Adverse impact of bone marrow transplantation on quality of life in acute myeloid leukaemia patients; analysis of the UK Medical Research Council AML 10 Trial.

The increasing success of intensive consolidation chemotherapy (CCT) as an alternative to bone marrow transplant (BMT) in acute myeloid leukaemia (AML) necessitates comparison of the impact on quality of life (QoL) of these two treatment modalities. Most QoL studies following BMT involve small patient numbers and provide ambivalent results. The present study examines QoL in a large number of patients 1 year from the end of treatment within the United Kingdom Medical Research Council (UK MRC) AML10 trial of BMT versus CCT. Allogeneic-BMT (Allo-BMT) was observed to have an adverse impact on most QoL dimensions compared with Autologous-BMT (A-BMT) and CCT. More patients receiving BMT had mouth dryness problems and worse sexual and social relationships, professional and leisure activities than CCT patients. QoL in A-BMT patients was less impacted than Allo-BMT. Intention-to-treat analysis showed similar results. These results indicate that a reconsideration of treatment strategies is warranted, and that further, good prospective studies are needed to evaluate more clearly the effects of these treatments in long-term survivors.

Comparison of 'sequential' versus 'standard' chemotherapy as re-induction treatment, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): results of the UK Medical Research Council AML-R trial.

This aim of the acute myeloid leukaemia (AML)-R trial was to compare sequential (Seq) ADE (cytarabine, daunorubicin, etoposide) with standard (Std) ADE as remission re-induction treatment and to assess any benefit of cyclosporine (CSA) as a multidrug resistance modulator in refractory/relapsed AML patients. Seq ADE, based on the concept of Timed Sequential Therapy, comprised the same drugs as Std ADE but given at higher doses and in a different sequence. Between 1992 and 1997, 235 patients with relapsed (175) and refractory (60) AML were entered: 170 were randomized between Std versus Seq ADE and 213 between CSA versus no CSA. CSA was initially given at a dose of 5 mg/kg/d and increased to 10 mg/kg/d in the latter part of the trial. Overall, the complete remission (CR) rate was 43%, with Std ADE being significantly better than Seq ADE (54% versus 34%, P = 0.01). CR rates did not differ between the CSA and no CSA arms (41% versus 45%, P = 0.6). Overall, 3 year disease-free survival (DFS) of remitters was 16%, with a relapse risk of 70%. DFS was not significantly different between the chemotherapy or the CSA arms. Overall, 3 year survival was 8%. Survival with Std ADE was significantly better than with Seq ADE (12% versus 6%, P = 0.03). CSA did not affect overall survival, except in patients > or = 60 years, who fared worse on CSA (P = 0.0003). No difference in haematological toxicity between the chemotherapy or CSA arms was seen. Survival was better with longer first CR duration (P < 0.0001). We conclude that Std ADE was superior to Seq ADE for CR achievement and survival, with no benefit with CSA, at the doses used in this study.

A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties.

Data on 1711 patients, aged up to 55 years, in the MRC AML 10 trial were used to create a prognostic index for use in risk-directed therapy decision making for younger patients with acute myeloid leukaemia (AML). Two parameters, response after course 1 and cytogenetics, were strongly predictive of outcome. For patients with complete remission, partial remission and resistant disease, 5-year survival from the start of course 2 was 53%, 44% and 22% and relapse rates were 46%, 48% and 69% respectively, and for patients with favourable, intermediate and adverse karyotypic abnormalities, survival was 72%, 43% and 17% and relapse rates were 34%, 51% and 75% respectively (all P < 0.0001). Patients with FAB type M3 but no cytogenetic t(15;17) also had a low relapse rate (29%). These three factors were combined to give three risk groups: good (favourable karyotype or M3, irrespective of response status or presence of additional abnormalities), standard (neither good nor poor), poor (adverse karyotype or resistant disease, and no good-risk features). Survival for these three groups was 70%, 48% and 15% respectively and relapse rates were 33%. 50% and 78% (both P < 0.0001). The index is simple (based on just three parameters), robust (derived from 1711 patients), highly discriminatory (55% survival difference between good and poor risk) and validated, so can be applied in the clinical setting to assist with therapeutic decisions as in the current AML 12 trial.

Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties.

BACKGROUND: Three strategies are used to prevent relapse in patients with acute myeloid leukaemia in first remission. Most of those with suitable donors are offered allogeneic haemopoietic-stem-cell transplant. Other patients may receive intensive chemotherapy or autologous transplantation; we undertook this randomised prospective trial to assess which is the better option. METHODS: After three courses of intensive chemotherapy, bone marrow was harvested from patients (<56 years of age) in remission who lacked an HLA-matched sibling donor. These patients were then randomised to receive, after one more course of chemotherapy, no further treatment (n=191) or an autologous bone-marrow transplant (BMT) after preparation with cyclophosphamide and total-body irradiation (n=190). Outcome comparisons were by intention to treat with adjustment for the most important risk factors for relapse. FINDINGS: 381 patients were randomised (38% of those eligible). Of the 190 patients allocated autologous BMT, 126 received it. On intention-to-treat analysis the number of relapses was substantially lower in the autologous BMT group than in the group assigned no further treatment (64/190 [37%] vs 101/191 [58%], p=0.0007), resulting in superior disease-free survival at 7 years (53 vs 40%; p=0.04). These benefits were observed in all risk groups and age-groups. There were more deaths in remission in the autologous BMT group than in the no further treatment group (22 [12%] vs 7 [4%], p=0008). In children (<15 years) and patients with good-risk disease, survival from relapse in the no further treatment group was 35% and 38% at 2 years. There was an overall survival advantage in the autologous BMT group at 7 years (57 vs 45%, p=0.2). INTERPRETATION: The addition of autologous BMT to four courses of intensive chemotherapy substantially reduces the risk of relapse in all risk groups, leading to improvement in long-term survival. The good chance of salvage for children or patients with good-risk disease who relapse from chemotherapy, and the mortality, morbidity, late effects, and expense of autologous BMT, suggest that delay of autograft until second remission in these two groups may be appropriate.

Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council.

The relative efficacy and toxicity of the chemotherapeutic agents thioguanine (6TG) and etoposide (VP16) were assessed by a randomized comparison of the DAT (daunorubicin, cytarabine, thioguanine) versus ADE (daunorubicin, cytarabine, etoposide) regimens in the Medical Research Council's 10th acute myeloid leukaemia trial (MRC AML 10), which was open to patient entry from May 1988 to April 1995. In this, the largest reported trial of AML therapy to date, 1,857 eligible patients, mostly less than 56 years old, were randomized: 929 (including 143 children under 15 years old) were allocated to DAT and 928 (143 children) to ADE. The two groups were well matched for presentation features. The complete remission (CR) rate was 81% with DAT and 83% with ADE (P = .3). The percentages of remitters achieving remission after 1, 2, or more than 2 courses were 70%, 22%, and 8% for DAT and 74%, 21%, and 5% for ADE. The percentages failing to achieve a CR due to resistant disease were 11% with DAT versus 9% with ADE (P = .07). There was a slightly higher death rate in CR during consolidation chemotherapy with ADE (9%) than with DAT (6%) (P = .06). Patients receiving DAT took slightly but significantly longer to recover from neutropenia and thrombocytopenia but the median number of days in hospital were similar in each group. ADE patients experienced slightly more severe nonhematologic toxicity. There was also no significant difference between the groups in the longer-term measures of efficacy: disease-free survival at 6 years from CR was 42% (+/-4) for DAT and 43% (+/-4) for ADE (P = .8); relapse rate at 6 years was 50% (+/-4) for DAT and 49% (+/-5) for ADE (P = .6); survival at 6 years was 40% (+/-4) for both DAT and ADE (P = .9). Subgroup analysis failed to show any benefit for etoposide in patients with monocytic or myelomonocytic disease, or in any other diagnostic subgroup. In conclusion, DAT and ADE both achieve high remission rates and good long-term survival, and are equally effective chemotherapy regimens for the treatment of AML patients aged up to 55 years.

