Unexpected remission of acute myeloid leukaemia after GM-CSF

Summary. The administration of granulocyte-monocyte colony-stimulating factor (GM-CSF) was associated with complete clinical and haematological response in an adult patient with minimally differentiated acute myeloid leukaemia who presented with pneumonia and moderate neutropenia, but no blast cells in the peripheral blood. The response lasted 9 months. At relapse, a second GM-CSF course resulted in a very good partial remission lasting 5 months, although differences in the kinetics of haemoglobin, neutrophil and platelet recovery were noted. Subsequent recurrences were managed with chemotherapy, a complete remission being obtained twice more and lastly consolidated with myeloablative chemo-radiotherapy supported by a peripheral blood stem cell autograft. This report suggests that GM-CSF should be further investigated as a therapeutic agent in selected cases of AML.     

Spontaneous remission in acute myeloid leukaemia

A summary of the literature of adult patients with acute myeloid leukaemia (AML) who have undergone spontaneous remission (SR) is presented together with a report of a patient whose SR was accompanied by cytogenetic remission. There are less than 20 reports of SR since the 1980s. SR is by no means synonymous with cure, since the average duration of the remission is only 7·1±9·2 months. Neither infections nor transfusions are absolute requirements of SR.     

Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission

Allogeneic bone marrow transplantation is an effective postremission strategy for patients with acute myelogenous leukemia (AML) in first complete remission (CR). The value of administering consolidation chemotherapy before human leukocyte antigen (HLA)-identical sibling transplantation is not established. Outcomes of patients with AML in first CR receiving no consolidation therapy, standard-dose cytarabine consolidation therapy, and high-dose cytarabine consolidation therapy before HLA-identical sibling transplantation were compared. Five-year treatment-related mortality rates were 30% (95% confidence interval [CI], 18% to 42%) in patients receiving no consolidation chemotherapy, 22% (95% CI, 17% to 28%) in those receiving standard-dose cytarabine consolidation, and 24% (95% CI, 17% to 31%) in those receiving high-dose cytarabine (P = NS). Five-year cumulative incidences of relapse were 19% (10% to 30%), 21% (16% to 27%), and 17% (11% to 24%), respectively (P = NS). Five-year probabilities of leukemia-free survival were 50% (36% to 63%), 56% (49% to 63%), and 59% (50% to 66%), respectively (P = NS). Five-year probabilities of overall survival were 60% (46% to 71%), 56% (49% to 63%), and 60% (51% to 67%), respectively (P = NS). The data indicate that postremission consolidation with cytarabine before allogeneic transplantation for AML in first CR is not associated with improved outcome compared to proceeding directly to transplantation after successful induction. (Blood. 2000;96:1254-1258)     

Expression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission

Many solid tumours have been shown to lack expression of either of the immune co-stimulatory molecules CD80 (B7.1) or CD86 (B7.2), which is thought to be one of the ways in which tumours may escape immune recognition. We have examined the surface expression of CD80, CD86, human leucocyte antigen (HLA) class I and II, CD11a, CD54, and CD58 on the blast cells from patients with acute myeloid leukaemia (AML) at presentation. CD80 was only rarely expressed on AML blasts and, in those leukaemic cells expressing CD80, the level of expression was low. In contrast, expression of CD86 was detected on the AML blasts in more than half of the samples tested and, in some cases, the level of expression was equivalent to that of mature monocytes and activated B lymphocytes. The percentage of leukaemic blasts expressing CD86 was higher in the M4 and M5 French-American-British (FAB) types, and expression of CD11a and HLA class II was higher in the M4 FAB type. There was no difference in expression of CD80, CD54, CD58, or HLA Class I between different FAB subgroups. There was no significant difference in duration of first remission with expression of CD80, CD86, CD11a, CD54 or HLA class II. However, when expression of CD80 and CD86 were considered together, a significantly longer duration of remission was found. We suggest that these molecules may play a role in immunosurveillance, resulting in prolonged remission in some patients treated for AML.     

Persistence of an activating N-RAS oncogene mutation in clonogenic progenitor cells from an acute myeloid leukaemia patient in remission

Summary A patient with acute myeloid leukaemia (AML) with an activating N- RAS oncogene mutation was studied in a haemopoietic clonogenic progenitor cell assay. Individual colonies and clusters were analysed by polymerase chain reaction and oligonucleotide hybridization for the original mutation. The mutation was detected in a majority of leukaemic clusters, but also in almost half of the differentiated colonies. After chemotherapy the patient entered clinical remission. However, the mutation could still be detected in the bone marrow. Only differentiated colonies and no leukaemic clusters were grown from the remission bone marrow, but the original mutation was still detectable in almost half of the colonies.     

