistently <0·1%) but not MR4 (MMR cohort) for 12 months or longer. Participants received half their standard TKI dose (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) for 12 months. Molecular recurrence was defined as loss of MMR (BCR-ABL1:ABL1 ratio >0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2-4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5-28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04-0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib. TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted. Newcastle University and Bloodwise.

Cytomegalovirus (CMV) Serostatus: High Importance of Choosing Seropositive Donors for Seropositive Patients When Using Rabbit Antithymocyte Globulin (ATG)

Introduction: In published studies that included mostly hematopoietic cell transplants (HCTs) not using in vivo T cell depletion by ATG, there is a substantial survival difference between D-R- and D+R- patients, and a very small or no survival difference between D-R+ and D+R+ patients. We set out to determine the impact of donor CMV serostatus on survival after HCTs using ATG.Methods: A total of 919 patients underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014, with a uniform graft versus host disease (GVHD) prophylaxis using ATG (4.5 mg/kg given between day -2 and 0) in addition to methotrexate and cyclosporine. Monitoring for CMV reactivation was performed until at least day 100 after transplant using pp65 antigenemia (before 2008) or CMV DNAemia by quantitative polymerase chain reaction (since 2008). Preemptive therapy typically with ganciclovir was started whenever pp65 antigenemia exceeded 10 to 20 positive cells/200,000 granulocytes or CMV DNAemia exceeded 25,000 IU/mL plasma. Significance of survival difference between patient groups was tested using Cox proportional hazards analysis. Significance of difference in nonrelapse mortality (NRM) or cumulative incidence of relapse (CIR) was tested using Fine-Gray analysis (nonrelapse death was a competing risk of relapse and vice versa, in addition to graft failure and second malignancy). In all analyses, covariates included patient age (>45 vs ≤45), disease stage (acute leukemia in first remission, chronic myeloid leukemia in first chronic phase and myelodysplasia with <5% marrow blasts were considered good risk, all others poor risk), graft type (marrow vs PBSCs) and donor type (human leucocyte antigen [HLA] matched sibling vs other [typically matched unrelated]).Results: D-R- and D+R- patients had similar survival (no significant difference) (blue vs orange curve, figure 1). D-R+ patients had a substantially lower survival than D+R+ patients with an estimated 5 year survival of 41% versus 60% respectively (Hazard Ratio [HR], 1.6; P = 0.001; 95% confidence interval[CI], 1.22-2.09) (red vs green curve, figure 1). This was due to higher NRM (sub hazard ratio [SHR], 1.76; P = 0.003; 95% CI, 1.212-2.58), not CIR. This appeared to be due to higher GVHD-associated mortality. We then compared D-R+ HLA matched sibling transplants with D+R+ HLA matched unrelated donor transplants to assess whether for a CMV seropositive patient with a CMV seronegative HLA matched sibling, search for a CMV seropositive HLA matched unrelated donor could be justified. D-R+ HLA matched sibling transplant recipients had a substantially lower survival than D+R+ 8/8 HLA allele matched unrelated donor transplant recipients with an estimated 5 year survival of 45% versus 66% respectively (HR, 1.7, P = 0.01, 95% CI, 1.10-2.89) (green vs orange curve, figure 2). This suggests that in the scenario of a seropositive patient with a seronegative matched sibling, unrelated donor search is justified.Conclusion: Contrary to recommendations for HCTs not using ATG, choosing a seronegative donor for a seronegative patient is unimportant, whereas choosing a seropositive donor for a seropositive patient is very important (~20% absolute 5 year survival gain). Even if a seronegative HLA matched sibling donor is available for a seropositive patient, it is better to select a seropositive HLA matched unrelated donor. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lower Transplant-Related Mortality and Improved Survival for Patients with AML in First CR Receiving BuCy Compared to Cy/TBI As Myeloablative Preparation for Allogeneic Transplantation: A Report From the Center for International Blood and Marrow Transplant Research (CIBMTR)

