Online First/Online Only
Articles/items published ahead of print or only online.
Tuesday, February 2, 2016
BY SARAH DIGIULIO
In a rare coordinated effort, all 69 National Cancer Institute-designated cancer centers issued a joint statement last week urging young adults, parents, and health care providers to take action to increase HPV vaccination rates for cancer prevention. The statement was published individually by each cancer center (a pdf version of the statement is available on The University of Texas MD Anderson Cancer Center website).
“Together we, the National Cancer Institute (NCI)-designated Cancer Centers, recognize these low rates of HPV vaccination as a serious public health threat. HPV vaccination represents a rare opportunity to prevent many cases of cancer that is tragically underused,” the statement notes. “HPV vaccination is our best defense in stopping HPV infection in our youth and preventing HPV-related cancers in our communities. The HPV vaccine is CANCER PREVENTION.”
Cancer centers serve patients and families affected by cancer, and therefore witness the tremendous suffering—emotional, physical, social, and financial—that a cancer diagnosis brings to patients and families on a daily basis, Ernest Hawk, MD, MPH, Vice President and Head of the Division of Cancer Prevention and Population Sciences at The University of Texas MD Anderson Cancer Center, explained via email. “Nothing could be more motivating for prioritizing a preventive action than that.
“And with the effectiveness of HPV vaccines standing at greater than 90% effectiveness in blunting the subsequent development of HPV-related pre-cancers and cancers, we felt it was time for concerted action across the cancer centers enterprise to draw the public's and providers' attention to this huge missed opportunity in a new way.”
How It Came About
Eighteen of the NCI-designated cancer centers had received supplemental NCI funding to do environmental assessments of their regional populations to understand why HPV vaccine uptake has been slow and establish plans to improve those vaccination rates. Representatives from those 18 centers, along with 18 other NCI centers met in November at MD Anderson, in collaboration with the NCI and Centers for Disease Control and Prevention, for a summit meeting to exchange data and work together on the effort. The meeting also included representatives from the American Cancer Society.
“An emerging priority resulting from that meeting was for NCI-designated centers to jointly develop, promote, and publish a strong statement of HPV vaccine endorsement for cancer prevention together,” Hawk said. Work has continued since November via a series of teleconferences and emails until the statement was issued last week, he said.
Rare Coordinated Effort for Population-Wide Impact
Concerted efforts have been made to implement new therapeutic strategies or argue for sustained Congressional support of research, Hawk said. “But we’re not aware of a past similar effort to advance a specific action in cancer control with this degree of consensus, coordination, and intentional drive.
“[The NCI-designated cancer centers] work independently to bring the very best in each of those domains to serve their catchment area populations. However they rarely work collectively in a coordinated and intentional effort involving cancer control to achieve population-wide impact.
“Hopefully, it is the first of many future efforts in collective action involving actions in cancer control to realize the potential of cancer prevention and health promotion across the population,” Hawk said.
Representatives from several of the signing cancer centers were vocal about the purpose behind the statement.
“The collective voice of the nation’s cancer centers sends a powerful message that this is a serious public health threat,” Candace Johnson, PhD, President and CEO of Roswell Park Cancer Institute, said in a statement—Roswell Park being one of the 69 cancer center signatories. “Most HPV-related cancers are preventable through the administration of safe and effective vaccines. This joint statement sends a strong message to the medical community encouraging health care providers to recommend this cancer-preventing vaccine to their patients and their families.”
In another statement, Lewis C. Cantley, PhD, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian, another NCI-designated, signing cancer center, added: “Vaccination is a highly effective weapon in the fight against cancer. … While we are constantly developing new therapies for cancer patients, vaccination can help reduce the number of cases we ever have to treat.”
The statement notes the latest HPV vaccination rates for girls and boys in the U.S.—40 percent and 21 percent respectively—both of which fall far short of the goal of an 80 percent vaccination rate by the end of the decade, which was established by the U.S. Department of Health and Human Services’ Healthy People 2020 mission. The statement summarizes the current CDC recommendations for HPV vaccination.