Dose intensification in acute myeloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's AML9 study. MRC Leukaemia in Adults Working Party.

Between 1984 and 1990, 972 patients aged 1-79 years with acute myeloid leukaemia (AML), from 85 British hospitals, were entered into the MRC's 9th AML trial. Patients were randomized between DAT 1 + 5 (daunorubicin for 1 d, with cytarabine and 6-thioguanine for 5 d) and DAT 3 + 10 (same dose drugs for 3 and 10 d respectively) as induction therapy. The 63% who achieved complete remission (CR) were randomized to receive two courses of DAT 2 + 7 alternating with two courses of either MAZE (m-AMSA, 5-azacytidine, etoposide) or COAP (cyclophosphamide, vincristine, cytarabine, prednisone). Finally, those still in CR were randomized to receive either 1 year of maintenance treatment with eight courses of cytarabine and thioguanine followed by four courses of COAP, or no further cytotoxic therapy. Resistance to induction therapy was less common with the DAT 3 + 10 regimen than with DAT 1 + 5 (13% v 23%; P = 0.0001) and hence, despite a 5% increase in the risk of induction death, the CR rate was higher (66% v 61%; P = 0.15). Moreover, CR was achieved more rapidly with DAT 3 + 10 (median 34 v 46 d; P < 0.0001) and thus patients required less time in hospital (mean 20 v 29 d) and less blood product support. 5-year relapse-free survival (28% v 23%; P = 0.05) and survival (23% v 18%; P < 0.05) were also better with DAT 3 + 10. Post-remission intensification of therapy with MAZE resulted in fewer relapses (66% v 74% at 5 years; P = 0.03) but patients allocated MAZE required considerably more supportive care and 14 (4.5%) died following 312 MAZE courses, whereas no deaths occurred following COAP. 5-year survival was not significantly higher with MAZE (37% v 31%). Finally, although 1 year of outpatient maintenance treatment appeared to delay, but not prevent, recurrence it did not improve 5-year survival which was non-significantly worse for those allocated maintenance treatment (41% v 44%). We conclude that the more intensive induction regimen, DAT 3 + 10, is not only more effective than DAT 1 + 5, even for older patients, but is also less expensive; intensive post-remission therapy with MAZE achieves better leukaemic control but at the cost of substantial toxicity; whereas low-level maintenance therapy confers no apparent advantage in survival as well as being inconvenient and costly.

Chemotherapy versus transplants for acute myelogenous leukemia in second remission.

The best therapy for persons with acute myelogenous leukemia (AML) in 2nd remission is unknown. Bone marrow transplants from an HLA-identical sibling are reported to be better than chemotherapy but this is controversial. The objective of the study was to compare 3-year leukemia-free survival (LFS) in comparable subjects receiving chemotherapy or a transplant. 485 persons with AML in 2nd remission were studied. The chemotherapy cohort included 244 persons treated on trials of the British Medical Research Council, Eastern Cooperative Oncology Group and MD Anderson Hospital. The transplant cohort included 257 persons transplanted worldwide and reported to the international Bone Marrow Transplant Registry (16 were also chemotherapy subjects.) Subjects were selected for comparable age and year of treatment. Preliminary analyses identified two factors correlated with LFS: age < or = or > 30 years and 1st remission duration < or = or > 1 year; subsequent analyses were partitioned accordingly. Three-year probabilities of treatment-related mortality with chemotherapy and transplants were 7% (95% confidence interval, 3-15%) vs 56% (49-63%). Three-year leukemia relapse probabilities were 81% (74-86%) vs 41% (33-49%). Three-year probabilities of LFS were 17% (12-23%) vs 26 (20-32%). Cohort analysis showed significantly higher LFS with transplants vs chemotherapy in persons < or = 30 years and 1st remissions > 1 year (41% (29-53%) vs 17% (7-32%); P = 0.017) and those in > 30 years with 1st remissions < or = 1 year (18% (9-29%) vs 7% (2-16%); P = 0.046). Others had comparable LFS with both treatments. These data indicate better LFS with HLA-identical sibling transplants than chemotherapy in some persons with AML in 2nd remission.