AbstractAbstract 217 Background:The most widely used myeloablative preparative regimens for allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies consist of cyclophosphamide in combination with total body irradiation (Cy/TBI) or with orally or intravenously (IV) administered busulfan (BuCy). The relative advantages and shortcomings of these regimens have been debated for more than 25 years, but definitive conclusions regarding their comparative effectiveness and limitations are lacking. Patients and Methods:Using data from the CIBMTR we retrospectively analyzed all patients who underwent first allo-HCT from a human leukocyte antigen (HLA)-matched sibling or adult unrelated donor from 2000 through 2006 for Chronic Myeloid Leukemia in first chronic phase or Acute Myeloid Leukemia (AML) in first complete remission following preparation with Cy/TBI or BuCy. Information regarding Bu pharmacokinetics was not collected during the period of study. Results:2284 patients aged 2 to 64 (median 34) years are included: 997 patients received Cy/TBI, 890 oral BuCy and 397 IV BuCy. In univariate analysis of the entire cohort, there were no significant differences in neutrophil recovery, chronic graft versus host disease (GVHD) or relapse between the groups. Platelet recovery occurred more rapidly (P=.002), grades 2–4 acute GVHD and transplant-related mortality (TRM) at 3 years were less frequent, and leukemia-free survival (LFS) and overall survival (OS) at 3 years were superior following IV or oral Bu compared to TBI (P<.001 for all comparisons).In multivariate analysis (adjusted for patient-related (age, gender, and Karnofsky performance score at transplant), disease-related (disease, time from diagnosis to transplant, and cytogenetic risk groups for AML), and HCT-related variables (donor-recipient gender and CMV match, donor and graft type, year of transplant, GVHD prophylaxis, and planned use of growth factors post-HCT)), the lower incidence of grades 2–4 acute GVHD with oral Bu vs. TBI (relative risk [RR] 0.85; 95% confidence intervals [CI] 0.73–0.99), and IV Bu vs. TBI (RR 0.76; 95% CI 0.64–0.91) remained significant. The incidences of chronic GVHD, TRM, and relapse within the first year post HCT did not differ between groups, however, relapse beyond the first year occurred significantly less frequently in those receiving IV(RR 0.39; 95% CI 0.21–0.73), but not oral Bu (RR 1.36; 95% CI 0.99–1.86) compared to TBI. OS was similar among the three groups. However, LFS was superior in patients receiving IV (RR 0.78; 95% CI 0.65–0.93), but not oral Bu (RR 0.97; 95% CI 0.84–1.12), compared to TBI (Figures 1).Multivariate analysis (adjusted for same set of variables listed above) restricted to AML patients only (median age 35, range 2–64 years) revealed less TRM in those receiving oral (n=473; RR 0.75; 95% CI 0.57–0.98) or IV (n=272; RR 0.67; 95% CI 0.49–0.92) Bu compared to those receiving TBI (n=646). Relapse within first year post HCT did not differ between the groups, however, relapse beyond first year occurred significantly less frequently in patients receiving IV (RR 0.26; 95% CI 0.10–0.65), but not oral Bu (RR 1.26; 95% CI 0.84–1.90), compared to TBI. LFS was superior in AML patients receiving IV (RR 0.74; 95% CI 0.59–0.92), but not oral Bu (RR 0.88; 95% CI 0.74–1.06) compared to TBI. OS was superior among AML patients receiving oral (RR 0.80; 95% CI 0.67–0.97) or IV (RR 0.73; 95% CI 0.58–0.91) Bu compared to TBI. Survival was not significantly different between oral and IV Bu (RR 1.10; 95% CI 0.86–1.42) patients (Figures 2). Conclusions:This large retrospective comparison of preparative regimens by the CIBMTR demonstrates a lower incidence of grades 2–4 acute GVHD in patients receiving Cy plus oral or IV Bu compared to TBI. Among the entire cohort, late relapses occurred less often and LFS was superior in patients receiving IV, but not oral Bu, compared with TBI.Among nearly 1400 AML patients, there were fewer late relapses and LFS was superior following IV, but not oral, Bu compared to TBI. TRM occurred less frequently and survival was superior in patients receiving either oral or IV Bu compared to TBI. This large multi-institutional retrospective analysis demonstrates that in patients with AML in first CR, in combination with Cy, Bu is associated with a significantly lower incidence of TRM and superior survival than TBI. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Unrelated donor peripheral blood stem cell transplants incorporating pre‐transplant in‐vivo Alemtuzumab are not associated with any increased risk of significant acute or chronic graft‐versus‐host disease

