Autologous peripheral blood haematopoietic stem cell transplantation for chronic myelogenous leukaemia.

In these last four decades there has been extraordinary progress in our understanding of the biology of, and therapeutic approach to, chronic myelogenous leukaemia (CML). During these decades new observations arising from studies of the biological behaviour of diploid and leukaemic stem cells and, recently, from clinical investigations have received the most attention. From a clinical point of view, allografting is still the only procedure which is able to cure CML. For patients without HLA-compatible donors, current therapeutic options include conventional chemotherapy (hydroxyurea), interferon-alpha (IFN-alpha) and autografting. While IFN-alpha (+/- low-dose ARA-C) must be considered the first-line therapy, autografting, according to our approach, or other procedures, raises the question of an ideal sequential strategy in the management of CML patients (diploid stem cell mobilization, autografting, IFN-alpha). Because it seems that the diploid haematopoietic reservoir declines with time, it may be desirable to mobilize and collect diploid stem cells in order to store them as soon as diagnosis is possible when the WBC count has been controlled by hydroxyurea.     

Risk assessment in haematopoietic stem cell transplantation: GvHD prevention and treatment

Graft-versus-host disease (GvHD) is the major cause of transplant-related mortality and morbidity. As it is closely related to the major therapeutic principle, graft-versus-leukaemia (GvL) effect, risk assessment has to balance both risks depending on the pre-transplant status. This is clearly demonstrated when comparing the two major strategies for prevention of GvHD. While the majority of approaches aiming at T-cell depletion show efficacy in reducing acute and chronic GvHD and transplant-related mortality, T-cell depletion also affects graft-versus-leukaemia effects and thus results in a higher relapse rate. Thus, standard prophylaxis relying on calcineurin inhibitors frequently results in at least equivalent or even superior long-term disease-free survival, and the risk of relapse has to be considered when selecting regimens for prevention of GvHD. In addition to this general dilemma, drug-specific side-effects and risks have to be considered when selecting regimens for GvHD prevention and treatment.     

Treatment of children with acute myeloid leukaemia who relapsed after allogeneic haematopoietic stem cell transplantation

Despite improvements in diagnosis and treatment, 30–40% of children with acute myeloid leukaemia (AML) experience relapse. For those who relapse after allogeneic haematopoietic stem cell transplantation (allo‐HSCT), the prognosis is particularly poor, with limited reported literature on these patients. We reviewed the clinical course of 49 children with AML (28 males, 21 females) who received allo‐HSCT between 1993 and 2011, and who had subsequently relapsed. Study endpoints included (i) complete remission (CR) rate after intensive chemotherapy, and prognostic factors for CR, (ii) disease‐free survival (DFS) and overall survival (OS) for patients who achieved CR and (iii) OS for recipients of intensive chemotherapy and prognostic factors for OS . Of the 36 patients who received intensive chemotherapy after post‐HSCT relapse, 26 (72%) achieved CR. For patients who achieved CR, 5‐year DFS and OS were 32·6 ± 10·2% and 44·4 ± 11·1%, respectively. For all recipients of intensive chemotherapy, 5‐year OS was 31·6 ± 8·7%. Cumulative incidence of treatment‐related death was 14·4%. All three recipients of second HSCT died. Amongst prognostic factors predicting improved survival, only disease status at HSCT (early first CR vs. others) proved significant in multivariate study (Hazard Ratio 2·42, 95% Confidence Interval 1·02–5·74, P = 0·045). Treatment with curative intent was able to salvage a minor but important subset of children with AML who relapsed post‐allogeneic transplant.     

Haploidentical haematopoietic stem cell transplantation for TP53-mutated acute myeloid leukaemia

Acute myeloid leukaemia (AML) patients with tumour protein p53 (TP53) mutations are often resistant to chemotherapy and have worse clinical outcomes than patients without TP53 mutations. In this study, we compared clinical outcomes of patients with AML with and without TP53 mutations who underwent haploidentical haematopoietic stem cell transplantation (haplo-HSCT). For the TP53-mutation group and TP53 wild-type group, the 2-year cumulative incidence of relapse (CIR) was (39.0% vs. 21.2% respectively, p = 0.088), the 2-year non-relapse mortality (NRM) rate was (3.2% vs. 8.4% respectively, p = 0.370), the 2-year leukaemia-free survival (LFS) was (57.7% vs. 71.3% respectively, p = 0.205), the 2-year overall survival (OS) rate was (69.9% vs. 81.3% respectively, p = 0.317), the 100-day cumulative incidence of Grade II–IV acute graft-versus-host disease (GvHD) was (6.5% vs. 20.7% respectively, p = 0.074), the 2-year cumulative incidence of chronic GvHD was (52.3% vs. 53.1% respectively, p = 0.493) and the 2-year GvHD-free/relapse-free survival (GRFS) was (57.7% vs. 69.6% respectively, p = 0.347). Our data showed that there were no significant differences in 2-year clinical outcomes between the two groups. Multivariable analysis showed TP53 mutations had no significant impact on CIR, NRM, OS, GvHD, LFS or GRFS. Our findings suggest that patients with AML with TP53 mutations may at least partially benefit from haplo-HSCT. Haplo-HSCT might be the recommended treatment for such patients.     

