Leukemiu and Lymphoma, Vol. 4, pp. 93-98 Reprints available directly from the publisher Photocopying permitted by license only

(c) 1991 Harwood Academic Publishers GmbH Printed in the United Kingdom

The Management of Relapsed and Refractory Acute Myeloid Leukaemia in Adults

LYDIA JONES and ADRIAN CHARLES NEWLAND

Department of Haematology, The Royal London Hospital, Whitechapel, London, UK

(Received 24 August 1990; in final form 20 September 1990)

The improved survival of patients with AML over the last 2&30 years can be attributed both to advances in cytotoxic therapy and in supportive care and up to 25% of responders may be cured. Nevertheless, most patients with AML eventually relapse and ultimately die from resistant leukaemia and up to 30% fail to attain initial complete remission (CR). This annotation reviews current therapeutic options in relapsed and refractory AML in adults.

KEY WORDS: Acute myeloid leukaemia relapsed refractory.

Modern conventional induction therapy comprises a combination of an anthracycline such as daunorubicin and cytarabine. Thioguanine is often included but probably contributes little to the expected complete remission rate of over 70%'. Regimens which incorporate 3 doses of daunorubicin at 45-75 mg/m2/day and cytarabine at 200 mg/m2/day as a continuous infusion for 10 days have probably reached the limits of tolerability. Patients who fail to remit with such standard first-line therapy are said to have primary refractory disease. The median duration of first remission is 9-16 months and the 3 year disease-free survival for adults between 16 and 40 years of age is between 25-40%2--9. For patients who relapse, it is useful to distinguish those relapsing early (within 6 months of achieving CR) and late (more than 6 months from initial CR and on no treatment) since their biological behaviour may be quite different". Some authors include early relapses with those with primary refractory disease. Comparison of data from small studies is difficult where the patient population is an heterogeneous mix of refractory disease and early and late relapse.

Address for correspondence: Dr A. C. Newland, Department of Haematology. The Royal London Hospital. Whitechapel, London El IBB. UK

RE-INDUCTION CHEMOTHERAPY

Following relapse the approach to patients should take into account their age and general condition. For some, supportive care alone is appropriate and the patient should be treated symptomatically with gentle chemotherapy, if any, on an outpatient basis. If salvage therapy is indicated, conventional induction regimens should be followed in those whose first CR lasted more than 6 months. In patients with primary refractory disease or with a short first CR, a more investigational approach to therapy may be justified since the response rate to conventional therapy is usually poor. Daunorubicin and cytarabine will induce a second CR in relapsed patients which depends on the extent of prior exposure to these drugs and the duration of first remission. At best, rates of 30-50% may be expected'. Many alternative regimens have been devised and usually aim to exploit the potential for response to a non cross-resistant agent and/or to escalate the dose of a drug to which the patient has ceased to respond at conventional doses in the hope of overcoming drug resistance. For example, the intracellular concentration of cytarabine depends primarily on facilitated diffusion through the membrane nucleoside carriers. Higher doses of the drug increases passive diffusion and in vitro studies

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94 L. JONES AND A. C. NEWLAND

indicate that this is the most likely mechanism by which high dose cytarabine (HDAC) has its clinical effect". Consequently, HDAC, either alone or in combination, has been widely studied over the last few years and in general displays the highest anti- leukaemic activity in comparison with other single agent therapies.

Dose schedules of HDAC vary widely and range from 6 to 36 g/m2 as either intermittent or continuous infusion over 3 to 6 days. Recent pharmacokinetic data indicate that the intracellular concentration of the active metabolite of cytarabine, Ara-CTP, is not further increased in individual patients with admin- istration of cytarabine over 0.5-1.0 g/m2 12. It seems likely that pushing the dose higher merely increases the risks of significant toxicity with little therapeutic benefit. Some authors distinguish intermediate dose cytarabine (IDAC) for schedules containing from 6-12 g/m2. Around 1/3 of all relapsed patients treated with HDAC alone can be expected to enter a second CRI3* 14. If distinction is made between relapsed patients who are sensitive or resistant to conventional dose cytarabine, then the CR rates with HDAC are respectively 59% and 15%5* 1 3 9 16. Many groups have tried to improve these results by looking at HDAC in combination with agents such as M-AMSA16-' 9,

anthra~yclines~-~', m i t ~ x a n t r o n e ~ l - ~ ~ , asparagin- aseZs and etoposide26. Analysis of pooled data shows that just over half of all patients will enter second CR with rates of up to 70% for patients in first relapse and 2540% for patients with refractory disease".". These results seem better than those achieved with HDAC alone though no one particular combination emerges as superior.

Idarubicin is a new anthracycline which differs from daunorubicin by the absence of a methoxyl group in the C4 position of the aglycone. Initial studies in laboratory animals showed that it had a significantly higher therapeutic index than daunorubicin in a variety of mal ignan~ies~~. 28. Early clinical studies showed promising activity in AML and, in combina- tion with cytarabine, second CR rates are comparable to the best obtained with older a n t h r a ~ y c l i n e s ~ ~ - ~ ~ . Once again, the most important factor in determining the rate of second CR is the duration of first remission. Harousseau and colleagues in their study of idarubicin and IDAC report second CR rates of 83% and 35% respectively for patients relapsing before and after 16 months of first remission (p = 0.003)32. Idarubicin is now being studied in first-line therapy of AML and it remains to be seen whether it will have a significant impact on the cure rate.