There is little information published comparing peripheral blood stem cells (PBSC) with bone marrow (BM) as the stem cell source in the long-term outcome in recipients of T-cell depleted (TCD) unrelated donor (UD) transplants. We present retrospective outcome data on 306 recipients of myeloablative, human leucocyte antigen-matched UD allografts using pre-transplant in-vivo Alemtuzumab. Transplants were performed between 2000 and 2007 for chronic myeloid leukaemia in first chronic phase and acute leukaemia in first or second complete remission; 184 patients received BM and 122 PBSC. The median age was 28·9 years (<1-58) and the median follow-up was 48 months. Overall survival at 8 years was 53%. The incidence of acute graft-versus-host disease (GvHD) was significantly higher in PBSC (65%) than BM recipients (49%; P=0·012). This represented only grade 1 GvHD with no difference in grade II-IV aGvHD (BM 23% PBSC 24%). The incidence of chronic GvHD, either overall (BM 47%, PBSC 49%) or extensive (BM 15%, PBSC 13%) was not increased with PBSC. The incidence of relapse, non-relapse mortality and survival were not significantly different. Whilst accepting the limitations of retrospective analyses, we suggest the increased risk of GvHD in recipients of PBSC in T-replete transplants is offset by in-vivo Alemtuzumab, and that either stem cell source can be used with good outcomes in this setting.

Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning

AbstractRisks of secondary solid cancers among allogeneic hematopoietic cell transplant (HCT) recipients who receive conditioning without total body irradiation are not well known. We evaluated the incidence and risk factors for solid cancers after HCT using high-dose busulfan-cyclophosphamide conditioning in 4318 recipients of first allogeneic HCT for acute myeloid leukemia in first complete remission (N = 1742) and chronic myeloid leukemia in first chronic phase (N = 2576). Our cohort represented 22 041 person-years at risk. Sixty-six solid cancers were reported at a median of 6 years after HCT. The cumulative-incidence of solid cancers at 5 and 10 years after HCT was 0.6% and 1.2% among acute myeloid leukemia and 0.9% and 2.4% among chronic myeloid leukemia patients. In comparison to general population incidence rates, HCT recipients had 1.4× higher than expected rate of invasive solid cancers (95% confidence interval, 1.08-1.79, P = .01). Significantly elevated risks were observed for tumors of the oral cavity, esophagus, lung, soft tissue, and brain. Chronic graft-versus-host disease was an independent risk factor for all solid cancers, and especially cancers of the oral cavity. Recipients of allogeneic HCT using busulfan-cyclophosphamide conditioning are at risk for developing solid cancers. Their incidence continues to increase with time, and lifelong cancer surveillance is warranted in this population.

Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. PATIENTS AND METHODS Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen-matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. RESULTS Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). CONCLUSION Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population.

The Kinetics of Transforming Growth Factor beta1 mRNA Expression and Its Serum Concentration in Graft-Versus-Host Disease After Allogeneic Hemopoietic Stem Cell Transplantation for Myeloid Leukemias.