Large granular lymphocytic leukaemia after solid organ and haematopoietic stem cell transplantation

T-cell large granular lymphocytic leukaemia (T-LGLL) is a chronic clonal lymphoproliferative disorder of cytotoxic T lymphocytes which commonly occurs in older patients and is often associated with autoimmune diseases. Among 246 patients with T-LGLL seen at our institution over the last 10 years, we encountered 15 cases following solid organ or haematopoietic stem cell transplantation. Here, we studied the clinical characterization of these cases and compared them to de novo T-LGLL. This experience represented a clear picture of the intricate nature of the disease manifestation and the complexities of several immune mechanisms triggering the clonal expansion.     

The graft-versus-leukaemia effect in haematopoietic stem cell transplantation using unrelated donors

We studied the graft-versus-leukaemia (GVL) effect in 185 patients with haematological malignancies who underwent unrelated donor haematopoietic stem cell transplantation (HSCT) at Huddinge University Hospital between May 1991 and June 2001. Ninety-five were in first CR/CP and 90 in later stages. Most (86%) of them had a HLA-A, -B and -DRbeta1 matched donor. Conditioning usually consisted of total body irradiation and cyclophosphamide, and GVHD prophylaxis of cyclosporine and methotrexate. In the multivariate risk-factor analysis of relapse, we found that disease stage beyond CR1/CP1 (P = 0.02), acute GVHD 0-I (P = 0.02), absence of chronic GVHD (P = 0.02) and ALL (P = 0.02) were independent risk factors for relapse. The incidence of relapse in those with acute GVHD grade II was 18% vs 46% in those with no or grade I (P = 0.04). In patients with or without chronic GVHD, the incidences of relapse were 32% and 48%, respectively (P < 0.01). The best RFS was seen in patients with chronic GVHD. No difference in RFS was seen in patients with no, mild or moderate acute GVHD. Risk factors for relapse after HSCT with unrelated donors were: acute lymphoblastic leukaemia, disease stage beyond CR1/CP1, absence of chronic GVHD and no, or mild acute GVHD. Overall and relapse-free survival were not improved by the occurrence of acute GVHD.     

Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukaemia

ALL in which the Philadelphia (Ph) chromosome is detected is one of the few diseases in which there is almost unequivocal agreement that a matched sibling allogeneic haematopoietic stem cell transplant in first CR is the most appropriate therapy for patients within certain age limits. Extension of allogeneic stem cell transplant to patients without matched sibling donors or to older individuals is increasingly possible due to unrelated donors, umbilical cord blood and reduced-intensity conditioning regimens. Here, we carefully review evidence supporting current practice and examine recent evidence relating to the use of newer allogeneic transplant technologies in Ph-pos ALL. We explore the burgeoning literature on the role of tyrosine kinase inhibitors in this disease and summarize their impact on the transplant practice.     

Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation

In patients with acute leukaemia, the relative risk of relapse influences the choice between chemotherapy and haematopoietic stem cell transplantation (HSCT). The demonstration that minimal residual disease (MRD) is the strongest overall prognostic indicator and can identify patients who are unlikely to be cured by standard chemotherapy has added a powerful new factor to consider when making this decision. There is substantial data indicating that the likelihood of relapse after transplant is directly correlated with levels of MRD before transplant. This knowledge can be used to adjust the timing of HSCT, and guide the selection of donor, conditioning regimen, and post‐HSCT strategies to maximize the graft‐versus‐leukaemia effect. Because MRD emerging post‐transplant carries a dire prognosis, its detection can trigger withdrawal of immunosuppression, additional cellular and molecular therapies, or preparations for a second HSCT. Although it is not yet clear whether any of these actions will significantly improve outcome, it is likely that they will be most effective for patients with a relatively low tumour burden, who can be identified only through MRD testing. In this article, we review the clinical significance of MRD in the context of autologous and allogeneic HSCT.     

Control of advanced and refractory acute myelogenous leukaemia with sirolimus-based non-myeloablative allogeneic stem cell transplantation

Non-myeloablative conditioning has extended the use of allogeneic haematopoietic transplant to many previously ineligible patients. We added the immunosuppressive and antitumour agent sirolimus (rapamycin) to an established transplant regimen of fludarabine 25 mg/m(2) days -7 through -3 and cyclophosphamide 1000 mg/m(2) days -7 and -6, with tacrolimus and methotrexate immunoprophyllaxis. A total of 23 patients with acute myelogenous leukaemia (AML) were treated, with a median age of 59 years (range: 28-72) at transplant. Only seven patients in total were in complete remission prior to transplantation. Nine patients were in chemotherapy-refractory progression and seven were primarily refractory to induction therapy. Six patients received matched sibling, 11 unrelated donor, 1-5/6 matched and five haploidentical (haplo - three of six or four of six matched) transplants. The haplo-recipients also received antithymocyte globulin, all patients engrafted. Only two, both recipients of haploidentical cells, have died from transplant-related causes. Twelve of 23 patients survived at 198-1162-d post-transplant (median 578). Four of 12 survivors relapsed at 83, 88, 243 and 508 d and three were in remission after chemotherapy and donor lymphocyte infusion. Although follow up is short, this data suggests that non-myeloablative haematopoietic cell transplantation with sirolimus (rapamycin)-based immunosuppression may provide disease control over several years in some patients with advanced and poor prognosis AML.     

