Introduction

Allogeneic and autologous stem cell transplant are therapies that are utilized to cure either patients with high-risk hematologic malignancy in first remission or those patients who suffer a relapse and have little or no other potential curative options. Autologous transplant historically has been utilized as a way of delivering high-dose chemotherapy to eliminate residual tumor cells, using cryopreserved stem cells to reestablish both hematopoiesis and immune reconstitution after clearance of the drugs. The major risk of the procedure in the autologous setting is recurrence of the disease, something that is, unfortunately, common in both Hodgkin and non-Hodgkin’s lymphomas and multiple myeloma, which are the major indications for the use of this approach.

For those patients undergoing allogeneic transplantation, the goal is similarly cure, but relies, in large part, on the graft-versus-tumor (GVT) effect mediated by the donor immune cells, be it from a related, unrelated, or cord blood donor. Although originally almost all transplants utilized high-dose chemoradiotherapy or a high-dose chemotherapy regimen alone, over the last decade, with increasing understanding of the role of the GVT effect, reduced-intensity transplant regimens have been utilized and have now been applied to the care of older patients with hematologic malignancy, especially acute leukemia and myelodysplasia. Although the risks of the transplant are different in the autologous and allogeneic settings, the major problem for many patients is relapse of the disease. This risk is related, in large part, to the disease status of the patient prior to transplant, the molecular nature of the genetic abnormalities associated with that disease, and the extent of prior therapy. Patients who are in remission tend to do better than those who are not in remission at the time of transplant, and now disease assessments include measurements of minimal residual disease (MRD) to further quantitate the burden of disease going into transplant and its impact on transplant outcomes. Thus, pretransplant, conditioning regimen, and post-transplant intervention strategies are being explored to reduce the chances of relapse and lead to better outcomes The clinical scenarios described in this chapter focus on the dilemma faced by physicians in assessing patients for transplant and dealing with the aftermath, should there be a relapse of the disease.

Case study 67.1

• Is there a role for a second allogeneic transplant in patients who suffer a relapse after a first transplant?

A 35-year-old man with FLT3-positive acute myeloid leukemia (AML) underwent allogeneic transplantation utilizing a myeloablative total body irradiation (TBI) conditioning regimen from a human leukocyte antigen (HLA)-matched sibling. Following transplantation, he developed some acute graft-versus-host disease (GVHD) that resolved with increased immunosuppression. The medications were subsequently discontinued, and he did not develop any evidence of chronic GVHD. Eighteen months after transplant, while off immunosuppression, he developed fatigue, and a blood count showed circulating blasts consistent with relapse of his disease. Among the various therapeutic questions are: is there a role for a second allogeneic transplant to treat his disease and, if so, which time, conditioning, and donor type would be best?

Relapse after allogeneic transplantation remains a major problem and requires a thoughtful discussion with the patient as to how to manage what was initially intended as a curative therapy. Among the choices are no further therapy with palliative care, withdrawal of immunosuppression to elicit a therapeutic GVT response, re-induction chemotherapy with the same or different agents, donor lymphocyte infusions with or without preceding chemotherapy, and, in some specific cases, depending upon the response, second transplant with or without preceding chemotherapy. There are a number of clinical nuances that influence this judgment, including whether there was any antecedent GVHD; the current status of the patient’s organ function; the willingness of the donor, either sibling or unrelated, to provide more cells; and, importantly, the time between transplant and relapse; also, the specific characteristics of the leukemia contribute to the difficulty of the decision. And, of course, the question arises whether any patients who undergo second allogeneic transplant after relapse from a first transplant are likely to be cured.

Despite the apparent heterogeneity of studies that have addressed this issue, several principles have emerged to help guide patients, families, and physicians. In general, most centers will use the same donor for both the first and second transplant, and most patients will undergo re-induction therapy in order to reduce the disease burden, knowing that the outcome for any transplant is improved if the patient is in remission. Typically, patients who underwent a TBI-based regimen for initial transplant would receive a non-TBI myeloablative regimen for their second transplant. However, with the increased appreciation of the role of a graft-versus-leukemia effect in facilitating cure of leukemia, reduced-intensity transplant regimens have been used for patients in this situation.