Abstract 4479 IntroductionGraft-versus-host disease (GVHD) remains one of the major complication following allogeneic haematopoietic stem cell transplantation (alloHSCT). Recent data indicates that transforming growth factor beta1 (TGF-β1) may play a role in the development of GVH reaction. Patients and methodsThe study included 40 adult patients who underwent allogeneic bone marrow transplantation for myeloid leukemias between 2001-2004. Twenty four patients were transplanted for acute myeloid leukemia in first complete remission and 16 patients for chronic myeloid leukemia in first chronic phase. 25 patients received stem cells from unrelated donor whereas the donor was sibling for the remaining 15 recipients. Conditioning regimen consisted of busulphan and cyclosphamide (BuCy) and ciclosporin (CyS) and methotrexate (Mtx) were administered for GVHD prophylaxis. In all cases, the expression of TGF-β1 mRNA by real-time quantitive polymerase chain reaction (RT-QPCR) using ABI PRISMTM 7700 (Taqman) and TGF-β1 serum concentration by commercial ELISA were measured fourfold in the peritransplant period (on days: -10, 0, +30 and +100). ResultsAcute GVHD (aGVHD) experienced 20 patients, in 4 patients the symptoms were classified as severe (grades III-IV). Chronic GVHD (cGVHD) occurred in 11 patients (in 4 as a diffuse form). A median TGF-β1 mRNA expression was 7088 copies/μg of total RNA at day -10 before transplant, dropped to 1907 copies/μg of total RNA after conditioning (p<0.005) and then significantly increased on days +30 (p<0.04) and +100 (p<0.003) when compared to the day of transplant (median: 3808 and 7531 copies/μg of total RNA, respectively). A median TGF-β1 serum concentration was 21411 pg/ml at day -10 before transplant, dropped to 8277 pg/ml at the day of transplant (p<0.000063), the low value (median: 12184 pg/ml) was still detected on day +30 (p<0.0026) in comparison to the pretransplant period. A median TGF-β1 serum concentration significantly increased on day +100 (median: 19509 pg/ml) when compared to the day of transplant and to the day +30 (p<0.0025 and p<0.0196, respectively). All patients demonstrated a prompt decrease in TGF-β1 mRNA expression and its serum concentration after conditioning. In patients with acute GVHD, TGF-β1 mRNA expression and its serum concentration remained low until day +30 after transplant if compared to the transplant day (p<0.03 and p<0.006, respectively). TGF-β1 mRNA expression and its serum concentration significantly increased on day +100 if compared to the transplant day (p<0.0009 and p<0.02, respectively) in patients who developed chronic GVHD. ConclusionsWe demonstrate the kinetics of TGF-β1 changes both on molecular and protein level in patients who underwent alloHSCT for myeloid leukemias. These results show that TGF-β1 is likely to be an additional regulator of donor engraftment, probably its low levels contributing to the development of acute GVHD, which may suggest that TGF-β1 exerts beneficial effects in the early post transplant period. In contrast, chronic GVHD symptoms seem to correlate significantly with high TGF-β1 levels, suggesting that TGF-β1 is likely to increase the risk of cGVHD by causing fibrosis of target organs, which remains in coherence with TGF-β1 profibrotic activity. Disclosures:No relevant conflicts of interest to declare.

Reduced-intensity allogeneic transplantation combined with imatinib mesylate for chronic myeloid leukemia in first chronic phase

Reduced-intensity allogeneic transplantation combined with imatinib mesylate for chronic myeloid leukemia in first chronic phase

Initial Liver Involvement in Acute Graft-Versus-Host Disease (GVHD) Predicts a Severe Acute Gvhd and Poor Long-Term Survival

