Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation

Although second allogeneic haematopoietic cell transplantation (allo-HCT2) is a therapeutic option for patients relapsing after first HCT (allo-HCT1), there is limited data on allo-HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo-HCT2 as a salvage treatment for relapse following allo-HCT1 between the 2000 and 2017. The median age at allo-HCT2 was 34·6 years (range: 18–74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo-HCT2. Acute graft-versus-host disease (GVHD) grade II–IV and III–IV occurred in 33% and 17% of the patients, respectively. The incidence of 2-year total and extensive chronic GVHD was 38% and 19%, respectively. The 2- and 5-year cumulative incidence of non-relapse mortality, relapse incidence, leukaemia-free survival, overall survival and GVHD-free, relapse-free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo-HCT1 to relapse, conditioning for allo-HCT1, Karnofsky score at allo-HCT2 and donor type for allo-HCT2. In conclusion, outcomes of allo-HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence.     

Sequential chemotherapy followed by reduced‐intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT

This study analysed the outcome of 267 patients with relapse/refractory acute myeloid leukaemia (AML ) who received sequential chemotherapy including fludarabine, cytarabine and amsacrine followed by reduced‐intensity conditioning (RIC ) and allogeneic haematopoietic stem cell transplantation (HSCT ). The transplants in 77 patients were from matched sibling donors (MSD s) and those in 190 patients were from matched unrelated donors. Most patients (94·3%) were given anti‐T‐cell antibodies. The incidence of acute graft‐versus‐host disease (GVHD ) of grades II ‒IV was 32·1% and that of chronic GVHD was 30·2%. The 3‐year probability of non‐relapse mortality (NRM ) was 25·9%, that of relapse was 48·5%, that of GVHD ‐free and relapse‐free survival (GRFS ) was 17·8% and that of leukaemia‐free survival (LFS ) was 25·6%. In multivariate analysis, unrelated donor recipients more frequently had acute GVHD of grades II ‒IV [hazard ratio (HR ) = 1·98, P  = 0·017] and suffered less relapses (HR  = 0·62, P  = 0·01) than MSD recipients. Treatment with anti‐T‐cell antibodies reduced NRM (HR  = 0·35, P  = 0·01) and improved survival (HR  = 0·49, P  = 0·01), GRFS (HR  = 0·37, P  = 0·0004) and LFS (HR  = 0·46, P  = 0·005). Thus, sequential chemotherapy followed by RIC HSCT and use of anti‐T‐cell antibodies seems promising in patients with refractory 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.     

Outcome after first relapse in adult patients with Philadelphia chromosome‐negative acute lymphoblastic leukaemia

To analyse the outcome of adult patients who developed a first relapse of acute lymphoblastic leukaemia (ALL), we collected the clinical data of 332 patients with Philadelphia‐chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first complete remission (CR1) between 1998 and 2008 in 69 institutions all over Japan, including 58 patients who relapsed after allogeneic haematopoietic stem cell transplantation (Allo‐HSCT) in CR1. The overall survival (OS) was 43·4% at 1 year, and 16·3% at 5 years from relapse in patients who received chemotherapy alone in CR1. Among patients who relapsed after chemotherapy alone in CR1, 123 (52·5%) achieved a second remission (CR2) following salvage chemotherapy, of whom 62 subsequently underwent Allo‐HSCT during CR2. Allo‐HSCT in CR2 was significantly associated with better OS. Moreover, the type of salvage chemotherapy influenced OS from relapse. A doxorubicin, vincristine, and predonisone‐based (AdVP‐type) regimen was related to better OS in patients with longer CR1 (more than 1 year), but was related to worse OS in patients with shorter CR1. In conclusion, the prognosis of patients with relapsed Ph‐negative ALL is poor. Allo‐HSCT after a first relapse could improve the prognosis. Selection of the optimal salvage chemotherapy might depend on the duration of CR1.     

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.     

Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children

Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0·0001). Achievement of a subsequent remission impacted survival (P = <0·0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0·046) and donor choice (matched family vs. matched unrelated donor, P = 0·029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.     

