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

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recommended. The patient should be made aware of the risk for CML followed by G-CSF stimulation. G-CSF was used for at least 4 days
progression during the pregnancy. while imatinib treatment was continued for stem cell mobilization in
58 patients with a CCyR. The cells were collected in two cytapheresis
DISCONTINUATION OF TYROSINE KINASE procedures in 74 percent of patients, and the cells of 84 percent of those
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cytapheresis products were negative for the Ph chromosome.
INHIBITOR THERAPY In another series, stem cells were mobilized in 32 patients in com-
Patients responding to TKI therapy are likely to maintain their response. plete cytogenetic remission after imatinib, with uninterrupted imatinib
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TKIs are associated with a significant symptom burden, however, and therapy in 50 percent of patients and with imatinib temporarily with-
one-third have persistent moderate to severe symptoms. Persistent held in approximately 50 percent. Blood levels of BCR-ABL1 transcripts
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CMR is seen in only a minority of patients, and the vast majority of were not changed by the use of G-CSF. In yet another series, 13 of
patients on TKIs have minimal residual disease even if their BCR-ABL1 15 patients were successfully mobilized with G-CSF while receiving
transcripts are undetectable, and this may lead to relapse if the drug is imatinib, and 28 percent of stem cell harvests were negative for BCR-
stopped. Thus, in the absence of a clinical trial, life-long therapy with a ABL mRNA. No change in blood BCR-ABL1 transcript level was noted
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TKI is recommended. after stem cell mobilization as assessed by RT-PCR. No series of
Some patients in a CMR for 2 years or more have been able to dis- patients autografted with cells mobilized while they were receiving ima-
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continue imatinib without relapse. 635,636 Discontinuation of imatinib in tinib have been reported. Autografting might find a role in cases of
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12 patients who had undetectable disease for at least 2 years resulted in imatinib resistance, or to reduce the level of residual disease in cases
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six patients having a molecular relapse within 1 to 5 months (imatinib without a molecular response. Imatinib can be effective and safe in
was reintroduced with a response) and six others remaining in CMR chronic phase CML patients who have previously undergone autograft-
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for a median of 18 months. There are numerous anecdotes of patients ing, although there is an increased frequency of hematologic toxicity.
relapsing when imatinib was stopped. In patients with intolerable side
effects on imatinib, the dose may be reduced in some cases without the ALLOGENEIC HEMATOPOIETIC STEM CELL
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loss of a CMR. In occasional patients in whom imatinib is stopped, a
cytogenetic response of up to 15 months has persisted. 639–642 In a study TRANSPLANTATION
of 100 patients with a CMR (>5-log reduction in BCR/ABL1 tran- Until imatinib became available in 2001, allogeneic transplantation was
scripts) for at least 2 years who stopped imatinib, 69 patients had at least used in most new patients with CML who were younger than 65 years of
12 months of followup. Of these, 39 percent were stable and 61 percent age and who had a suitable donor. The advent of imatinib treatment and
relapsed, most within the first 6 months. The outcome of stopping was the projected survival of patients with a complete cytogenetic remission
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better for those with a lower Sokal risk score at diagnosis. In another has changed the indications for transplantation in CML. 658,659 There has
study, 40 patients were evaluated, and treatment-free remission at been a marked reduction in number of transplants performed for CML
24 months was 47.1 percent for all patients and was higher if patients worldwide and a decline in the proportion performed in first chronic
had prior IFN treatment. Female sex and early molecular response phase. 660,661 Although no randomized trials of imatinib versus transplan-
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predict stable undetectable BCR-ABL1 transcripts in chronic phase tation have been or are likely to be conducted, there is circumstantial
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CML, the criteria for early stopping. In a series of 423 CML patients evidence that survival is superior for populations of patients treated
treated with imatinib, the rate of undetectable BCR/ABL1 transcripts with drugs who have a CCyR as compared to transplantation. Allog-
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and stable MMR (4.5-log decrease) was 36.5 percent. A model to rafting continues to play a role in the treatment of patients, who are
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analyze the risk of molecular relapse after cessation of TKIs has been refractory or intolerant to serial TKIs, and remains the optimal therapy
developed. Reports of discontinuations, reappearance of the clone, in those who progress to accelerated or blast crisis in the face of treat-
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treatment with a second prolonged course of imatinib, discontinuation ment with a series of TKIs.
with retention of MMR at 32 months followup, and retention of CMR in Patients in the chronic phase of CML who are younger than approx-
12.5 percent have been described. 645 imately 70 years and who have an identical twin, or a histocompatible
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Discontinuation of nilotinib or dasatinib has not been reported sibling, 664,665 or access to a histocompatible unrelated donor, can be
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in a significant series, and larger prospective studies will be needed to transplanted after intensive therapy, usually with cyclophosphamide
determine in which patients stopping treatment can be safely attempted. and fractionated total-body irradiation (TBI) or a combination of
Because early, quiescent Ph chromosome–positive cells (CD34+Lin−) busulfan and cyclophosphamide. Busulfan can be administered as an
are insensitive to imatinib in vitro, at present it is advisable to main- intravenous preparation and as a single daily dose. When targeted
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tain treatment indefinitely until the criteria for cessation, if any, can steady-state busulfan levels are used, a 3-year survival rate of 86 per-
be established in clinical trials. Intermittent imatinib dosing has been cent and a disease-free survival rate of 78 percent with no age effect is
explored in selected elderly patients with CML without adverse impact achieved. With nonmyeloablative or “reduced-intensity” condition-
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on overall and progression-free survival. 647 ing regimens, older patients and those with comorbidities can undergo
successful allografting. With the success of TKI therapy, allogeneic
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HIGH-DOSE CHEMOTHERAPY WITH stem cell transplantation is no longer recommended as a treatment
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AUTOLOGOUS STEM CELL INFUSION option in chronic phase CML responding to any sequence of TKIs.
Allogeneic transplant should be considered for patients with disease
Since the availability of imatinib, autografting in CML is rarely used. progression to accelerated or blast phase on TKI therapy. In these cases,
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Ph chromosome–negative stem cells are present in most patients with TKIs to which the patient has not been previously exposed and for
CML at the time of diagnosis. Techniques that use these cells to recon- which they do not possess a resistant mutation can be used to bridge
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stitute hematopoiesis after high-dose therapy have been developed. or prepare for the transplant. Allogeneic transplant can be used in
Ph chromosome–negative progenitors can be mobilized with G-CSF those rare patients who present with blast crisis and in those with T315I
and collected from the blood of patients who have responded to prior mutations who do not respond to ponatinib. 672,673 In those who do not
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treatment with a TKI. Such cells also can be collected after recovery respond to their first TKI exposure and are switched to a second TKI,
from chemotherapy regimens, such as after idarubicin and cytarabine, transplantation in chronic phase would be indicated for those patients

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