© Springer Science+Business Media, LLC 2015
Richard T. Maziarz and Susan Schubach Slater (eds.)Blood and Marrow Transplant Handbook10.1007/978-3-319-13832-9_3232. Posttransplant Relapse
(1)
Division of Hematology/Oncology and the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania Medical Center, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, 2 West Pavilion, 19104 Philadelphia, PA, USA
Keywords
RelapseGraft-versus-leukemia (GVL)Donor lymphocyte infusion (DLI)Targeted therapyMaintenance therapyCellular therapyMinimal residual disease (MRD)Outcomes after autologous and allogeneic hematopoietic stem cell transplant (HSCT) have improved substantially as advances in supportive care and conditioning regimens, such as the introduction of reduced-intensity allogeneic transplants, have dramatically reduced treatment-related morbidity and mortality. Unfortunately, disease relapse remains a major cause of transplant failure and patient mortality. Center for International Blood and Marrow Transplant Research (CIBMTR) data identify relapse as the cause of 78% of autologous transplant-related deaths, 34 % of related allogeneic transplant deaths, and 23 % of unrelated transplant deaths. A lack of effective and well-tolerated therapeutic options for relapse after transplant is a major barrier in the care of these patients. To optimize outcomes, management of disease relapse after HSCT must be highly individualized and based on both patient and disease features.
32.1 Relapse After Autologous HSCT
1.
Autologous HSCT is offered with either curative intent or with the goal of improving progression-free and overall survival. After relapse, further therapy may be pursued with either curative or noncurative intent and is guided by status and type of disease, prior therapies, and host factors.
2.
In heavily pretreated patients, limited marrow reserve and patient comorbidities may limit eligibility for further cytotoxic chemotherapy including second transplant.
3.
Benefit of second autologous HSCT is predicted by underlying malignancy and, in some cases, history of durable response to first transplant (> 1 year), and continued presence of chemosensitive disease.
4.
Allogeneic HSCT with reduced-intensity conditioning may be considered as a curative treatment option for select patients who relapse after autologous HSCT.
5.
Targeted and other novel therapies play an expanding role in the management of patients who relapse.
6.
Maintenance and consolidation strategies, generally using novel agents, are used with the goals of improving durability and rate of cure after transplant.
32.2 Relapse After Allogeneic HSCT
1.
Allogeneic HSCT is offered to patients with high-risk hematologic malignancies with curative intent.
2.
Management of relapse is influenced by status and type of disease, prior therapies, and host factors including performance status, comorbidities, presence of transplant-related complications (particularly the presence of active graft-versus-host disease (GVHD)), and timing and kinetics of disease relapse.
3.
Allogeneic HSCT is successful in part due to the graft-versus-leukemia (GVL) effect. GVL effect is particularly potent against chronic myelogenous leukemia (CML), but has been identified to be active against acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL), as well as most other hematologic malignancies. Disease relapse may be addressed by manipulations that enhance the GVL effect; however, these approaches are limited in the setting of active GVHD.
a.
Withdrawal of immunosuppression
i.
Not effective in the majority of patients but there are anecdotal responses in relapsed leukemia. May be most effective to control some cases of low tumor-burden, indolent disease relapse.
ii.
High risk of GVHD.
b.
Donor lymphocyte infusions (DLI)
i.
Most successful in patients with relapsed chronic phase CML (durable remission rates of approximately 70 %) .
ii.
Less successful in relapsed AML (10–40 % overall survival).
iii.
Although GVL activity is important to cure ALL with allogeneic HSCT, there is limited benefit for conventional DLI.
iv.
Patients who relapse early (within 6 months after transplant) are unlikely to benefit.
v.
Reasons for failure include rapid disease kinetics and ability of leukemia cells to evade immune recognition and blunt the immune response.
vi.
Responses occur several weeks after infusion of donor lymphocytes necessitating administration of cytotoxic chemotherapy prior to DLI in settings of high kinetic relapse. It is unclear if pre-DLI chemotherapy improves outcome.
vii.
DLI is more successful in the setting of minimal disease burden/complete remission.
viii.
Low-dose DLI and subsequent dose escalation
May minimize risk of GVHD and retain GVL activity in relapsed chronic phase CML.
Is not practical for relapsed advanced phase CML or acute leukemia given the pace of disease progression.
ix.
The use of growth factor mobilized DLI versus unstimulated DLI may speed hematopoietic recovery after cytotoxic chemotherapy, but unclear if this improves outcome.
x.
Methods to improve DLI are being actively investigated (see 32.3.4.below).
xi.
Toxicities are significant and include GVHD, marrow aplasia, and increased risk of infection.
c.
Second allogeneic HSCT
i.
Myeloablative approaches are limited by significant treatment-related morbidity and mortality. A minority of patients will be eligible.
ii.
Reduced-intensity approaches may be considered in select patients
Often considered after failed autologous HSCT for lymphoma and myeloma.
iii.
Known to achieve long-term disease control (20–30 %) in groups of highly selected patients but with high risk of relapse and nonrelapse morbidity and mortality (40 % each). Optimal patient selection (identification of who is most likely to benefit), donor selection (same versus different donor), and conditioning regimens are not well defined.
d.
Chemotherapy
i.
Inadequate efficacy and durability in the relapse setting.
ii.
Limited use in heavily pretreated and vulnerable patient populations.
iii.
May be used as a bridge to DLI or second allogeneic HSCT.
e.
Supportive care and palliation
1.
Appropriate for patients unlikely to benefit from or unable to tolerate available therapy.
4.
Disease-specific approaches
a.
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CML
i.
Tyrosine kinase inhibitors (TKIs)
Imatinib, dasatinib, nilotinib, bosutinib, or ponatinib. Choice of agent determined by side-effect profile, previous exposure, and BCR/abl mutational analysis.
May be sufficient in chronic phase relapse.
ii.
DLI dramatically effective but associated with significant GVHD
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