And the statement makes these three calls to action:
- Parents and guardians should have their sons and daughters complete the three-dose HPV vaccine before their 13th birthday, and as soon as possible in children 13 to 17;
- Young men (up to 21) and young women (up to 26) who were not vaccinated as preteens or teens, should complete the three-dose HPV vaccine as soon as possible; and
- Health care providers should join forces to educate parents, guardians, and colleagues about the importance and benefit of HPV vaccination; and be advocates for cancer prevention by making a strong recommendation for childhood HPV vaccination.
Friday, January 15, 2016
BY ANDREA WANG-GILLAM, MD, PHD
ANDREA WANG-GILLAM, MD, PHD, is Associate Professor and Clinical Director of the Gastrointestinal Oncology Program in the Division of Oncology at Washington University in St. Louis.
Research in gastrointestinal cancers has evolved rapidly. In 2015, there were a few landmark studies that either dramatically transformed our clinical practice or significantly advanced our understanding of tumor biology.
Immunotherapy has emerged as the mainstay treatment in solid tumors, especially with the recent media coverage on the dramatic disappearance of melanoma lesions in former president Jimmy Carter. Similarly, immunotherapy has made a striking appearance in GI cancers. The study led by Dung Le et al was based on the concept that tumors with “neoantigens” encoded by somatic mutations may be responsive to immunotherapy, so tumors with a high mutation burden due to mismatch-repaired (MMR) deficiency would generate more “neoantigens” and potentially respond better to immunotherapy.
Indeed, this phase II study reported an immune-related objective response rate of 40 percent (four out of 10) in patients with MMR deficient colorectal cancer while on pembrolizumab, an anti-programmed death protein 1 (PD-1) inhibitor, compared with 0 percent (0 out of 18 patients) in the MMR proficient group (N Engl J Med 2015;372:2509-20).
Additionally, the study confirmed a high somatic mutation load of 1,782 (mean) in the MMR deficient group, compared with 73 in the MMR proficient group, and a high mutation burden was associated with significantly longer progression-free survival. The drastic difference in treatment response between two groups illuminated the fact that a large sample size may not be necessary for a well-designed, hypothesis-driven trial. The similar impressive treatment response toward immune checkpoint inhibitors is anticipated across different tumor types with MMR deficiency. Meanwhile, anti-PD-1/PD-L1 inhibitors have continued to flourish in other GI tumors, including hepatocellular carcinoma and gastroesphogeal cancer, among others.
Comprehensive genomic analysis has not only identified novel oncogenic drivers, but also shed the light on potential therapeutic targets. A study led by Jeffery Ross et al has shown that two-thirds of patients with bile duct cancer have potential clinically actionable genetic alterations. Next-generation sequencing for 315 cancer-relevant genes was applied to 554 tumors, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder cancer. Interestingly, actionable alterations such as ERBB2 amplifications and PIK3CA/mTOR alterations were observed in gallbladder cancer in nearly the same proportion of breast cancers. Other therapeutic targets—FGFR fusion, IDH1/2 substitution and BRAF substitution—were seen in intrahepatic cholangiocarcinoma (2015 Gastrointestinal Cancers Symposium, Abstract 231). In an uncommon disease with few active agents such as bile duct cancer, individualized treatment matched to its genomic alteration carries great translational promise. The current challenge is to test this approach in the prospective setting, preferably by enrolling patients with actionable mutations in the NCI-MATCH trial.
Along the same line of genomic research, instead of looking for individual actionable mutations, a mutation signature approach has been developed as a new strategy tailoring therapeutic intervention. In particular, signature 3 is a mutation signature of a defective double-strand DNA break repair, which has great clinical implications, as it may predict response to DNA damaging agents. The study led by Ludmil Alexandorv and his colleagues examined the signature 3 (mutation signature) by analyzing 607 whole-genome sequences across 36 different human tumor types. Signature 3 was not only observed in breast, ovarian and pancreatic cancer, but also 7-12% gastric cancers (Nat Commun. 2015;6:8683). This signature approach is highly translational as it expands the potential therapeutic benefit of platinum compounds and PAPR inhibitors beyond the known deleterious germline BRCA 1 and BRCA 2 mutations.
A similar observation was made in pancreatic cancer by Nicola Waddle et al through deep whole-genome sequencing and copy number variation analysis of 100 pancreatic ductal adenocarcinomas (Nature 2015;518:495-501). The patterns of structure variation were used to classify pancreatic cancer into four subtypes with potential clinical utility. The subtype “genomic unstable” (14% of all samples) showed a large number of structure variations, suggesting the genomic instability associated with defective DNA repair. Therefore, patients with the genomic unstable subtype may be more sensitive to DNA damaging agents. Hopefully, the concept that tumors harboring a signature of defective DNA repair respond better to the DNA damaging agents is being tested in a prospective trial.
Early Detection and Screening Tools
Pancreatic cancer has a dismal prognosis with the only cure being surgical resection. Early detection remains the key to improving survival in this deadly disease. Exosomes are lipid-covered extracellular vesicles containing cellular material; they can also be derived from cancer cells.
A study led by Sonia Melo et al demonstrated the feasibility of using glypican-1 enriched cancer exosomes in serum as a biomarker for early stage pancreatic cancer detection (Nature 2015;523:177-82). The presence of glypican-1 (GPC1) exosomes can be used to distinguish healthy subjects and those with benign pancreatic disease from individuals with pancreatic cancer. Although the use of GPC1 exosomes as a screening biomarker for early stage pancreatic cancer needs to be largely validated, this novel approach has reignited the interest in the field of cancer early detection.
While exosomes appears to be novel, panel 3-protein biomarkers (LYVE1, REG1 and TFF1) in urine for early pancreatic cancer detection have also been recently explored. A study led by Tomasz Radon and his colleagues has validated a biomarker panel in urine samples from 192 pancreatic cancers, 87 healthy volunteers and 92 chronic pancreatitis. The urinary biomarker panel performed well in the study by ROC curve analysis in the training and validation (Clin Cancer Res 2015;21:3512-21). This urine test has an advantage of its non-invasive nature, although how to move this test forward as a screening test in a cancer with low incidence remains to be a challenge.
Tuesday, January 12, 2016
BY SARAH DIGIULIO
The American Society of Clinical Oncology has issued a new policy statement intended to ensure that clinical pathways in oncology promote high quality patient care. The statement, published online ahead of print in the Journal of Oncology Practice, includes nine specific recommendations to improve how these treatment management tools are developed and used (DOI:10.1200/JOP.2015.009134).
“There’s a proliferation of pathways in oncology and they’re not all being developed in a transparent way,” statement co-author Robin Zon, MD, FACP, Chair of ASCO’s Task Force on Clinical Pathways, said in a phone interview. “ASCO decided to comment now to increase the awareness of the growing use of clinical pathways and the concerns that exist about the manner to which they are being deployed.
“The policy statement is intended to help ensure that there is quality, transparency, and consistency in the design and implementation of these treatment management tools—and also to ensure that they are used in the ways in which they are intended to be used: to improve quality care and reduce costs.”
The policy statement was developed by the ASCO Task Force on Clinical Pathways and is based on a review of the current use of clinical pathways in oncology. The policy statement was adopted by the Society’s Board of Directors.
The statement and its recommendations were developed to address the following concerns about clinical oncology pathways, according to an ASCO news release about the statement:
· Oncology pathways are not developed or applied consistently by insurers and other pathways creators, resulting in wide variations in quality and utility.
· Oncology pathways are often too rigid and many place too much emphasis on cost control. These relatively simplistic pathways may restrict patient choices and may conflict with physicians' clinical judgment.
· Oncology pathways are often focused only on the selection of anticancer agents and do not include other critical aspects of cancer care, including diagnostic evaluation, laboratory testing, and palliative care services, which are central to quality patient care.
· The oncology pathway development process today, in many cases, is not transparent to patients and providers. As a result, there is no assurance that a given set of pathways has been developed without conflict of interest and in a manner that ensures they reflect the latest scientific evidence.
· There is no system in place to guarantee the integrity of pathways coming to market, or to ensure they are implemented in a manner that supports high-quality patient care.
ASCO President Julie M. Vose, MD, MBA, noted in the ASCO news release: “In too many cases, clinical pathways are undermining physicians' ability to optimally care for their patients with cancer and limiting patient choice."
The ASCO policy statement supports the use of pathways in oncology and recognizes that pathways are part of the answer to improve quality of cancer care, Zon added. “But, we’re saying let’s get back to caring for the patient and stop having to ‘care’ for the pathway.”
