Page 1486 - Williams Hematology ( PDFDrive )

1460 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1461

with BCR-ABL1 transcripts greater than 10 percent or less than a PCyR CD25-high are associated with higher rates of relapse after allografting
at 3 and 6 months, minor or no cytogenetic response at 12 months, and in CML. 689
only a PCyR at 18 months or cytogenetic relapse at 12 or 18 months. 417
Nonmyeloablative Allogeneic Transplants
Myeloablative Allogeneic Transplants Nonablative regimens have been developed in an attempt to expand the
Stem cell transplantation from HLA-compatible siblings results in indication for allogeneic transplantation to older patients. These regi-
engraftment and an actual or projected long-term survival in 45 to 85 mens rely on immunosuppressive therapy to allow engraftment of cells
percent of recipients. 674–676 In patients older than age 50 years, survival that potentially will generate a graft-versus-leukemia effect. These pro-
rates are slightly less at 5 years. The risk of CML relapse is approxi- cedures in general are associated with acceptable degrees of engraftment,
mately 20 percent, with a plateau of relapse at 5 to 7 years. Transplanted less mortality, similar rates of GVHD, and possible durable effects on
T lymphocytes, especially if activated by a (mild) GVHD, may be an persistent or recurrent disease. Approximately 60 percent of patients,
690
important factor in preventing leukemic relapse. This phenomenon, mostly in initial chronic phase (median age: 50 years) and transplanted
referred to as graft-versus-leukemia reaction, is thought to suppress the with reduced-intensity conditioning regimens, had a 3-year survival
634
leukemic process through T-cell–mediated cytotoxicity. The relative and about one-third had a 3-year progression-free survival. Patients
691
benefit of marrow compared to mobilized blood stem cells as the source no longer in first chronic phase do not fare as well. Conditioning
712
of the allograft has not been established. 677,678 Mobilized blood stem cells regimens include fludarabine and busulfan, 693,694 low-dose TBI and flu-
engraft more rapidly but may be associated with more chronic GVHD. darabine, and low-dose TBI and cyclophosphamide, but no prospec-
The majority of survivors have no evidence of residual leukemia. 679 tive randomized trials comparing regimens or comparing ablative and
For younger patients who do not have a histocompatible sibling, nonmyeloablative transplant approaches have been conducted. 693,695,696
an unrelated donor or a mismatched family member as a source of In one case, imatinib given concurrently with nonmyeloablative stem
stem cells is feasible. When class I HLA genes are typed with molecu- cell transplantation did not compromise engraftment and resulted in a
lar methods, an improvement in matching and better outcomes using cytogenetic remission in a patient with CML in blast crisis. Whereas
697
unrelated donors have been demonstrated and are comparable to those nonmyeloablative or reduced intensity regimens are still considered
transplanted with a matched-sibling donor. When matched-unrelated investigational, they can achieve molecular remissions.
donor and sibling donor transplants were compared, unrelated donor
transplants had increased risk of graft failure and acute GVHD, but
only a slightly poorer survival and disease-free survival. For patients USE OF TYROSINE KINASE INHIBITORS AFTER
who survived to 1 year, only a slightly inferior disease-free survival was
observed. The rate of extensive chronic GVHD is up to 60 percent STEM CELL TRANSPLANT
680
with unrelated donor transplants, but 63 percent disease-free survival In patients treated with stem cell transplantation before the wide avail-
in younger CML chronic phase patients has been reported. Cord blood ability of imatinib, complete cytogenetic remissions with imatinib treat-
stem cell transplantation from an unrelated donor has also been used in ment can occur if treated at relapse after allografting and after donor
adults with CML. 681 lymphocyte infusion (DLI) fails to give a response. Such remissions
698
Pretransplantation imatinib is not associated with increased may include a molecular response. Complete responses after ima-
transplant-related morbidity or decreased survival, but those who are tinib therapy have been noted in accelerated or blast phase CML per-
699
transplanted with suboptimal response to imatinib or loss of response sisting after stem cell transplantation. In another series, 45 percent of
to imatinib fare worse, probably related to a higher disease burden at relapsed patients had a CCyR of up to 28 months and without signifi-
700
the time of transplantation and more aggressive disease. 682,683 Second- cant GVHD. In a series of 28 adults with relapse after allogeneic stem
684
generation TKIs do not increase transplant-related toxicity. Disease cell transplantation who then received imatinib, the response rate was
status after allografting can be monitored with cytogenetic studies, 74 percent, and the complete cytogenetic remission rate was 35 percent.
PCR, or FISH analysis. A positive PCR assay 3 months after allogeneic Five patients had recurrence of GVHD, and 13 had received previous
transplantation has not been found to correlate with an increased risk DLI infusions. In one series, imatinib was able to generate complete
698
of relapse compared with PCR-negative patients. A positive assay at 6 molecular remissions in 26 percent of chronic phase patients after allog-
701
months and beyond is associated with subsequent relapse. In one series, rafting, with full donor chimerism usually observed. One study found
42 percent of patients with a positive PCR assay at 6 to 12 months relapsed that more relapsed patients had a molecular remission with DLI at
685
versus 3 percent with a negative assay. Paradoxically, patients who 5 years than with imatinib alone. Most of these patients had cytogenetic
remain BCR-ABL1 positive more than 36 months after transplantation relapses only. In a retrospective comparison of 37 patients with hema-
702
685
have little propensity for relapse. Serial quantitative RT-PCR analysis tologic or molecular relapse of CML who received imatinib, DLI, or a
of blood specimens has been proposed to distinguish patients destined combination of both in concurrent or sequential regimens, the over-
to relapse. Patients who remain in remission have undetectable, low, all survival was 100, 89, and 54 percent for both modalities, imatinib,
686
703
or falling BCR-ABL1 levels on sequential analysis. After 6 to 9 months, alone, and DLI alone, respectively. There are few studies examining
these levels are undetectable in most cases. Recognition of relapse at the use of nilotinib or dasatinib for posttransplantation relapses. 704
molecular level may allow for early therapeutic intervention. Prophylactic administration of imatinib after transplantation has
Killer immunoglobulin-like receptors (KIRs) are expressed by NK been used for patients at high risk of relapse. Posttransplantation
705
cells and subpopulations of T cells. NK clones from a single individual imatinib may also postpone the requirement for DLI with its atten-
706
can vary substantially in the type of KIR molecules they express. The dant risks of GVHD and marrow aplasia. Some have found that DLI
ligands for several of the inhibitory KIR have been shown to be sub- are superior to imatinib therapy in preventing relapse and increasing
sets of HLA class I molecules. Missing KIR ligands in recipients lead leukemia-free survival. Posttransplantation imatinib is usually well-
687
to less relapse and increased GVHD based on NK alloreactivity. KIR tolerated; pancytopenia is the principal toxicity. The cytopenias resolve
ligand mismatch has also been found to be an important prognostic fac- with doses adjustments or temporary drug discontinuation. Many
tor in achieving molecular responses after transplantation for CML. questions remain regarding the use of posttransplantation TKIs. When
688
Increased frequency of regulatory T cells characterized as CD4+, should they be started? Which drug is superior? For how long should

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