Treatment regimens not containing cytarabine are

relatively rare. Etoposide and mitoxantrone produced a second CR rate of 43% in a series of patients with relapsed and refractory AML33 but etoposide and M-AMSA was unsuccessful in a series of refractory patients reported by Hiddemanj4.

Finally, Laporte et al. have investigated the potential for synergism between intercalating agents in the treatment of refractory AML. Using mitoxan- trone, daunorubicin and vincristine, they obtained a remarkable 53% CR rate in a poor risk group of patients in which most remitters were considered resist ant to ant hracyclines 5 .

Remission duration after successful salvage therapy is usually short and ranges from 3-6 months in most studies. There have been few studies on the influence of pre-treatment variables on response to treatment. Keating et al. reviewed the outcome of salvage therapy in 243 patients at a single centre over a 10 year period up to 1985j6. Although certain karyotypic abnormali- ties were associated with a more favourable outcome (e.g. translocations such as t(15;17) and t(8;21)), the factor most strongly associated with response and survival was the duration of the initial remission. Using multivariate analysis, after allowing for prognostic factors, specific treatment regimens were not strongly associated with prognosis. Five per cent overall and 16% of the CR patients were predicted to survive more than 5 years. Patients who relapse late (> 18 months from first CR) appear to have different biological characteristics with correspondingly great- er disease sensitivity to ~ h e m o t h e r a p y ~ ~ .

BONE MARROW TRANSPLANTATION

The optimal timing of allogeneic bone marrow transplantation (BMT) in AML is a matter of some c o n t r o ~ e r s y ~ * ~ ~ . At first sight, disease-free survival (DFS) figures for BMT in first CR appear superior. Data both from a single centre" and from the International Bone Marrow Transplant Registry indicate a projected 5 year DFS of around 45-50%40. The corresponding figure for AML patients treated with conventional chemotherapy is around 20% for those achieving CR4'. The difficulty arises from the biases introduced into the BMT data-.g. patients who proceed to BMT may well have been in CR for 6 months or more and thereby preferentially selected for a higher probability (perhaps 4&50%) of remaining in CR regardless of whether they proceed to BMT. Likewise, patients who relapse before BMT may be censored from transplant data. In order to

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RELAPSED ACUTE MYELOID LEUKAEMIA 95

satisfactorily answer the question of optimal timing for BMT, patients in first CR would need to be randomised to immediate or delayed transplant in a prospective study. The balance of opinion at present favours BMT in first CR, unless risk factors can be identified which favour chemotherapy or would be predictive of a poor outcome from t ran~planta t ion~~.

The next dilemma in the management of the relapsed patient is whether to proceed immediately to transplantation or whether to wait until a second CR has been achieved. The available data indicates that around 30% of patients transplanted either in early relapse or in second CR may be The disadvantage of delaying transplant until second CR has been achieved is that a significant number of patients (40% or more) will fail re-induction therapy. This will then jeopardise the successful outcome of BMT. This assumes however that the transplant centre can accept patients for BMT without delay.

The relapse rate after allografting in first CR is around 20Y04*. The fate of these patients has been reviewed by the Seattle group4j. They found that performing a second allograft could only really be justified for those in whom relapse occurred more than one year from the initial transplant. Approx- imately 20% of patients might be salvaged by a second transplant.

AUTOGRAFTING

The rationale behind autologous bone marrow transplantation (ABMT) depends on escalation of post-remission treatment to a lethal myelo-ablative dose followed by stem cell rescue. Since the potential for ABMT is not limited by donor availability as in allografting, it is now being widely utilised. Older patients may be included who would otherwise be unsuitable for an allograft because of age. However, interpretation of the data requires caution because of the problems of time censoring and patient selection discussed in relation to allografting. Gale and Butturini have reviewed this subject extensively and conclude that there is no substantial improvement in DFS for patients undergoing ABMT in first CR compared with chemotherapy using age and time censored matched cohorts of patient^^^,^^. Until data from prospective controlled trials in which patient with AML in first CR are randomised to receive ABMT or other post-remission therapy, ABMT remains investigational. It is perhaps easier to evaluate the contribution of ABMT in second remission AML since, as already discussed, so few

patients can expect significant long term survival after chemotherapy alone. The European Bone Marrow Transplant Group have published pooled data on the outcome of ABMT in second remission AML and the projected DFS at 4 years is 30%46. The best results from a single centre come from the Rome group who report that 13 of 21 evaluable patients autografted in second CR survive, disease free after a median follow-up of 28 months4'. Their conditioning regimen comprised BCNU, amsacrine, etoposide and cytar- abine.