Outcomes of haploidentical haematopoietic stem cell transplantation for adolescent and young adults with acute myeloid leukaemia

We aimed to identify the efficacy of haploidentical related donor (HID) haematopoietic stem cell transplantation (HSCT) in adolescent and young adults (AYAs) with acute myeloid leukaemia (AML) in a large cohort. Consecutive AML AYAs (15–39 years old, n = 599) receiving HID HSCT in complete remission (CR) were included. The 3-year cumulative incidence of measurable residual disease occurrence, relapse and non-relapse mortality after HID HSCT was 28.6% (95% CI: 25.0–32.2), 11.6% (95% CI: 9.0–14.2) and 6.7% (95% CI: 4.7–8.7) respectively. The 3-year probability of event-free survival, leukaemia-free survival (LFS) and overall survival (OS) after HID HSCT was 60.7% (95% CI: 56.9–64.8), 81.7% (95% CI: 78.7–84.9) and 85.6% (95% CI: 82.8–88.4) respectively. In multivariable analysis, AML risk category at diagnosis and comorbidity burdens before HID HSCT were independently associated with LFS and OS. Compared to the older adults (≥ 40 years, n = 355) with AML receiving HID HSCT in CR during the same time period, AYAs have a lower incidence of non-relapse mortality and higher probabilities of LFS and OS. Thus, we firstly confirmed the safety and efficacy of HID HSCT in AYAs with AML-CR.     

Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry

Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft-versus-host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post-transplant follow-up was 5.6 years (range, 0.2--16.7). Multivariate analysis of transplant-related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia-free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined.     

Persistent aplasia after chemotherapy for acute myeloid leukaemia treated with stem cell transplantation from a matched unrelated donor after dose-reduced conditioning

Persistent aplasia is a rare complication with poor prognosis after intensive chemotherapy for acute leukaemia. A 59-year-old man with acute myeloid leukaemia (AML), was treated after 186 d of chemotherapy-induced persistent aplasia with an allogeneic peripheral blood stem cell transplantation (PBSCT) from a matched unrelated donor (MUD) after dose-reduced conditioning. The patient remains in complete haematological remission more than 8.5 months after haematological recovery. We believe that this is the first reported case of treatment for chemotherapy-induced persistent aplasia with MUD-PBSCT after dose-reduced conditioning, a procedure that can be successfully performed even in elderly patients.     

Evaluation of schistocyte monitoring after haematopoietic stem cell transplantation

Introduction: Observation of schistocytes on the peripheral blood following haematopoietic stem cell transplantation (SCT) is a common finding. As their presence is not specific to the onset of SCT‐related thrombotic microangiopathy, we evaluated the interest of schistocyte measurement twice a week during the entire follow‐up of 195 patients undergoing SCT, particularly focussing on the 125 allogeneic SCT. Methods: Schistocytes were strickly defined as triangular‐, crescent‐ or helmet‐shaped red blood cells according to consensus standards and were checked blindly under the microscope and with computer image analysis. Results: Mean schistocyte percentage was 0.7% (±0.5%, reference value ≤0.5). High schistocyte percentage was observed after allografts (0.79%) when compared to autologous SCT (0.47, P < 0.001). All but one patients undergoing allogenic SCT had schistocytes ≥0.6%. Conversely, significant schistocytosis was observed in 20% of the autologous SCT. Initial diagnosis [chronic myelocytic leukaemia, acute lymphoblastic leukaemia (ALL)], high‐risk status, unrelated transplant and conditioning regimen including total body irradiation influenced higher schistocyte percentage (≈0.9%). Significant rise in the schistocyte percentage was observed during acute/chronic graft‐versus‐host disease, veno‐occlusive disease (VOD), cholestatic hepatitis, haemorrhagic cystitis (HC) and pulmonary complications. Multivariate analysis showed a significant association between thrombotic microangiopathy (TM), renal impairment and delayed thrombopaenia after day 50, and schistocyte >1.2%. SCT‐TM grade ≥2 occurred in nine patients. A marked rise in schistocyte >4.5% was observed, which was not reached during the other SCT‐related complications. Children with ALL, undergoing unrelated allogeneic SCT, with early acute graft‐versus‐host disease refractory to steroids were prone to present SCT‐TM, associated with VOD, interstitial pneumopathy and HC, resulting in a high mortality rate (six of seven patients). Our data confirmed that schistocytosis was common after SCT. Mild percentages were likely concomitant with extensive endothelial damage but higher percentage should have prompted to a close monitoring with SCT‐TM investigation. Conclusion: In our experience, systematic schistocyte count after HSCT proved to be useful: the occurrence of an increased percentage was a surrogate marker for complications even if unspecific for TM.