Economic impact of genomic diagnostics for intermediate‐risk acute myeloid leukaemia

Acute Myeloid Leukaemia (AML) is a rare but serious group of diseases that require critical decision‐making for curative treatment. Over the past decade, scientific discovery has revealed dozens of prognostic gene mutations for AML while sequencing costs have plummeted. In this study, we compared the cost‐effectiveness of multigene integrative analysis (genomic analysis) with the standard molecular testing currently used for diagnosis of intermediate‐risk AML. We used a decision analytic model with data for costs and outcomes from British Columbia, Canada, to assess the long‐term (10‐year) economic impacts. Our results suggest that genomic analysis would result in a 26% increase in the use of first‐remission allogeneic stem cell transplantation. The resulting treatment decisions and downstream effects would come at an additional cost of $12 556 [2013 Canadian dollars (CAD)] per person and the incremental cost‐effectiveness ratio would be $49 493 per quality‐adjusted life‐year gained. Cost‐effectiveness was dependent on quality of life during the long‐term (5–10) years of survival, relapse rates following first‐remission chemotherapy and the upfront cost of transplantation. Non‐relapse mortality rates, short‐term quality of life and the cost of genomic sequencing had only minor impacts. Further research on post‐remission outcomes can lead to improvements in the cost‐effectiveness of curative treatments for AML.     

Autologous and allogeneic bone marrow transplantation in acute myeloid leukemia in first complete remission: an update of the Genoa experience with 159 patients

Summary In the attempt to evaluate the role of Autologous and Allogeneic Bone Marrow Transplantation, we have retrospectively analyzed 159 patients with Acute Myeloid Leukemia in first complete remission treated in our Unit, most of whom were referred from other Institutions. High-dose therapy was uniform and consisted of cyclophosphamide 60 mg/kg/d on two consecutive days and TBI in a single dose (10 Gy) for ABMT patients and in fractionated doses (3.3 Gy × 3 days) for BMT patients. Eight years actuarial survival was similar in two groups (52% for BMT and 49% for ABMT). The actuarial risk of relapse for BMT and ABMT was 29% and 43%, respectively. Considering that none of ABMT patients was purged with in vitro technique, this review seems to confirm the importance of in vivo purging with postremission intensification, immediately before the harvesting. Of course, more patients and a longer follow-up are needed to drow final conclusions.     

Hematopoietic cell transplantation from unrelated donors for treatment of patients with acute myeloid leukemia in first complete remission

Hematopoietic cell transplantation from a histocompatible sibling is generally recommended for patients with acute myeloid leukemia in first remission with intermediate or high risk disease. Two-thirds of patients lack a matched sibling raising the question of the utility of matched unrelated transplantation for such patients. Retrospective studies from single institutions and registry data report 44-50% disease-free survival at 5-years following ablative unrelated donor transplantation for adults. The German AML 01/99 is the only prospective study evaluating the utility of matched related and unrelated transplantation for AML patients in first remission with high risk disease and reported 4-year survival of 68% with matched related transplants, 56% with matched unrelated transplants and 23% with autografting. Thus, results suggest that for patients with AML in first remission with high risk features (as determined by cytogenetics or >5% blasts on day 15 of induction) who lack matched siblings, unrelated donor transplantation should be considered. Current challenges are to improve our ability to identify those patients most likely to benefit from early transplantation, to better select donors, and to develop transplant preparative regimens that are safer and more effective.     

Effect of allogeneic hematopoietic stem cell transplantation from matched siblings or unrelated donors during the first complete remission in patients with cytogenetically normal acute myeloid leukemia

We retrospectively examined the impact of hematopoietic stem cell transplantation (HSCT) during the first complete remission (CR1) in 81 patients with cytogenetically normal acute myeloid leukemia (CN-AML). Eligible patients were divided into three subgroups: HSCT recipients with allogeneic sibling or matched unrelated donors (MUD) (allogeneic HSCT, n = 47), recipients of autologous HSCT (n = 12), and patients receiving chemotherapy alone (n = 22). We examined factors associated with overall survival (OS) in these patients, focusing particularly on the effect of allogeneic HSCT. Comparing to those receiving chemotherapy alone, patients in the allogeneic HSCT group had significantly better OS, which was independent of the presence of comorbidities. Furthermore, patients who received allogeneic sibling HSCT had the best OS and disease-free survival (DFS). Patients who received MUD HSCT also had significant advantage in DFS but not in OS, when compared with patients in the chemotherapy group. The study results suggest that patients with CN-AML in CR1 who are eligible for HSCT may have a survival benefit from HSCT, especially the allogeneic HSCT. We suggest that future studies employ molecular classification of AML to better define the benefits of HSCT during CR1 in patients with CN-AML.     