Peripheral blood stem cells (PBSC) have been used as an alternative to autologous bone marrow in autografting and have been shown to be capable of rapid, sustained and complete haemopoietic recon- stitution if a sufficient CFU-GM dose is A potential advantage to PBSC autografting is the low level of leukaemic contamination. However, it is likely that relapses after autografting in second CR or beyond are due to failure of eradication of leukaemia in the patient. PBSC autografting, like purging autologous marrow, will make little impact on the relapse rate and needs to be studied prospectively in first remission patients. Meanwhile, the time-consum- ing technique of PBSC collection compared with a bone marrow harvest make it unattractive to most centres. Thus there appears to be a significant role for ABMT in relapsed leukaemia provided second CR is attained and the results seem more durable than conventional salvage chemotherapy. There is no evidence as yet that purging or PBSC are of any value, at least for ABMT performed beyond first remis- ~ i o n ~ ~ . 50. Optimal conditioning remains to be defined but current toxicity is acceptable.

IMMUNOTHERAPY

Immunotherapy in AML was first looked at in the mid 1970's as an approach to maintenance treatment. Agents such as BCG and Corynebacterium parvum, with or without allogeneic or autologous myeloblasts were i n v e ~ t i g a t e d ~ l - ~ ~ . Early reports were encour- aging but after some adverse results, immunotherapy fell out of favour and later analysis of pooled data showed no improvement of survival'. More recently, it has been postulated that transplant related immune-mediated anti-leukaemia effects are as active as myeloablative conditioning in eradicating leukae- mia56. The question is whether transplant related immune effects can be exploited in the treatment of leukaemia in patients not undergoing transplantation. One such immunological mechanism is the graft-

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96 L. JONES AND A. C. NEWLAND

versus-leukaemia effect thought to be independent of GVHD. This is probably mediated by MHC- unrestricted activated natural killer cells (NK) which can be detected in the circulation of patients following both autologous and allogeneic (including T-depleted) BMT5'. They may exert an anti-leukaemic effect capable of mopping up minimal residual disease either by direct cell-mediated cytotoxicity or by secondary release of cytotoxic cytokines such as tumour necrosis factor and y-interferon which are inhibitory to myeloid cell growth. Such an effect may be induced in vitro by the cytokine interleukin-2 (IL-2). Lymphokine activated killer (LAK) cell cytotoxicity and secondary cytokine secretion can be generated by incubation of peripheral blood or bone marrow of patients with active AML or in r e m i s s i ~ n ~ ~ * ~ ~ . This approach seems most likely to be beneficial when disease bulk is at a minimum hence early clinical studies have looked at the effect of giving IL-2 after intensive cytoreductive therapy. The successful pro- duction of anti-neoplastic effector cells has been achieved with acceptable toxicity but it is not yet known whether this will translate into improved disease free surviva160*6 '. Further studies are now underway looking at IL-2 as an integral component of salvage protocols for relapsed AML and results are eagerly awaited. Other workers have used cyclosporin to induce graft-versus-host-disease after ABMT. Cyclosporin may augment the development of anti-Ia autoreactive lymphocytes which, in addition to mediating a GvHD-like reaction, may have anti- tumour activity. This has not so far been substantiated in clinical studies62.

GROWTH FACTORS

Molecules known as growth factors that regulate growth of normal haemopoietic stem cells have recently been isolated and can now be synthesised using recombinant DNA t e c h n o l ~ g y ~ ~ . ~ ~ . Working from the hypothesis that leukaemia results from an imbalance of proliferation, self-renewal and differ- entiation, the potential application of growth factors to treating leukaemia can be considered in the following ways. Firstly, non-proliferative leukaemic stem cells are insensitive to cell-cycle dependent cytotoxic drugs. Correctly timed administration of appropriate growth factors could increase the proportion of proliferating leukaemia stem cells and thus increase the efficacy of subsequent chemo- therapy65. Secondly, growth factors could be used to

regulate normal stem cells. For example, use of G-CSF or GM-CSF after myeloablative therapy and BMT or ABMT can significantly shorten the engraftment time and potentially reduce procedure- related morbidity and mortality66-68. They could also permit dose escalation of conventional chemotherapy. Thirdly, growth factors could be used to modulate the immune system-either by direct inhibition of leukaemia cell growth (e.g. the interferons) or indirectly via the LAK mechanisms discussed earlier. Many trials are underway addressing these various approaches but it is not yet known what the impact of growth factors will be towards curing leukaemia.

SUPPORTIVE CARE

As discussed earlier, consideration must be given on an individual basis as to whether or not to offer active treatment for relapsed AML. Indeed, many patients decide themselves against further hospitalisation when faced with the poor prognosis. Such patients may well maintain a reasonable quality of life for many months with supportive red cell and platelet transfusions, preferably as outpatients. In addition, it may be justified to treat febrile episodes with broad-spectrum antibiotics and even antifungals if the patient's overall condition is otherwise good. An oral cytotoxic such as thioguanine or idarubicin may stabilise the peripheral blast cell count and relieve systemic symptoms such as bone pain. Finally, the patient and his relatives require much psychological support. They may greatly benefit from early referral to terminal care support teams who can provide domiciliary nursing or hospice admission if preferred. Voluntary organisations also make a valuable contribution and may offer continued help to bereaved relatives.

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