Nine Specific Recommendations
The nine recommendations in the policy statement to improve the development and use of clinical pathways in oncology are:
1. Pursue a collaborative, national approach to reduce the unsustainable administrative burdens associated with the unmanaged proliferation of oncology pathways;
2. Adopt a process for development of oncology pathways that is consistent and transparent to all stakeholders;
3. Ensure that pathways address the full spectrum of cancer care, from diagnostic evaluation through medical, surgical, and radiation treatments, and include imaging, laboratory testing, survivorship, and end-of-life care;
4. Update pathways continuously to reflect new scientific knowledge, as well as insights gained from clinical experience and patient outcomes to promote the best possible evidence-based care;
5. Recognize patient variability and autonomy and allow for physicians to easily diverge from pathways when evidence and patient needs dictate;
6. Implement oncology pathways in ways that promote administrative efficiencies for both oncology providers and payers;
7. Promote education, research, and access to clinical trials in oncology clinical pathways;
8. Develop robust criteria to support certification of oncology pathway programs; pathway programs should be required to quality based on these criteria, and payers should accept all oncology pathway programs that achieve certification through such a process; and
9. Support research to understand the impact of pathways on care and outcomes.
Thursday, January 7, 2016
BY PEGGY EASTMAN
Longtime Oncology Times Editorial Board member Ellen Stovall died on Jan. 5 of cardiac complications related to her cancer treatments.
From 1992 to 2008 Ellen was President and CEO of the National Coalition for Cancer Survivorship (NCCS), the oldest survivor-led organization advocating for quality health care for all Americans. A 45-year survivor of three bouts with cancer, she was Senior Health Policy Advisor to NCCS at the time of her death. She worked tirelessly on behalf of cancer patients, advocating for comprehensive written care plans that reflect the continuum of cancer care, including treatment summaries and follow-up care plans.
Ellen was also my friend, and we shared a personal connection. She was from Honesdale, Pennsylvania, as was my late husband, Jim Eastman. Her parents and my in-laws knew each other. Honesdale is a small town nestled in the northeastern corner of Pennsylvania; in snowy winter months it resembles a scene from a Currier and Ives print. Ellen always treasured her roots, and we spoke fondly together of our visits to Honesdale.
Over the years I saw Ellen at cancer meetings as I covered them as a science writer for OT. As the number of cancer survivors increased, so did Ellen’s influence. As a speaker, she gave voice to the concerns and needs of patients along the cancer care continuum. She was an eloquent spokesperson, especially for those who were too stunned by a cancer diagnosis or too overwhelmed by the complexity of the health care system to speak up for themselves.
Ellen could cut through Washington’s alphabet soup of acronyms and speak clearly about complicated topics to the lay public as well as to oncologists, members of Congress and laboratory scientists. I heard her do this many times, deftly adjusting her delivery to her audience.
A founding member of the National Cancer Policy Board of the prestigious Institute of Medicine and its successor, the National Cancer Policy Forum, Ellen co-chaired the influential Institute of Medicine report “From Cancer Patient to Cancer Survivor: Lost in Transition.” That report highlighted the challenges, uncertainties and fears facing cancer patients as they complete their active treatment and change to survivorship status.
Ellen was generous with her time; she served as Vice Chair of the Robert Wood Johnson Foundation’s National Advisory Committee to Promote Excellence in Care at the End of Life. She also served on the boards of directors of the National Committee for Quality Assurance and the Leapfrog Group, and she was a member of a committee of the National Quality Forum working to establish consensus around cancer quality measures. She also served on several advisory panels, working groups and committees of the National Cancer Institute (NCI), American Association for Cancer Research and the American Society of Clinical Oncology. She served six terms on the NCI’s National Cancer Advisory Board, an appointment given her by President Bill Clinton.
I knew that Ellen had had cardiac complications from her cancer treatments, because she told me. But if she sometimes found her responsibilities and demanding schedule tiring, it never showed. She was always composed, always prepared, always on top of the complex issues facing cancer patients and survivors. She had high standards, believing that patients and survivors deserved the very best care and nothing less.
After her passing, NCCS Chairman of the Board Sandy Welton stated: “To many of us—likely thousands—she was a trustworthy friend, a mentor, a collaborator, a visionary. Ellen was all of this and more, and always with a generous heart, a keen mind, a quick wit, and unswerving ethics.”
Shelley Fuld Nasso, MPP, the NCCS CEO, is committed to carrying on Ellen’s legacy of advocacy for cancer patients. The NCCS has posted information on the Ellen Stovall Memorial Fund on its web site, www.canceradvocacy.org.