Expansion of cytotoxic effectors with lytic activity against autologous blasts from acute myeloid leukaemia patients in complete haematological remission

New therapeutic approaches are needed to improve the cure rates in acute myeloid leukaemia (AML). The present study was designed to investigate whether: (1) cytotoxic lymphocytes could be expanded from AML patients in complete remission; (2) their signal transduction machinery was preserved; (3) these cells were capable of producing cytokines involved in the cytolytic process; and (4) these cells showed cytotoxic activity against allogeneic and autologous blasts. By co-culturing blood mononuclear cells with feeder cells, we obtained an average 5.3-fold increase in the total cell number and a 35-fold increase in natural killer (NK) cells. Expression of the zeta chain and of tyrosine kinases of the Src and Syk-ZAP families involved in the triggering of NK functions was analysed on expanded cells. The results demonstrated a signal transduction apparatus preserved and quantitatively similar to that of normal donors. After phorbol myristate acetate and ionomicin stimulation, the ability of expanded cells to produce interferon gamma and tumour necrosis factor alpha was documented. Patients' expanded cells showed a cytotoxic activity against target lines and allogeneic blasts which was similar to that of normal donors. Purification experiments indicated that the NK cell fraction was responsible for most of the lytic effect. More significantly, these cells also exerted a lytic effect against autologous blasts that could be further enhanced following incubation with low-dose interleukin 2. These findings document the possibility of expanding cytotoxic effectors with preserved signal transduction machinery and autologous killing capacity from AML patients in remission, and suggest a new potential immunotherapeutic strategy for the management of early disease recurrence or of residual disease.     

Prospects for achieving treatment-free remission in chronic myeloid leukaemia

In addition to the best possible overall survival, discontinuation of the tyrosine kinase-inhibitor (TKI) treatment [treatment free remission (TFR)] without observing a recurrence of the disease has become a major goal of the therapy of chronic myelogenous leukemia (CML). Many clinical studies have demonstrated that TFR is possible, although for the moment limited to a fraction of the CML patients able to achieve a stable deep molecular response (DMR). The factors associated to the possibility of remaining in TFR or of losing it, have been investigated by a number of controlled and observation clinical trials and although total TKI treatment duration, DMR duration and stability and, more recently, also the depth of the molecular response obtained at the time of discontinuation have been shown to be significant elements, most of the factors associated with a higher possibility of a successful discontinuation still remain elusive and are here reviewed.     

Criteria for defining a complete remission in acute myeloid leukaemia revisited. An analysis of patients treated in HOVON-SAKK co-operative group studies

Complete remission (CR) in patients with acute myeloid leukaemia (AML) is the primary endpoint for the evaluation of induction treatment and treatment strategies. However, the choice and application of the criteria for a haematological CR can often become a subject of debate because of regeneration more than 5% blasts may be present at the time of response evaluation; platelet and neutrophil recovery may be incomplete and marrow cellularity can vary. This study examined the individual parameters for CR in 1250 adult patients with de novo AML treated according to three successive study protocols. Patients with < or =5% blasts showed the best overall survival (OS) and the lowest relapse risk (RR). This was independent of blast cells present in the peripheral blood or bone marrow (BM) cellularity. In the same patient group, the presence of extramedullary leukaemia, incomplete platelet (<100 x 10(9)/l) or neutrophil (<1.0 x 10(9)/l) recovery caused a reduced OS and increased RR. In conclusion, < or =5% blasts in the BM, recovery of neutrophils and platelets, and the absence of extramedullary disease constitute the cornerstones for the definition of a haematological CR in patients with AML.     

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.     

Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard‐risk acute lymphoblastic leukaemia in first complete remission

We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard‐risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared with human leucocyte antigen (HLA)‐matched sibling donor (MSD) and HLA‐matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II–IV acute graft‐versus‐host disease (aGVHD) was 39·5%, 24·0% and 40·3% for HID, MSD and MUD, respectively (P = 0·020). However, there was no difference in grade III–IV aGVHD (11·4%, 7·7%, 13·5%, respectively, P = 0·468). The 5‐year cumulative transplant‐related mortality was 16·4%, 11·6% and 19·6% (P = 0·162), the 5‐year relapse rate post‐transplantation was 14·8%, 21·1% and 16·7% (P = 0·231), the 5‐year overall survival was 70·1%, 73·7% and 69·8% (P = 0·525), and the 5‐year disease‐free survival was 68·7%, 67·3% and 63·7%, respectively (P = 0·606). Furthermore, the 3‐year GVHD‐free, relapse‐free survival was not different (50·8%, 54·9% and 52·2%, respectively, P = 0·847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard‐risk adults with ALL in CR1 who lack matched donors.     

Cytogenetic and hematological spontaneous remission in a case of acute myelogenous leukemia

Several cases of spontaneous remission (SR) interrupting the invariably progressive course of untreated acute myeloblastic leukemia (AML) have been reported so far. We shall add to this series the hematological and cytogenetic SR occurring in a 72-yr-old man affected by AML following myelodysplastic syndrome. At diagnosis cytogenetic analysis showed the 48, xy, del (6) (p22-pter), +13, +14 karyotype. Owing to a lobar pneumonia, the chemotherapy was deferred and a broad spectrum antibiotic therapy was established. Supportive care included red cells and platelet transfusions and low-dose corticosteroid. Two months later, after the pneumonia had completely disappeared, a complete remission, lasting about 5 months, was documented on bone marrow morphological and cytogenetical examination, although some degree of myeloid dysplasia persisted. Possible mechanisms of the various SRs described during the course of AML are discussed with a review of the literature.