Objectives: Current grading systems in acute GVHD can not effectively identify patients with poor prognosis at time of GVHD diagnosis. The aim of this study was to evaluate clinical or biological parameters at the onset of GVHD associated with poor prognosis of acute GVHD.Methods: Among 257 patients (pts) who received an allogeneic stem cell transplant (SCT) after a myeloablative conditioning regimen between 1993 and 1999, 146 pts developed acute GVHD. One hundred-day cumulative incidence of acute GVHD was 57.3% (95%CI 51.1–63.4) whereas 100-day cumulative incidence of death non related to GVHD was 5.3% (95%CI 2.5–8.1). Patients with acute GVHD were analyzed for risk factors associated with non-relapse-mortality (NRM) using proportional cause-specific hazards models.Characteristics of patients: Median age was 32 years (from 4 to 60 years). Sex ratio men/women was 1,4. Disease was defined as low risk (n=43) (acute leukemia in first remission, aplastic anemia without more than 20 blood transfusions before transplantation and chronic myeloid leukemia in first chronic phase) and high risk (n=99, all other diagnosis). Source of stem cell was bone marrow in 106, peripheral blood stem cells in 23 and cord blood in 13 pts. 87 patients received SCT from a sibling donor and 55 patients from an unrelated donor. 85 patients were HLA identical with their donor. Median follow-up was 76 months.Results: At time of diagnosis, GVHD involved a single organ in the majority of the patients (109 pts, 78%): skin for 63, gut for 35, liver for 11 pts. 37 patients had multiple organs affected by GVHD: 34 patients had 2 organs and 3 had 3 organs (liver, skin and gut). The Table 1 shows acute GVHD grade from diagnosis to maximal grade.Table 1Maximal gradeInitial gradeNo GVH1234TotalNo GVH111----111 (43%)1-311631060 (23%)2-056131483 (32%)3-00213 (1%)Total111 (43%)31 (12%)72 (28%)18 (7%)25 (10%)257Overall 1-year NRM was 54.9% (95%CI 46.6–63.2). 57 patients experienced a failure to corticosteroid treatment and were considered as “non-responders”. Covariates tested for NRM predictive factors were gender, CMV status, conditioning regimen, source of SCT, HLA match, hematological disease, initial characteristics of GVHD and response to treatment after 7 days. Significant (p < 0.05) risk factors for NRM were non sibling donor (NRM: 64.5% [51.5–77.5]), absence of methotrexate in GVHD prophylaxis (NRM: 67.3 [50.2–84.5]), initial liver involvement (NRM: 80.2% [62.2 to 98.2]) and acute GVHD resistant to corticosteroids (NRM: 78.9 % [68.1–89.8]). Patients who were responder to corticosteroids had same NRM than patients who did not develop any GVHD. Albumin level (alb) was associated with NRM in patients with initial gut involvement (NRM 21.4% [0.0–44.0] in pts with alb > or = 35 and 61.1% [37.4–84.8] in pts with alb < 35 gr/L, p=0.035). Initial grade was not significantly associated with NRM: 1-year cumulative incidence was 52.4% (39.3–65.6), 56.3% (45.3–67.4) and 66.7% (0.0–00) in patients with initial grade I, II and III, resp. as compared to 26.2% (17.4–5.0) in patients without GVHD. In multivariate analysis, initial liver involvement (HR: 2.45 (1.46 to 4.12), p=0.0007) and non sibling donor (HR: 1.58 (1.02 to 2.43, p= 0.0039) were both associated with NRM.Conclusion: In this study, classification of GVHD at time of diagnosis was not predictive for NRM. Initial liver involvement was the most important clinical predictor and may be considered in clinical management and need prospective clinical trials.

Imatinib mesylate versus allogeneic BMT for patients with chronic myeloid leukemia in first chronic phase

Imatinib mesylate (IM) is now first-line treatment for CML. To study the results of treatment with IM after IFN failure/intolerance versus allogeneic BMT (allo-BMT), we retrospectively analyzed 264 patients treated for CML in first chronic phase in three different institutions. Over a 6-year period (2001-2006), 174 patients received IM after failure of or intolerance to IFN. During the same period of time, 90 patients received an allo-BMT from an HLA-matched sibling (n=83) or an unrelated donor (n=7). The IM group was older (41 versus 33 years, P<0.001). Five-year EFS was 62% among patients receiving IM and 52% among patients undergoing allo-BMT (P=0.0002). OS at 5 years was 93% for IM-treated patients and 59% for patients undergoing allo-BMT (P<0.0001). Allo-BMT cannot be considered as first-line treatment for CML patients in first chronic phase.

Therapy adapted to molecular response in patients with chronic myelogenous leukaemia in first chronic phase: results of the Duesseldorf study

This study evaluates response-adapted treatment of chronic myelogenous leukaemia (CML) in chronic phase using molecular response criteria. bcr-abl/G6PDH ratios were assessed by Light-Cycler quantitative real-time polymerase chain reaction (PCR( in 277 peripheral blood samples from 33 patients, before and every 3 months during therapy. Sixty-six per cent (22/33) of the patients fulfiled our molecular response criterion of > or = 1 log decrease in bcr-abl transcript after 6 or > or = 2 log decrease after 9 and every following 3 months. Dose escalation was necessary for 33% (11/33) of the patients. Of these, 54% (6/11) achieved a reduction of bcr-abl mRNA by > or = 2 log (n = 3) or > or = 3 log (n = 3) with 800 mg Imatinib. Forty-five per cent (5/11) showed insufficient molecular response with 800 mg Imatinib and received Nilotinib. In conclusion, the assessment of molecular response permits an individual patient-tailored treatment of CML in first chronic phase, resulting in the majority of patients achieving a major molecular response after 2 years of therapy.

Imatinib Mesilate Versus Allogeneic Bone Marrow Transplantation for Patients with Chronic Myeloid Leukemia in First Chronic Phase - A Brazilian Point of View.

Imatinib has profoundly change indication of allogeneic bone marrow transplantation (alloBMT) worldwide for CML and is now the first line of treatment in most countries. However, in Brazil, Imatinib for CML in first chronic phase is provided by Federal Health Agency only for patients refractory/intolerant to interferon (IFN). In order to study results of treatment with imatinib and alloBMT in this particular scenario we retrospectively analyzed 266 patients treated for CML in first chronic phase (less than 60 years-old) in three different institutions in Brazil. End points were event free survival (EFS = absence of hematological response, lost of hematological/cytogenetic response, relapse in accelerated phase/blast crisis or death) and overall survival (OS). From jan/2001 to dec/2006, 176 patients received imatinib 400 mg after failure or intolerance to IFN. Median time from diagnosis to imatinib treatment was 19 months (range: 2 to 205). At the same period of time, 90 patients received an allo-BMT from an HLA-matched sibling (n=83) or an unrelated donor (n=7). Patients receiving peripheral blood stem cell or umbilical cord blood were excluded. Eighty-two patients received busulfan+cyclophsphamide as conditioning regimen and all patients received cyclosporin+methotrexate±steroids as GVHD prophylaxis. Median time from diagnosis to allo-BMT was 16 (range: 5 to 104) months. Gender distribution was similar between groups. Imatinib group had a higher median age (40.7 vs. 32.8 years, P<0.001). With a median follow up of 3 years, 5-year estimate EFS was 67.6% for patients receiving imatinib and 51.8% for patients receiving an allo-BMT (P=0.0002). Estimate overall survival at 5 years was 92.7% for patients treated with imatinib and 58.8% for patients receiving an allo-BMT (P<0.0001). Allo-BMT should be no more recommended as a first line alternative treatment, even if imatinib is available only for patients refractory/intolerant to IFN. Impressively, OS in Imatinib group were quite similar to those seen at the imatinib arm of IRIS study (Druker BJ et al. N Engl J Med 2006; 355: 2408).

Impact of HLA class I and class II DNA high-resolution HLA typing on clinical outcome in adult unrelated stem cell transplantation after in vivo T-cell depletion with alemtuzumab

