Highdose Chemotherapy And Autologous Stem Cell Support

The role of HDC/ASCS is somewhat controversial at present. Many clinicians consider HDC/ASCS to be the "standard of care" for suitable candidates early in the course of their treatment, typically after two to four cycles of induction therapy. The data available from published studies has recently been summarized in overviews and management guidelines,7' 55' 75 and will be reviewed here briefly (also, refer to Chapter 90).

A randomized trial from the Intergroupe Francophone du MyƩlome (IFM) comparing HDC/ASCS to nonmye-loablative therapy (VMCP/VBAP) demonstrated a supe rior outcome for those patients treated with intensive therapy.34 In this trial involving 200 patients aged 65 years or less, the myeloablative preparative regimen consisted of melphalan 140 mg/m2 plus 8 Gy total body irradiation. The response rate, 5-year event-free survival (EFS) and 5-year OS were all higher in the transplant arm of the trial (81% vs 55%, 28% vs 10%, and 52% vs 12%, respectively). The median OS for the HDC/ASCS arm was just over 1 year longer (57 months vs 44 months). A similar 1-year OS advantage (54 months vs 42 months) was also demonstrated in the more recent Medical Research Council (MRC) VII trial,76 which involved 401 patients randomized to either HDC/ASCS or a conventional chemotherapy ("ABCM,"77 Table 83.1). The fact that the transplanted patients in the MRC study did not do any better than those in the IFM trial is disappointing, since the patients in the MRC study received stem cells instead of bone marrow, and generally received a transplant preparative regimen (melphalan 200 mg/m2 (MEL 200)) proven to be superior to that used in the IFM study.78

Two nonrandomized studies comparing the outcome of HDC/ASCS to historical controls also suggest survival benefit from transplant. The Arkansas group compared outcome for 123 patients treated with the "Total Therapy I (TTI)" tandem transplant regimen with that of matched historical controls treated on prior Southwest Oncology Group (SWOG) with conventional chemotherapy.79 Median EFS and OS were 49 and 62 months in the TTI group versus 22 and 48 months in the conventionally treated group. The Nordic Myeloma Study Group compared the results of therapy in 274 patients treated with HDC/ASCS and 274 matched historical controls who would have met current criteria for HDC/ASCS.80 The intensive therapy group had a 3-year OS of approximately 70% versus 55% in the nontransplant group. Log-rank comparison of the survival curves showed a difference that was highly statistically significant. Based on the preceding data, several experts in the field of MM have concluded that HDC/ASCS offers some benefit over standard regimens and it should be considered standard therapy for suitable patients.7, 55

In contrast to the results of the above-mentioned studies, a preliminary report from the PETHEMA investigators of a randomized trial comparing continued conventional chemotherapy to HDC/ASCS (MEL 200) in more than 200 patients who responded to initial conventional chemotherapy showed a similar median OS of approximately 5.5 years for both groups.81 It is possible that the exclusion of patients who did not respond to initial chemotherapy influenced the outcome of this study, making the results difficult to compare with those of the IFM and MRC studies. The Dutch-Belgian Hemato-Oncology Cooperative Study Group (HOVON) also conducted a randomized study in which patients received either HDC/ASCS or

"intermediate dose melphalan" (140 mg/m2). EFS and OS were the same for each arm (21 vs 22 months, and 50 vs 47 months, respectively).82

More recently, the preliminary results of a US Intergroup randomized study were reported, and as in the PETHEMA trial, no survival benefit was observed.83 Following VAD induction and high-dose cyclophos-phamide with stem cell collection, patients received either HDC/ASCS (MEL 140 + 12 Gy TBI) or two cycles of the M2 regimen. Eight hundred and four patients started VAD, but only 510 were randomized after induction. For nearly all of the almost 300 patients who did not proceed with randomization, the reason was failure to respond to induction therapy. Thirty-nine patients on this trial with matched sibling donors underwent allogeneic stem cell transplant before this arm of the study was closed due to a high (but not surprising) treatment-related mortality of 39% in the first year. In the other two arms, there was no difference in the response rate, 7-year progression free survival (17% for HDC/ASCS vs 16% for chemotherapy), or 7-year OS (37% vs 42%). Interestingly, despite the early mortality seen in the small group of patients who underwent allogeneic transplantation, there was a 7-year OS of approximately 40% (very similar to that for the other groups), with an apparent survival curve plateau suggesting possible cures in some cases.33 Reasons offered by the investigators for the lack of benefit with HDC/ASCS include unexpectedly good outcome in the conventional therapy arm compared to prior experience and the fact that over half of the patients progressing after M2 went on to be treated with HDC/ASCS.33 A previously published French randomized study demonstrated equivalent survival for patients randomized to treatment with HDC/ASCS as rescue therapy upon progression, versus immediately following conventional therapy,84 lending some credence to the latter assertion. It is possible that improved supportive measures and postprogression use of newer antimyeloma agents such as thalidomide or bortzeomib could have contributed to the longer-than-expected survival seen in this study, as well. Regardless of the reason(s), the equivalent results with nonmyeloablative therapy and HDC/ASCS in this large, well-conducted study will likely complicate decision making for patients and clinicians.

It has become evident that the subset of MM patients with deletion of all or part of chromosome 13 (A 13), detected by either standard cytogenetic techniques or by fluorescence in situ hybridization (FISH), have inferior outcome compared to patients lacking A13.85-87 Even with tandem melphalan-based autologous transplants, the 5-year OS for patients with A13 is only 16%,85 slightly inferior to the 22% observed for similar patients treated in another trial with the non-myeloablative VBMCP regimen.88 With poor outcome despite HDC/ASCS consistently demonstrated, other treatment options ought to be explored. At our center, we have offered patients under age 60 with A13 HDC/ASCS followed by a nonmyeloablative ("mini") allogeneic transplant. The rationale for this is to try and gain "graft-versus-myeloma" benefit89, 90 without the excessive early mortality seen with standard allo-geneic transplantation.91' 92 There is published anecdotal evidence that patients with A13 can enjoy extended benefit after such treatment.93, 94 Variations on this approach have been described in several published reports.94-96 Large studies more formally evaluating the strategy of HDC/ASCS "conditioning" followed by nonmyeloablative allogeneic stem cell transplant are currently underway.

All of the randomized trials of HDC/ASCS exclude patients with markedly impaired renal function, as well as patients older than 65-70 years. The available data suggests HDC/ASCS is possible in these groups, 97-102 though the potential for increased treatment-related toxicity should be recognized. For example, a preparative regimen of melphalan 140 mg/m2 may be optimal for patients with impaired renal function.103 It may also be desirable to use less intensive IV melphalan (i.e., 60-140 mg/m2) in older patients with MM to reduce toxicity.97 Such regimens in older patients may be able to achieve results comparable to those seen with more intensive transplant regimens.104

New issues related to HDC continue to emerge. Tandem autologous transplant has been shown in one randomized trial to yield superior outcome to single transplant,5 but there is evidence to suggest that the subset of patients actually benefiting from a second transplant are those not attaining a CR or nCR with the first one and who are able to undergo the second procedure within 6-12 months.5, 105 Given the mixed data on single HDC/ASCS, the role of tandem transplant in any patient group remains ambiguous. As allo-geneic stem cell transplant techniques become increasingly refined, the potential role of this modality will need to be explored further. Finally, the rapid expansion of novel antimyeloma agents in recent years has led to vigorous debate as to how these agents should be incorporated into both transplant and nontrans-plant treatment paradigms.

0 0

Post a comment