Thursday, December 31, 2015
ELIAS JABBOUR, MD (left) is Associate Professor in the Leukemia Department of the University of Texas MD Anderson Cancer Center. HAGOP M. KANTARJIAN, MD, is Professor and Chairman of the Department of Leukemia and the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of one to two cases per 100,000 adults. It accounts for approximately 15 percent of newly diagnosed cases of leukemia in adults. CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome.
The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL1 oncoprotein. Three tyrosine kinase inhibitors (TKIs)--imatinib, nilotinib, and dasatinib--are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic-phase (CML-CP).
Clinical trials with second-generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. For patients who fail frontline therapy, second-line options include second- and third-generation TKIs. Although second- and third-generation TKIs are potent and selective TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients’ comorbidities, disease stage, and BCR-ABL1 mutational status.
Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs, and for all patients in advanced phase disease.
Bone marrow aspiration is mandatory for all patients in whom CML is suspected, as it will confirm the diagnosis (e.g., cytogenetic analysis), and provide information needed for staging in terms of the blast and basophil percentages. Baseline reverse transcriptase-polymerase chain reaction is imperative to identify the specific type of rearrangement that can be appropriately followed when assessing for response to TKI therapy.
About two to five percent of patients have b2a3 or b3a3 (not b2a2 or b3a2) variants of p210 BCR-ABL1 or p230 transcripts that may yield a false-negative PCR by routine probes and (if not tested at diagnosis) would give the false impression that a patient may be in complete molecular response on TKI.
Frontline Treatment Options
Current guidelines recommend any of the three TKIs--imatinib, dasatinib, and nilotinib--as good therapeutic options with a category 1 recommendation for initial treatment of CML-CP. Second-generation TKIs produced a higher rate of early optimal responses, but have so far have had no impact on long-term survival (probably because of available effective salvage therapies).
The main advantage of second-generation TKIs is obtained in patients with high-risk disease; a relevant decrease in the rate of transformation to accelerated phase (AP) and blast phase (BP) was achieved with nilotinib and dasatinib. As such, second-generation TKIs in the frontline setting could be reserved to patients with higher-risk disease. Furthermore, when choosing an agent, we consider issues such as comorbidities, patient’s age, adverse event profile, risk stratification score, transcript’s type, and cost. Kinase domain mutation profile plays no role in selecting an initial TKI, but becomes relevant in the relapse setting.
Higher dose imatinib and combination approaches in the frontline setting are investigational due to conflicting results of various studies to date. These strategies are also not benign interventions, as they add to the economic and toxicity burden of the overall treatment plan.
Allogeneic stem cell transplantation (allo-SCT) or other chemotherapy agents are not recommended as upfront treatments for CML-CP given the excellent outcomes and long-term survival achieved with the TKIs. An exception may be in emerging nations where allo-SCT is a one-time procedure costing $ 14,000 to $20,000, accessible to most patients. On the other hand, generic imatinib in such geographies (e.g., India) costs only less than $400 per year of therapy.
At MDACC, patients with low-risk disease are offered frontline therapy with imatinib. Patients with high-risk disease are candidates for second-generation TKIs for the time being; this practice may change once the generic formulation of imatinib is available in the United States.
Because of the higher rates of durable complete molecular responses with second-generation TKIs (which could lead to discontinuation of TKI therapy and potential molecular cures discussed later), considerations of second-generation TKIs in younger patients with CML (e.g., age <50 years) versus older patients, may be entertained.
Monitoring Treatment Response: Surrogate Endpoints and Milestones
In several studies, the achievement of a complete cytogenetic response (CCyR; Ph-positive metaphases 0%; BCR-ABL1 transcripts [IS] ≤ 1%) at 12 months or later on TKI therapy was associated with significant survival benefit compared with achievement of lesser degrees of response.
Achievement of CCyR is the primary endpoint of TKI therapy. Achievement of BCR-ABL1 transcripts [IS] ≤ 0.1% (major molecular response; MMR) was associated with modest improvements in event-free survival rates, possible longer durations of CCyR, but not with a survival benefit.