Survival after volunteer unrelated donor (VUD) stem cell transplantation (SCT) is influenced by matching for human leucocyte antigens (HLA). We analysed the effects of serological and molecular typing at HLA-A, -B, -C and -DRB1 in 100 patient/VUD pairs from a single transplant centre. Patients received SCT for good risk [chronic myeloid leukaemia in first chronic phase (CML-CP1), n = 55] or poor risk ( n = 45) diseases after myeloablative conditioning and T-cell depletion with alemtuzumab. By serological typing, 70 pairs were fully matched, whereas molecular typing revealed 10 pairs with additional mismatches. The day 100 transplant related mortality was 15%. Acute graft versus host disease (GvHD) grades III–IV occurred in 11%, whilst extensive chronic GvHD in 13% of evaluable patients. There was no statistical difference in GvHD rates between patients who received grafts from fully matched or from mismatched donors. In univariate analysis the disease risk group and CMV seronegativity of recipient and donor were the only significant predictors for survival, with 3-year survival probabilities of 71.2% for CML-CP1 and 28% for poor risk diseases. In the poor risk group, HLA mismatches had a negative impact on survival ( p = 0.003) and progression free survival ( p = 0.009) contrary to CML-CP1 patients, in whom HLA mismatches at molecular or serological level did not have any impact.

Quality of life, reproduction and sexuality after stem cell transplantation with partially T-cell-depleted grafts and after conditioning with a regimen including total body irradiation

Thirty-four men and 36 women (median age 43 and 45 years, respectively) underwent stem cell transplantation (SCT) for acute leukaemia in first complete remission or chronic myelogenous leukaemia in first chronic phase between 1981 and 2001 from HLA-identical siblings. The conditioning regimen included TBI and all grafts were partially depleted of T cells. Changes in quality of life (QOL), reproduction and sexuality were studied using a questionnaire, and the previously given information related to these problems was assessed. In addition, endocrine status was assessed and semen analysis was performed. After SCT, patients reported less energy (n=50) and a deterioration in the job situation (n=31). Patients experienced a negative change in sexual relations (n=41). Important problems of sexual dysfunction were vaginal dryness in women (n=19) and erectile dysfunction in men (n=16). None of the patients was fertile based on their gonadotrophin levels, sperm concentrations and reproductive outcomes. Women experienced climacteric symptoms (n=24). Quality of life was negatively influenced by these changes. One-fifth of the patients were not satisfied with the information given with regard to reproduction, premature menopause and sexual problems.

Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy + G-CSF in patients with chronic myelogenous leukemia in first chronic phase

The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph−) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1).During 1994 – 1999 12 centers included 37 patients <56 years. All patients received 6 months' IFN, stopping at median 36 (1 – 290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m2 and 1 hour infusion on days 1 – 3, and cytarabine (ara-C) 200 mg/m2 24 hours' i.v. infusion on days 1 – 7 (DA) followed by G-CSF 526 μg s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34+ cells was >5/μl blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m2/day and 1 hour i.v infusion, etoposide 100 mg/m2/day and 1 hour i.v. infusion and ara-C 1 g/m2/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 μg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice.Twenty-three patients (62%) were successfully (MNC >3.5 × 108/kg, CFU-GM >1.0 × 104/kg, CD34+ cells >2.0 × 106/kg and no Ph+ cells in the apheresis product) [n = 16] or partially successfully (as defined above but 1 – 34% Ph+ cells in the apheresis product) [n = 7] mobilized. There was no mortality during the mobilization procedure.Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN <0.5 × 109/l was 10 (range 7 – 49) and with platelets <20 × 109/l was also 10 (2 – 173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47 – 90%), with a median follow-up time of 5.2 years.We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph− BSC sufficient for use in auto-SCT.

Impact of HLA Class I and Class II DNA High-Resolution HLA Typing on Outcome in Adult Unrelated Stem Cell Transplantation after In Vivo T-Cell Depletion with CAMPATH 1H: A Single Centre Experience in 100 Patients.

