Page 1222 - Hematology_ Basic Principles and Practice ( PDFDrive )

1068 Part VII Hematologic Malignancies

Graft Versus Leukemia Effect in Chronic Myeloid BCR-ABL-negative patients subsequently relapsed compared with
14% of 90 BCR-ABL-positive patients. The advent of reliable quan-
Leukemia titative PCR testing further refined risk prediction of BCR-ABL
detection. Olavarria and colleagues studied 138 transplant patients
Although evidence for a GVL effect can be found in many settings, at 3 to 5 months posttransplant and were able to define patients as
nowhere is it as strong as in the setting of allogeneic HCT therapy having a low risk for relapse (16%), an intermediate risk (43%), or
for CML. Evidence in support of such an effect includes the follow- a high risk (86%) based on BCR-ABL quantification. Further studies
ing: the higher rates of relapse following syngeneic and T-cell–depleted have confirmed the importance of quantitative BCR-ABL monitoring
transplants compared with unmodified allogeneic transplants; the of minimal residual disease after transplantation for CML, which
close association between the development of acute and chronic offers an obvious opportunity for early intervention for patients with
GVHD and freedom from relapse following non-T-cell–depleted residual or recurring disease.
transplants; and the high response rate to donor lymphocyte infusions
(DLIs) to treat posttransplant relapse (range: 50–100%), which is
higher than in any other malignancy. The markedly increased relapse Treatment of Posttransplant Relapse
rates seen with T-cell depletion indicate a role for T cells in GVL.
T-cell targets might include minor histocompatibility antigens shared The pace of disease progression after posttransplant relapse is variable;
by most cells in the body, thus accounting for the association of GVL some patients remain low-level PCR positive for BCR-ABL for years
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with GVHD. Alternatively, there may be polymorphic minor histo- without relapsing, and some relapse with low levels of Ph metaphases
compatibility antigens, with expression limited to hematopoietic and remain stable for many years. An appreciation of the likely tempo
tissue. A third possible category of targets for the GVL effect in CML of progression is thus important when considering treatment inter-
is the overexpression of protein targets in CML cells. Understanding vention options.
the cells and their targets responsible for the potent GVL effect seen An increasing number of potential interventions are available for
in CML will be critical to the development of more effective, less relapsing disease. IFN can produce both clinical and cytogenetic
toxic transplant-based therapies in the future. remissions in patients who have relapsed after transplantation. Results
with IFN appear better if treatment is initiated at the time of cyto-
genetic relapse instead of waiting until hematologic relapse. A large
Reduced-Intensity Conditioning number of studies now demonstrate cytogenetic CR rates of 50% to
100% in patients treated with DLI for clinically relapsed CP CML.
Reduced-intensity conditioning (RIC) or nonablative transplant Response rates tend to be higher for patients treated earlier at the
approaches have been introduced with the aim of avoiding the toxici- time of cytogenetic relapse and lower for patients in AP. The two
ties of high-dose preparative regimens while retaining GVL effects. major complications of DLI are transient marrow failure and the
These approaches are of particular relevance for patients with CML development of GVHD. Marrow failure only occurs in patients
because their median age at diagnosis is 67 years. Using a preparative treated in hematologic relapse. Treatment earlier in the course of
regimen consisting only of 200-cGy TBI, and GVHD prophylaxis relapse can avoid this complication. The overall incidence of GVHD
using cyclosporine and mycophenolate mofetil, McSweeney and following DLI is approximately 50% in most series. It has since been
colleagues reported CMRs in five out of nine patients transplanted reported that large numbers of T cells are tolerated with less GVHD
for CML in CP (n = 6) or AP (n = 3). The other four patients rejected if administered in a fractionated fashion rather than as a single bulk
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their grafts. By adding 30 mg/m fludarabine pretransplant, graft dose. A recent report from the European Group for Blood and
rejection has been eliminated as a problem following matched sibling Marrow Transplantation provides further support for starting at lower
transplantation. Or and colleagues recently reported similar encour- doses of lymphocytes and escalating dosage as required.
aging results using a preparative regimen of fludarabine, low-dose Imatinib mesylate has been shown to be active as posttransplant
BU, and antithymocyte globulin. The MD Anderson Cancer Center therapy. In a report of 128 patients who were treated with imatinib
group reported outcomes of 64 CML patients with advanced-phase for posttransplant relapse, an overall response rate of 79% was seen,
disease (80% beyond first CP), not eligible for myeloablative prepara- with CHR seen in 100% of patients in CP, 83% in AP, and 43% in
tive regimens because of older age or comorbid conditions, who BC. CCR was seen in 29% of patients. Recurrence of GVHD was
received transplants with fludarabine-based reduced intensity condi- seen in 18%, and granulocytopenia requiring dose adjustments of
tioning regimens (matched related, n = 30; one antigen-mismatched imatinib developed in 43% of patients. Imatinib appears to be well
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related, n = 4; matched unrelated, n = 30). At 5 years, the OS and tolerated if given early after transplantation to prevent relapse in
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PFS were 33% and 20%, and treatment-related mortality was 48%. high-risk Ph cases. Twenty two patients with Ph ALL or advanced-
In multivariate analysis, only disease stage at time of HSCT was phase CML received imatinib at a median of 28 days postengraft-
significantly predictive for survival. These results indicate that ment. Of these patients, 17 out of 19 adults and all 3 children
reduced-intensity transplantation may offer a safe and effective way tolerated imatinib at the targeted dose (400 mg/day for adults,
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to treat CML in the CP, but alternative treatment strategies need to 260 mg/m /day for children), and 19 completed the planned course
be explored in patients with advanced disease. of 1 year of imatinib therapy. At a median follow-up of approximately
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1 2 years, 12 out of 15 of the Ph ALL and 5 out of 7 of the CML
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patients were in molecular remission. The use of TKI early post-
Residual Disease Posttransplantation transplant appears to be safe and effective in reducing relapse in CP
CML, but less effective in advanced CML. Administration of TKIs
The detection of BCR-ABL transcripts posttransplant is a strong with DLIs appears to be safe and does not increase the risk of GVHD.
predictor of relapse following transplantation. In a study of 346 Two retrospective analyses suggested that posttransplant TKI therapy
patients after transplantation, 40% of patients were positive for was associated with a lower incidence of extensive chronic GVHD.
BCR-ABL residual disease at 3 months posttransplant, but this However, prospective studies are needed to determine the benefit of
finding was not predictive of outcome, suggesting that eradication of posttransplant TKIs, as well as to optimize TKI dose and duration.
the CML clone posttransplant takes an extended period of time. In
contrast, at 6 or 12 months posttransplant, 27% of patients were
BCR-ABL positive and at this time the assay was a powerful predictor Indications for Allogeneic Transplant in the TKI Era
of outcome, as only 3% of PCR-negative patients eventually relapsed
compared with 42% of PCR-positive patients. The predictive power In the period before the advent of TKIs, allogeneic transplant was the
of PCR detection of BCR-ABL among longer term survivors is front-line treatment of choice for CML, especially for younger
somewhat weaker. At 18 months posttransplant, 1% of 289 patients. With the firm establishment of imatinib and other TKIs as