The achievement of complete molecular response (CMR; non-measurable BCR-ABL1 transcripts) offers the possibility of treatment discontinuation in clinical trials only. Lack of achievement of MMR or of CMR should not be interpreted as a need to change TKI therapy or to consider allo-SCT. Response assessments at earlier times on frontline TKI therapy (3-6 months) have shown better outcomes with achievement of a major cytogenetic response by three to six months on imatinib therapy (Ph-positive metaphases ≤ 35%; BCR-ABL1 transcripts [IS] ≤ 10%).
While this is interpreted to mean that a change to second TKI therapy may be considered if such outcome is not obtained, no studies have shown that changing therapy from imatinib to second TKIs has improved patients ’outcomes.
When nilotinib or dasatinib are used in front-line therapy, achievement of complete cytogenetic response by three to six months of TKIs therapy has been associated with improved outcomes. At MDACC, our major treatment milestones are at 6 and 12 months. Patients with lack of partial cytogenetic response (PCyR; BCR-ABL1 transcripts [IS] > 10%) at six months, or without CCyR (BCR-ABL1 transcripts [IS] ≤ 1%) at 12 months, or with loss of response at any time are candidates for a switch of therapy. The choice of TKIs is based on the mutation profiles and patients comorbidities.
We do not consider a change of TKI therapy in patients in CCyR but without MMR.
Management of TKI Resistance
Second- and third-generation TKIs have not been compared head-to-head. Selection of one or the other is based on the side-effect profiles, mutations profile, drug interactions, compliance issues, and the patient's preexisting medical conditions. Mutational analysis are required in patients who are failing imatinib or second-generation TKIs, or those who progress to AP/BP. Baseline mutational analysis on patients with newly diagnosed CML-CP are not done, as this has not proven to predict treatment outcome.
At MDACC, post imatinib failure, the choice of second- or third-generation TKI is based on the disease phase, mutation profile, and patient’s comorbidities. In advanced phases, we favor a combination of chemotherapy and TKI (mainly ponatinib or dasatinib). In patients with CML-CP with T315I mutation, ponatinib will be the first choice followed by allo-SCT if a donor is available and an optimal response is not achieved.
Outside the context of T315I mutations, the type of mutation will dictate the choice of therapy. Of note, patients with poor response to imatinib and compound mutations may not respond well to second-generation TKI. A close monitoring should be offered. If an optimal response is not achieved, a switch of therapy to a third-generation TKI and/or allo-SCT is warranted.
In patients with no mutation or a mutation sensitive to all second-generation TKIs, the choice will be based on comorbidities. Patients with vascular risk factors and metabolic dysfunctions are not candidates for nilotinib, while patients with lung injuries are not candidates for dasatinib. Bosutinib may be the best choice for patients with cardiac and rhythmic problems.
Treatment Duration and Discontinuation
TKIs discontinuation studies in patients with durable CMR demonstrate that stopping TKI therapy is feasible, and some patients may be cured. While the results thus far are encouraging, it is still recommended that TKI therapy be stopped only under the auspices of a clinical trial. Many laboratories are not able to produce precise and reliable PCR results as those used in the above mentioned trials.
Going forward, it is important to continue to investigate the possibility of safe treatment cessation. Measures of quality of life and adverse event avoidance should be studied in subsequent trials. The economic impact of long-term discontinuation of imatinib is substantial. At MDACC, therapy discontinuation is offered only for patients in durable CMR and in the context of clinical trials.
Allo-SCT should be considered early in patients in CML-AP based on response to TKI therapy. The only curative option for patients in CML-BP disease is allo-SCT. TKIs alone or in combination with chemotherapy may serve as a good option for those who are not candidates for transplant, or as a bridge to allo-SCT.
The role of TKIs before and after transplant is being evaluated. Accumulating data show that TKIs do not increase transplant-related complications and when used after low-intensity conditioning regimens, may delay relapse rates and need for donor lymphocyte infusions.
At MDACC, patients with CML-BP are treated with combination of chemotherapy (type depends on the immunophenotype) and third-generation TKI followed by allo-SCT once a complete response is achieved and placed on maintenance TKI therapy. Patients with de-novo CML-AP are treated with frontline second-generation TKI infinitely if an optimal response (CCyR; BCR-ABL1 transcripts [IS] <1%) is achieved within six months of therapy All other patients in CML-AP are treated with second/third generation-TKI followed by allo-SCT.