Aspects of treatment of acute myeloid leukemia in adults.

The treatment of acute myeloid leukemia has made steady rather than spectacular progress in the past few years, principally because of improved supportive care. The use of hematopoietic growth factors may contribute to the speed of normal bone marrow recovery following treatment; however, their potential role as modifiers of drug pharmacokinetics may be equally valuable in overcoming drug resistance. The full range of expression of the phenomenon of resistance is being intensively explored, and therapeutic opportunities for overcoming the P-glycoprotein pump are now being introduced. Gene therapy and exciting immunologic manipulations are also developing rapidly, and the role of suppressor genes has reached a fascinating point in research and clinical applications.

Resistance circumvention strategies tested in clinical leukaemia specimens using the MTT colorimetric assay.

We have used a 4-day MTT colorimetric assay to study drug sensitivity of leucocytes from leukaemia patients and from normal donors. Response to Adriamycin, vincristine, aclacinomycin A, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), and melphalan has been determined, together with the effects of the resistance modifiers verapamil, cyclosporin A, and ethacrynic acid. Sensitivity of chronic lymphoblastic leukemia (CLL) lymphocytes to vincristine was much greater than that of normal lymphocytes or of leucocytes from myeloid leukaemia patients. These cells were also more sensitive to melphalan. Verapamil and cyclosporin A at clinically achievable doses of 1 microgram/ml produced significant chemosensitisation in normal and leukaemic specimens, but the sensitisation ratio was greater than or equal to 2 only in a minority of specimens, except in the case of sensitisation to vincristine seen in the majority of CLL specimens. Sensitisation was generally greater in the more chemo-resistant specimens. The ratio of sensitivities of cells to Adriamycin compared with aclacinomycin A was greatest in the more Adriamycin-resistant specimens which supports the idea that cross-resistance between these agents may not be great. This was not, however, true for the ratio of Adriamycin/MX2 sensitivity. Use of the MTT assay may allow the identification of patients who would benefit from treatment with resistance modifiers or with 'low-resistance' anthracyclines.

Selective toxicity of ethacrynic acid towards lymphocytes of chronic lymphocytic leukemia in vitro.

We have used the MTT colorimetric assay to determine the sensitivity to ethacrynic acid of lymphocytes from normal donors and of peripheral blood cells from leukaemia patients. Whereas normal lymphocytes and cells from acute or chronic myeloid leukaemia showed similar sensitivities (median inhibitory dose, ID50 = 20-22 microM), lymphocytes from chronic lymphocytic leukaemia patients were much more sensitive (ID50 = 6 microM). This result was found irrespective of the assay duration.

Prognostic importance of Sudan Black positivity: a study of bone marrow slides from 1,386 patients with de novo acute myeloid leukaemia.