Aim: Outcome of unrelated donor stem cell transplantation (SCT) is influenced by matching for HLA class I and II. We investigated the effects of HLA typing on acute and chronic graft-versus-host disease (aGvHD and cGvHD) and overall survival (OS) in adult patients/donors typed for HLA-A, B, Cw, DRB1, DPB1 at high resolution (HR) and low resolution (LR).Patients: 100 patients (pts.)(median age 32 y, 17 – 54) were treated with allogenic SCT for diseases: 55 Ph-positive chronic myeloid leukaemia in first chronic phase (CML CP1), 21 CML in advanced phase (CML AP) and 24 acute leukaemias (AL). Pre-transplant conditioning consisted in 98 pts of total body irradiation (TBI) and cyclophosphamide (91) or etoposide (7) and in 2 pts of cyclophosphamide and busulphan. In all pts. GvHD prophylaxis was provided by cyclosporin A and short-term methotrexate with in vivo T-cell depletion (TCD) by CAMPATH 1H (Anti CD52).Results: With LR typing 68 pts./donors were fully matched but 32 had class I (31) or class II (1) mismatches (MisM). HR typing revealed 9 pts with additional class I (7) or II (7) MisM, thus 59 pts./donors were fully matched. AGvHD grade III–IV occured in 11 pts (11%) whilst extensive cGvHD was seen in 12 pts (14% out of 83). There was no statistical difference in the occurrence of aGvHD or cGvHD between fully matched and mismatched pts./donors at LR or HR. The probability of transplant-related mortality (TRM) of the whole cohort was 15% at day 100 and 23% at day 180 and engraftment failure 1%. The 3-year survival probabilities were significantly different (p=0.004) for pts. with CML CP1 at 63% (good risk group) when compared with CML AP and AL at 23% (poor risk group). In multivariate analysis patients age, diagnosis group and negative CMV status of patient and donor were the only significant predictors for survival. In the entire group the full compatibility at LR or HR for class I or class II or for a single HLA antigen or the KIR ligand mismatch in the GvHD direction did not have an impact on survival. In contrast to the CML CP1 group (n=55) we found that in the poor risk group (n=45) a MisM at HR had a negative impact on survival (p=0.03) and a trend towards worse survival was found for patients with HLA B HR mismatch. Patients with more than one HR MisM had a worse survival when the combination of HLA B and HLA D MisM was present (p=0.008).Conclusion: In 100 pts. treated with unrelated SCT and in vivo TCD with CAMPATH 1H the HR typing did have an impact on survival only in the poor risk group but not in pts with CML CP1. Thus, T-cell depletion with in vivo CAMPATH 1H permits the use of mismatched unrelated donors in patients with CML CP. The overall rates for aGvHD and cGvHD were low compared to published data in non TCD SCT. Further investigations on larger cohorts are needed to elucidate the impact of HR typing in unrelated SCT and the significance of HR MisM at single HLA loci in transplants T-cell depleted with in vivo CAMPATH 1H.

Results of a Phase II Trial Testing Interferon Alpha 2b and Cytarabine in Children with Chronic Myelogenous Leukemia.

Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.

A single-centre assessment of long-term quality-of-life status after sibling allogeneic stem cell transplantation for chronic myeloid leukaemia in first chronic phase.

A total of 75 patients underwent sibling allogeneic stem cell transplantation (SCT) for chronic myeloid leukaemia in first chronic phase from 1984 to 2000. Of these patients, 51 (68%) were alive at a median follow-up of 98 months (range 34-217 months). Nine (18%) patients relapsed and seven (14%) received donor lymphocyte transfusions. Quality of life (QoL) was assessed cross-sectionally using the EORTC QLQ-C30, a Leukaemia-BMT-specific module and questionnaires on sexual functioning, fertility and late effects. A total of 46 (90%) replied. Scores for Role (P=0.018) and Cognitive (P<0.001) function were significantly lower when compared to an age-adjusted general population. Dyspnoea (P=0.022) and Financial Difficulties (P<0.001) were significantly more common in the SCT group. No difference was found for scores in the Physical, Emotional and Social domains or the overall Global Health Status/QoL. Decreased sexual functioning was found in one-third of respondents. Although most BMT recipients reported a good QoL, a minority have difficulty with reintegration into professional roles and consequent monetary problems. Identified cognitive and sexual impairments highlight the need for long-term access to psychosocial support.