Allogeneic haematopoietic stem cell transplantation for infant acute lymphoblastic leukaemia with KMT2A (MLL) rearrangements: a retrospective study from the paediatric acute lymphoblastic leukaemia working group of the Japan Society for Haematopoietic Cell Transplantation

Allogeneic haematopoietic stem cell transplantation (HSCT) is still considered to play an important role as a consolidation therapy for high‐risk infants with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed outcomes of HSCT in infants with ALL based on nationwide registry data of the Japan Society for Haematopoietic Cell Transplantation. A total of 132 allogeneic HSCT for infant ALL with KMT2A (MLL) gene rearrangements, which were performed in first complete remission (CR1), were analysed. The 5‐year overall survival rate after transplantation was 67·4 ± 4·5%). Although recent HSCT (after 2004) had a trend toward better survival, no statistical correlation was observed between outcomes and each factor, including age at diagnosis, initial leucocyte count, cytogenetics, donor types or conditioning of HSCT. Myeloablative conditioning with total body irradiation did not provide a better survival (60·7 ± 9·2%) over that with busulfan (BU; 67·8 ± 5·7%). Two of the 28 patients treated with irradiation, but none of the 90 BU‐treated patients, developed a secondary malignant neoplasm. In conclusion, allogeneic HSCT using BU was a valuable option for infant ALL with KMT2A rearrangements in CR1.     

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.     

Acute myeloid leukaemia relapse after allogeneic haematopoietic stem cell transplantation: Mechanistic diversity and therapeutic directions

Emerging biological and clinical data, along with advances in new technologies, have exposed the mechanistic diversity in post-haematopoietic stem cell transplant (HCT) relapse. Post-HCT relapse mechanisms are relevant for guiding sophisticated selection of therapeutic interventions and identification of areas for further research. Clonal evolution and emergence of resistant leukemic strains is a common mechanism shared by relapse post-chemotherapy and post-HCT, other mechanisms such as leukemic immune escape and donor T cell exhaustion are unique entities to post-HCT relapse. Due to diversity in the mechanisms behind post-HCT relapse, the subsequent clinical approach relies on clinician discretion, rather than objective evidence. Lack of standardized selection based on post-HCT relapse mechanism(s) could be a contributing factor to observed poor outcomes. Therapeutic strategies including donor lymphocyte infusion (DLI), second transplant, immunotherapies, hypomethylating agents, and targeted strategies are supported options and efficacy may be enhanced when post-HCT AML relapse mechanism is established and guides treatment selection. This review aims, through compilation of supporting studies, to describe mechanisms of post-HCT relapse and their implications for subsequent treatment selection and inspiration for future research.     

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.     

Outcome of haematopoietic stem cell transplantation for paediatric acute lymphoblastic leukaemia in third complete remission: a vital role for graft-versus-host-disease/ graft-versus-leukaemia effect in survival

Children with acute lymphoblastic leukaemia (ALL) receiving haematopoietic stem cell transplantation (HSCT) in third complete remission (CR3) are at high risk for transplant-related mortality (TRM) and relapse. Twenty-two consecutive children with ALL in CR3 received HSCT between January 1994 and August 2005. Ten patients died of TRM, seven patients relapsed, six did not have graft-versus-host disease (GVHD). Five patients were long-term survivors, (median follow-up, 5·8 years; range 2·9–11·7). Three-year event-free survival was 0·32 (95% confidence interval 0·19 and 0·59). Survivors had moderate to severe GVHD. Allowing some GVHD or exploring means of inducing GVHD should be considered in CR3 patients.     

Allogeneic transplantation as post-remission therapy for cytogenetically high-risk acute myeloid leukemia: landmark analysis from a single prospective multicenter trial

Background Allogeneic hematopoietic cell transplantation is considered the preferred post-remission therapy in patients with acute myeloid leukemia cytogenetically defined as being at high risk. To substantiate evidence for allogeneic hematopoietic cell transplantation in first complete remission in these high-risk patients we performed a landmark analysis within a single prospective multicenter treatment trial. DESIGN AND METHODS: By the time of analysis, 2,347 patients had been accrued into the AMLCG 99 trial between 1999 - 2007. Out of this population, 243 patients under 60 years old fulfilled the criteria for high-risk cytogenetics. Landmark analyses were performed with a control cohort, who remained in first complete remission at least the median time from complete remission to transplantation in the intervention group. RESULTS: After standardized induction therapy, 111 patients under 60 years old achieved complete remission. A matched allogeneic donor was identified for 59 patients (30 sibling donors, 29 unrelated donors). Fifty-five patients received an allogeneic hematopoietic cell transplant after a median time of 88 days in first complete remission. Of the remaining 56 patients, 21 relapsed within 90 days after achieving first complete remission and for 7 patients with relevant comorbidities no donors search was initiated, leaving 28 patients given conventional post-remission therapy as the control cohort. The median follow-up of surviving patients was 60.4 months. Patients with an allogeneic donor had substantially better 5-year overall and relapse-free survival rates than the control group (48% versus 18%, P=0.004 and 39% versus 10%, P<0.001, respectively). A survival benefit from transplantation was evident regardless of donor type, age and monosomal karyotype. Conclusions Beyond evidence available for subgroups of high-risk patients, the findings of this study establish in a broader manner that allogeneic hematopoietic cell transplantation is a preferable consolidation treatment for patients with acute myeloid leukemia and high-risk cytogenetics. The study was registered at Clinicaltrials.gov as NCT00266136.     

Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse

Background

Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse.

Design and Methods

Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy.

Results

Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission.

Conclusions

We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.     

Magnetic resonance imaging of femoral marrow predicts outcome in adult patients with acute myeloid leukaemia in complete remission

Accurate assessment of residual disease is important for the prediction of outcome in patients with acute leukaemia in complete remission (CR). To investigate whether abnormalities on magnetic resonance (MR) images of femoral marrow in adult patients with acute myeloid leukaemia (AML) in CR can predict outcome, 28 newly diagnosed patients with AML underwent MR imaging when bone marrow aspiration or biopsy was performed to verify the state of CR after induction therapy. MR abnormalities on short TI (inversion time) inversion recovery (STIR) techniques persisted in all four patients who did not achieve CR. In 13 CR patients abnormalities on STIR images resolved, to result in normal appearance at the time CR was achieved. All 13 patients remained in CR for 3-104 months (median, 73 months). In the other 11 CR patients, STIR abnormalities persisted at the time CR was achieved. Seven of them relapsed between 1 and 28 months (median, 3 months) after MR evaluation. Disease-free survival of patients with persistent abnormal STIR images was significantly shorter than that of patients with normal STIR images (P < 0.01). MR imaging of femoral marrow may predict outcome in adult patients with AML in CR.     

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.     

Comparison of umbilical cord blood allogeneic stem cell transplantation vs. auto‐SCT for adult acute myeloid leukemia patients in second complete remission at transplant: a retrospective study on behalf of the SFGM‐TC

This retrospective study considered the outcomes of 181 patients with acute myeloid leukemia (AML) transplanted in second complete remission (CR2) between January 2005 and April 2012 and who received either a myeloablative autologous stem cell transplant (Auto‐SCT; n = 82; median age: 48 years; median follow‐up: 45 months) or an umbilical cord blood (UCB) allogeneic SCT (n = 99, median age: 46 years; median follow‐up: 36 months; conditioning regimens: myeloablative n = 21, reduced n = 78; single unit n = 37, double units n = 62). Although the Auto group showed a significant better prognostic profile at transplant, with longer median interval between diagnosis and time of graft, higher incidence of good‐risk cytogenetics and lower number of previously transplanted patients, 3‐year OS and LFS were similar between both groups (Auto: 59 ± 6% vs. 50 ± 6%, P = 0.45; and 57 ± 6% vs. 46 ± 6%, P = 0.37). In multivariate analysis, UCB allo‐SCT was associated with lower relapse incidence (HR: 0.3, 95% CI: 0.11–0.82, P = 0.02), but higher non‐relapse mortality (NRM) (HR: 4.16; 95% CI: 1.46–11.9, P = 0.008). Results from this large study suggest that UCB allo‐SCT provides better disease control than auto‐SCT, which is especially important in the setting of high‐risk disease. However, this disease control advantage is counterbalanced by higher toxicity, highlighting the need for novel approaches aiming to decrease NRM after UCB allo‐SCT.     

Autologous bone marrow transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukaemia in first complete remission: a prospective randomized Dutch-Belgian Haemato-Oncology Co-operative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial

The question as to whether autologous stem cell transplantation (SCT) after consolidation chemotherapy improves the probability of survival of patients with acute myeloid leukaemia (AML) in first remission has not been settled. Here, we present the results of a phase III study conducted in newly diagnosed adult AML patients aged <60 years. Patients who had reached a complete remission (CR) after two courses of induction chemotherapy and who were not eligible for a human leucocyte antigen-matched sibling SCT (n = 130), were randomized after a third consolidation cycle of chemotherapy between high-dose cytotoxic treatment and autologous bone marrow transplantation or no further treatment. No significant differences in disease-free survival and overall survival were observed between the two treatment arms. A slightly better overall survival in the no further treatment arm was because of fewer deaths in the first CR and a significantly better overall survival after the first relapse. The results are discussed in relation to the generic problems of applying autologous transplantation and in the perspective of the limited statistical power of this and other previously published studies.