Analysis of bone marrow slides from 1,386 patients entered into the Medical Research Council's 8th and 9th trials in Acute Myeloid Leukaemia confirmed that features associated with differentiation in blast cells, in particular increasing Sudan Black (SB) positivity, were the most important morphological features for predicting remission achievement (P = 0.002) and hence survival (P less than 0.0001). SB positivity was also weakly predictive of remission duration (P = 0.05). A low complement of maturing granulocytes was associated with early induction death and a high percentage of blasts with shorter remissions. The few patients with acute promyelocytic leukaemia (FAB M3) had a high haemorrhagic death rate during induction and a low relapse rate. Apart from this, lineage involvement was not predictive of outcome. Multiple lineage leukaemias, in particular those with megakaryocytic and/or erythroid involvement, which had been reported previously to have a poor prognosis, did not have any worse remission rates in this series. When more than one cell line was involved, no combination with particularly good or poor prognosis could be identified. Multivariate analysis suggested that percentage SB positivity was adequate on its own to divide granulocytic leukaemias into poorly differentiated (less than 50% SB +ve) and well-differentiated groups (50% or more SB +ve) without the need for further measurements. This simple and reproducible test was strongly predictive of resistant disease but not of induction deaths. It was of considerably greater prognostic value--and was less open to inter-observer disagreement--than the FAB criteria which are usually used to classify granulocytic lineage leukaemias into the M1 and M2 subgroups. It is proposed that greater than or equal to 50% of blasts with SB positivity should replace blasts greater than 10% of maturing myeloid cells for this sub-categorization between M1 and M2.

A biological hypothesis for the FAB classification of acute myeloid leukaemias.

A biological hypothesis which is based upon the response of AML blast cells to retinoic acid alone and in combinations with other differentiating agents in primary culture, is proposed for the FAB classification of Acute Myeloid Leukaemias. The present biological hypothesis accounts for the biological and clinical observations in AML.

Synergistic interactions between recombinant human interleukin-3, GM-CSF and G-CSF in normal human marrow granulocyte-macrophage colony formation.

The network of interactions between human myelopoietic growth factors can lead to signal amplification that all regulate normal myelopoiesis. The present study identified synergistic interactions between recombinant human interleukin-3, GM-CSF and G-CSF on normal human marrow day 14 CFU-GM suggesting that the interactions between these human myelopoietic growth factors are mainly confined to the early stages of normal human myelopoiesis. The synergistic combinations of recombinant human interleukin-3 plus G-CSF and GM-CSF plus G-CSF warrant clinical trial for the recovery from cancer chemotherapy or radiotherapy-induced myelosuppression and for augmenting human defence against infections.

New synergistic combinations of differentiation inducing agents in the treatment of acute myeloid leukaemia.

Differentiation inducing agents in double and triple combinations can induce differentiation in primary culture of more than 80% of blast cells from some AML patients. In the present study, the interactions between these differentiating agents have been analysed using Berenbaum's general algebraic solution and three new, potentially clinically useful synergistic combinations: have been identified all trans retinoic acid (RA) + hexamethylene bisacetamide (HMBA), cytosine arabinoside (Ara-C) + HMBA and RA + Ara-C + HMBA. A measure of the effectiveness of these combinations was that the doses of Ara-C and HMBA required to induce 50% differentiation were decreased about 10-fold and 5-fold, respectively, in combination with 1 microM RA. The new synergistic combinations are important not only to limit toxicity but also because multiple drug combinations may better overcome the inherent molecular heterogeneity of the differentiation defect in AML patients. They warrant clinical trial in AML patients who are either unsuitable for or are unresponsive to conventional cytotoxic chemotherapy.

T-Cell Receptor and Immunoglobulin Gene Rearrangements in Acute Myeloid and Undifferentiated Leukemias of Adults: Correlation with Weak Surface Expression of CD45 and CDw52 Antigens.

We examined 150 cases of acute myeloid leukemia (AML) and 8 cases of acute undifferentiated leukemi (AUL) of adults for both phenotypic and genotypic evidence of commitment to the lymphoid lineages. There was no correlation between expression of lymphoid differentiation antigens and rearrangement of T-cell receptor (TCR) and immunoglobulin (Ig) DNA sequences. In particular 8 cases of CD7(+) AML were germline for all TCR α, ß,µ, and δ Also none of the 11 cases with IgJH rearrangement expressed CD19 either on the cell surface or within the cytoplasm. Ten out of 13 cases with TCR/Ig gene rearrangement were either cytologically undifferentiated AML of FAB type M1 or AUL. None had clear immunophenotypic evidence for commitment to lymphoid lineages but 9 expressed only very small amounts of CD45 'framework' antigens and 7 expressed small amounts of CDw52 (CAMPATH-1). This phenotypic combination is otherwise seen only in precursor B cell ALL. TCR/Ig gene rearrangement in AML and AUL of adults appears to have become dissociated from the rest of the lymphoid differentiation 'program'. Recognition of these cases may be facilitated by the weak expression of both CD45 and CDw52 antigens.

Auer bodies in acute myeloid leukaemia patients.

Auer bodies have been reported in several clinical studies to be the single most important favourable prognostic parameter for induction remission rate and survival duration in patients with acute myeloid leukaemia (AML). The presence of Auer bodies in 205 AML patients was studied and its relationship with five cytological and cytochemical features of leukaemic cell maturation: the presence of granules, low nuclear/cytoplasmic ratio, Sudan black positivity, esterases positivity and the maturation index was assessed in bone marrow smears of each AML patient. The results showed a significant correlation between the presence of Auer bodies and both young age and more differentiated leukaemic cells. These findings may explain their favourable prognostic significance in AML patients.

Retinoic acid induces granulocytic differentiation of myeloid progenitors in congenital agranulocytosis bone marrow cells.

Congenital agranulocytosis is a rare fatal infantile disease characterised by recurrent bacterial infections, persistent absence of neutrophils and maturation arrest at the promyelocyte/myelocyte stage. The effectiveness of retinoic acid in inducing differentiation of congenital agranulocytosis marrow myeloid progenitor cells was studied. Non-adherent mononuclear marrow cells were treated in an in vitro culture with retinoic acid at various concentrations from 1nM to 1 microM for seven days. Morphological and functional differentiation into mature granulocytes was induced by retinoic acid in a dose-response stimulation with a maximum response at a concentration of 1 microM. These results suggest a potential therapeutic role for retinoic acid in the treatment of congenital agranulocytosis.

Relation between age and blast cell differentiation in acute myeloid leukaemia patients.

The relation between age and the cytological and cytochemical features of blast cell differentiation in 211 patients with primary acute myeloid leukaemia (AML) was investigated. Five cytological and cytochemical features of blast cell differentiation-the presence of Auer rods, the presence of granules, low nuclear/cytoplasmic ratio, Sudan black positivity and the maturation index-were studied in bone marrow smears of each AML patient. The results showed significantly more AML cases with both cytological and cytochemical features of blast cell differentiation in young patients (less than 60 years old) than in elderly patients (greater than 60 years old). These findings support the existence of two forms of primary AML: one more frequently detected in younger patients with more differentiated blast cells and the second with less differentiated blast cells mainly found in elderly patients.

Triple combination of retinoic acid, low concentration of cytarabine and dimethylformamide induces differentiation of human acute myeloid leukaemic blasts.

Differentiation induction therapy provides an alternative for treatment of patients with acute myeloid leukaemia (AML) who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + low concentration of cytarabine (Ara-C) + dimethylformamide (DMF) on the differentiation of blasts from 24 AML patients was studied. Nonadherent mononuclear cells were cultured at a concentration of 5 x 10(5) cells/ml in 24-well tissue culture plates containing RPMI 1640 culture medium with 20% fetal calf serum, 10% autologous serum and 10% 5637-conditioned medium and incubated with 10(-6) M RA, 10(-6) M Ara-C and/or 100 mM DMF alone and in combination with each other for 6 days in primary culture at 37 degrees C in a humidified incubator under 5% CO2. The triple combination of 10(-6) M RA + 10(-6) M Ara-C + 100 mM DMF induced 90% of blasts from 22 out of 24 AML patients to differentiate. These highly effective results justify a clinical trial of this triple combination for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.