Patients with chemosensitive disease in remission who have had a long initial remission (defined as greater than 6–12 months after the first transplant) and who never developed any GVHD are likely the ones who benefit most from a second transplant. Conversely, when patients have had a very short remission and did not respond to re-induction chemotherapy, they are unlikely to benefit from a second allogeneic transplant. In those patients who do undergo a second transplant in a second remission of their disease and who had no significant chronic GVHD the first time, it is generally advised to taper the post-transplant immunosuppression more quickly in order to harness a therapeutic GVT effect in the post-transplant setting. In addition, patients who had both acute and chronic GVHD but, despite this, suffered a relapse and thus had an ineffective GVT effect are less likely to benefit from a second transplant from the same donor. In this setting, the decision to undergo a second transplant needs to be weighed against the associated comorbidities that contribute to transplant-related mortality and the use of another donor. Sometimes when there is a second match within the family, transplant will be done with a different donor in an attempt to harness a more effective immune system, and for patients who have had a longer remission, it is worth considering an unrelated donor.

Case study 67.2

• Should patients with relapsed AML or acute lymphoblastic leukemia (ALL) undergo re-induction therapy before allogeneic transplant?

A 37-year-old man with pre-B ALL (CD19+), Philadelphia chromosome negative, with normal cytogenetics presented with a white blood cell (WBC) count of 60,000, hemoglobin of 4 g/dl, and a platelet count of 20,000. The diagnosis was confirmed by bone marrow and peripheral blood analysis, and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) chemotherapy was initiated. It was his physician’s assessment that, based on his age, lack of BCL/ABL mutation, and the fact that he achieved a remission with chemotherapy in the first cycle, transplant was not indicated. He had four siblings, but none of them were typed at the time of diagnosis. He then received alternating cycles of hyper-CVAD part A and part B, but prior to initiation of treatment with cycle 4A, he remained pancytopenic, not having recovered from the previous cycle. Because of concerns about the status of the marrow and continuing therapy, a bone marrow biopsy was performed that showed approximately 40% lymphoblasts of a very similar phenotype and no additional chromosome abnormalities.

Most induction regimens use intensive chemotherapy to achieve a remission, followed by consolidation and, in the case of ALL, maintenance therapy, with many patients being cured with this approach. However, for patients who suffer a relapse of disease, the treatment options are limited. Depending upon the duration of remission, sometimes the same drugs can be effective in achieving a second remission, particularly if the first remission was greater than 1–2 years. For patients whose remission lasted less than 6 months, the 1-year overall survival has been 14%, but if greater than 18 months, it has been reported to be 57%. Therefore, the ability to achieve a second remission is contingent upon several clinical and biological factors. Although patients who relapse will have reduction of the leukemic burden with additional treatment, it is very rare for a patient to be cured by this approach. Among a large number of patients who had relapsed in the German ALL study, no patient without transplant survived more than one year after relapse. Therefore, the salvage therapies in transplant-eligible patients should be viewed as a bridge to transplant. For patients who achieve a second remission without any limiting organ toxicities that would preclude proceeding to transplant and who have a donor, the cure rate can be as high as 50%. The major problem, however, for those patients with a relatively short remission is that the treatment options are somewhat limited, as in the case discussed here.

For patients with relapsed AML, there are some new treatment options utilizing hypomethylating-based therapy, combined with histone deacetylase inhibitors or lenalidomide, or the use of FLT3 inhibitors to achieve a remission as bridges to transplant. New drug development in ALL has been more limited, but recently promising options, especially those including immunologic approaches, are being developed. These include BiTE® immunotherapy, an approach that fuses an antibody fragment recognizing the CD19 antigen on pre-B ALL, to an anti-CD3 antibody fragment that engages a local T-cell response to elicit the patient’s immune system in tumor cell killing. These studies have shown an impressive rate of response and depth of remission (MRD negative) and can act as a bridge to transplant. This approach is being tested, both as treatment of relapsed patients, such as the one described here, and as part of upfront treatment to combine both chemotherapy and immunotherapy in the initial treatment of the disease. In addition, immunoconjugates that deliver a drug directly to CD19⁺ cells, as well as the use of genetically altered T-cells that can recognize CD19, are also being explored as novel approaches to treat ALL patients. These novel approaches, will give patients a better option for achieving a second remission after relapse of the disease and facilitate a more successful transplant. Thus, even for patients with disease relapsing relatively early, new options are evolving that may change the outcome, hopefully achieving a minimal disease state that would improve the chances of cure after an allogeneic transplant. Similar approaches focusing on myeloid antigen targets are being developed for AML that could also serve as bridge therapies to transplant.

For patients with an early relapse after a relatively short remission (ALL and AML), if a donor can be identified quickly, early transplant without re-induction therapy can sometimes lead to a cure. To facilitate this, it is prudent to do family typing at diagnosis in all adult patients with ALL or AML, as this will help determine the transplant strategy in case of relapse or even failure to achieve a first remission. In the above-noted case, we would advise re-induction therapy with either chemotherapy or, if eligible, an immunotherapy protocol and, of course, typing the siblings.

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue