The treatment options for chronic myelogenous leukemia (CML) continue to evolve rapidly. Imatinib mesylate (Gleevec, Glivec, formerly STI571) has continued to show remarkable clinical benefits and the updated results with this agent are reviewed. As relapses using single agent imatinib have occurred, particularly in advanced phase patients, the issue of whether combinations of other antileukemic agents with imatinib may yield improved results is addressed. In addition, data on new agents that have potential in the treatment of CML are reviewed. These agents are presented in the context of their molecular mechanism of action. The most recent data for stem cell transplantation, along with advances in nonmyeloablative transplants, are also reviewed. In Section I, Drs. Stephen O'Brien and Brian Druker update the current status of clinical trials with imatinib and review ongoing investigations into mechanisms of resistance and combinations of imatinib with other agents. They also present their views on integration of imatinib with other therapies. In Section II, Dr. Jorge Cortes describes the most recent data on novel therapies for CML, including farnesyl transferase inhibitors, arsenic trioxide, decitabine, and troxatyl, among others. These agents are discussed in the context of their molecular mechanism of action and rationale for use. In Section III, Dr. Jerald Radich updates the results of stem cell transplants for CML, including emerging data on nonmyeloablative transplants. He also presents data on using microarrays to stratify patients into molecularly defined risk groups.

Chronic Myelogenous Leukemia

Treatment of Chronic Myelogenous Leukemia: Current Status and Investigational Options

Autologous transplants for chronic myelogenous leukaemia: results from eight transplant groups

Expansion of Philadelphia Chromosome–Negative CD3+CD56+ Cytotoxic Cells From Chronic Myeloid Leukemia Patients: In Vitro and In Vivo Efficacy in Severe Combined Immunodeficiency Disease Mice

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.

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 1992, 21 patients with chronic myeloid leukaemia (CML) in chronic phase (CP) were treated with high-dose chemotherapy (or chemoradiotherapy) followed by autografting with unmanipulated peripheral blood stem cells (PBSC). 12 of these patients survive at a median of 82 months from the time of autografting (range 9-105 months). Nine patients died, six of leukaemia in transformation and three from other causes. Survival of these 21 autograft patients was compared to that of 636 age-matched controls on the Medical Research Council's (MRC) data base, who had been treated with conventional chemotherapy over the same period. Autografted patients had a significantly longer survival at 5 years post autograft than chemotherapy patients (56% v 28%) even after appropriate allowance for time at risk before autograft (Mantel-Byar, 2P = 0.003). There was no difference in survival whether autografting was performed early in the disease or later or whether the PBSC had been harvested soon after diagnosis or later. If the benefits of autografting in chronic phase seen in this non-randomized series can be confirmed in a randomized study, autografting might be the treatment of choice for younger CML patients who do not have suitable donors for allogeneic transplant.

Autografting for patients with CML in chronic phase: an update. Hammersmith BMT Team LRF Centre for Adult 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.

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

The optimal approach for curing patients with chronic myeloid leukemia (CML) in chronic phase (CP) is an allogeneic bone marrow transplant (BMT). However, this approach is not available to the majority of patients. Autografting, using either purged or unpurged bone marrow or peripheral blood stem cells (PBSC), could be beneficial for patients who are not eligible for BMT. Between 1984 and 1992, 21 patients with CML in CP were autografted using unmanipulated PBSC harvested either at diagnosis or thereafter. Ten of 21 patients survived at a median of 84 months following autografting (range: 12-108 months). Eleven patients died, seven of blast transformation and four from other causes. The timing of the autograft or the harvest does not appear to have a bearing on survival.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.5530110907

Autografting for patients with chronic myeloid leukemia--the Hammersmith experience.

The treatment of patients with CML in chronic phase by high dose chemotherapy followed by transfusion of autologous haemopoietic stem cells collected and cryopreserved previously may theoretically prolong survival. This benefit could result from reducing the number of leukaemia stem cells at risk for transformation or by partial re-establishment of Ph-negative haematopoiesis. In practice some patients achieve partial Ph-negative haematopoiesis after autografting but most patients have entirely Ph-positive haematopoiesis by one year after autografting. Results may be improved if methods to favour reconstitution with Ph-negative haematopoiesis can be perfected.

Christine Hoyle

Papers

Autografting for patients with CML in chronic phase: an update. Hammersmith BMT Team LRF Centre for Adult Leukaemia.

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

Autografting for patients with chronic myeloid leukemia--the Hammersmith experience.

Peripheral blood stem cell autografts in CML.