Nonmyeloablative Stem Cell Transplantation in the Treatment of Hematologic Malignancies 25

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Allogeneic hematopoietic stem cell transplantation (SCT) is an effective, potentially curative treatment of advanced or high-risk hematologic malignancies.¹ High-dose chemoradiotherapy with allogeneic SCT is associated with significant morbidity and mortality because of the toxicity of the preparative regimen, graft-versus- host disease (GVHD), and the immune-deficiency state that accompanies the procedure. These risks are significantly increased with advanced age, concurrent medical problems, or extensive prior therapy, limiting standard SCT to younger patients in good medical condition. Hematologic malignancies are more common and have a worse prognosis in the elderly. Additionally, disease and prior therapy may result in comorbidities precluding further intensive therapy. Thus, many patients with hematologic malignancies who could benefit from SCT were often deferred from a potentially curative approach. Extensive research has been directed toward the develop- ment of safer and less toxic approaches to allogeneic SCT. The introduction of nonmyeloablative and reduced-intensity conditioning regimens is a major step toward extension of allogeneic SCT to a much wider patient population by reducing transplant-related complications.² Much experience has been gained with the clinical use of this novel approach over the last decade. In this chapter, we discuss the rationale for nonmyeloablative stem cell transplantation (NST), and the use of immune therapeutic interventions with NST as the curative approach. We discuss how NST reduces some,

but not all transplant-related complications, and our personal approach in selecting patients for NST.

Rationale for NST

SCT was initially developed as a means to deliver high-dose chemotherapy and radiation for elimination of the underlying disorder.

Escalation of treatment doses results in better tumor kill but leads to irreversible myelosup- pression. SCT was viewed as a supportive-care modality to restore hematopoiesis after treatment. However, it has subsequently become apparent that high-dose chemoradiotherapy does not eradicate the disease in many patients and that much of the therapeutic benefit of SCT relates to an associated, immune-mediated, graft-versus-leukemia (GVL) or graft-versus- malignancy (GVM) effect. Extensive experimental and clinical data support the presence of this GVL effect.²Higher relapse rates were observed after syngeneic and T cell-depleted transplants whereas patients having acute or chronic GVHD have a reduced relapse risk suggesting the importance of T cell-mediated immunity in eliminating the malignancy and the association of this GVL effect with GVHD. Perhaps the most direct evidence for GVL/GVM was the ability to restore remissions in patients relapsing after SCT by infusion of donor lymphocytes with no additional chemotherapy. The discovery of the

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Nonmyeloablative Stem Cell Transplantation in the Treatment of Hematologic Malignancies

Avichai Shimoni and Arnon Nagler

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curative potential of the immune-mediated GVL/GVM effect has led to a novel therapeutic approach. Low-dose, relatively nontoxic and tolerable conditioning regimens have been designed, not to eradicate the malignancy, but rather to provide sufficient immunosuppression to achieve donor cell engraftment and to allow induction of GVL as the primary treatment.^2–4

NST does not eliminate all host hematopoiesis and often leads to a state of mixed chimerism (MC). MC describes persistence of donor cells with either normal host hematopoietic cells and/or cells of the underlying malignancy (Figure 25.1).

Stable long-lived MC has been reported in ani- mal models and in patients having NST for non- malignant disorders. However, in patients with malignancies, MC is most often transient and conversion to complete chimerism (CC), autologous reconstitution, or relapse occurs either spontaneously or after immune manipulations within the first few months after NST.⁵The initial nonmyeloablative treatment is expected to produce only transient suppression of the underlying malignancy, but it allows time for the immune GVM effect to develop. This effect may result in gradual elimination of the malignancy and spontaneous delayed achieve- ment of complete remission (CR), over a few months, especially in indolent malignancies.

However, patients with MC or with detectable residual malignancy after NST may require additional immune-therapeutic approaches.

Immunosuppressive therapy given post-SCT for prevention of GVHD can also suppress the GVL effect.⁶Early withdrawal of immunosuppressive therapy allows the occurrence of potent graft-versus-hematopoietic tissue effect that can potentially eliminate both residual disease and

host hematopoiesis producing CC and CR (Figure 25.1). If this does not occur, donor lymphocyte infusions (DLIs) may harness this effect and switch the balance toward CC/CR. The GVL and graft-versus-hematopoietic tissue effects are highly associated with GVHD although may also occur in its absence. The initial NST and donor cell engraftment thus serve as a platform for additional allogeneic cellular therapy.

NST Regimens

NST regimens comprise a spectrum of regimens with different immunosuppressive and myelosuppressive properties. The kinetics of engraftment, chimerism, and eradication of residual disease differ accordingly.⁵ Conditioning regimens have been referred to as nonmyeloablative if they do not completely eradicate host hematopoiesis and immunity.² A few of these regimens have been given as chemotherapeutic regimens with no stem cell support and allow relatively prompt hematologic recovery.

Autologous reconstitution of hematopoiesis is expected if the allograft is rejected. These nonmyeloablative regimens have potent immunosuppressive effects. They are only mildly myelosuppressive and often result in induction of MC. The Seattle regimen consisting of low- dose total body irradiation (TBI, 200 cGy) with (or initially without) fludarabine and intensive pre- and posttransplant immunosuppression is the prototype of these regimens.⁷Other exam- ples are the combinations of fludarabine and cyclophosphamide (FC) and the Flag/Ida regimen developed initially at the MD Anderson for

m m

Nonmyeloablative conditioning

IST withdrawal

±DLI

recipient donor mixed chimerism

+MRD

complete chimerism

Figure 25.1. NST program: The initial NST regimen induces MC with persistence of both donor and recipient hematopoietic cells. The underlying malignancy (m) is suppressed but not completely eliminated. In the second phase, immune-therapeutic interventions, e.g., withdrawal of immunosuppressive therapy (IST) supplemented if necessary by DLI, induce graft-versus-hematopoietic tissue and graft-versus-tumor effects eliminating recipient hematopoiesis and the underlying malignancy and converting to CC.

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non-SCT treatment of lymphoid and myeloid malignancies, respectively, and later explored as nonmyeloablative conditioning regimens for SCT.^4,8These are very tolerable regimens, allowing in some cases ambulatory treatment, and treatment of elderly patients.

More intensive regimens have also been developed. These regimens have been referred to as reduced-intensity conditioning regimens.² They have not been given without stem cell support, and autologous recovery after treatment may be slow if at all. These regimens usually combine immunosuppressive agents such as fludarabine with or without serotherapy [with anti- thymocyte globulin (ATG) or alemtuzumab]

and agents with moderate myelosuppressive effects (such as busulfan or melphalan).^3,9,10The Hadassah group³and the MD Anderson group⁴ pioneered the use of purine analogs in NST regimens and they emerged as the cornerstone of these regimens. These are well-tolerated agents, with potent immunosuppressive effects, in addi- tion to antitumor activity against a range of hematologic malignancies. They have synergistic effects with alkylating agents and inhibit DNA repair systems responsible for repair of cellular damage induced by these agents. Although these regimens are more intensive than the nonmyeloablative regimens, dose intensity is still reduced compared with standard ablative regimens allowing reduction of toxicity. Reduced- intensity regimens, in similarity to standard myeloablative regimens, rapidly induce CC and antitumor responses, but are more toxic, and associated with a higher risk for GVHD.⁵

A third approach is using a double-step strategy. Initially, high-dose chemotherapy sup- ported by autologous stem cell transplantation is used for cytoreduction and also as an immunosuppressive platform for the second stage of allogeneic SCT with nonmyeloablative or reduced-intensity regimens usually administered 2–3 months later. The separation of high- dose chemotherapy and allogeneic effects results in reduced toxicity and better tolerability than when allogeneic transplantation immedi- ately follows high-dose chemotherapy.^11,12

A novel approach is to combine nonmyeloablative or reduced-intensity regimens with targeted therapy. Imatinib is being explored as adjuvant to reduced-intensity conditioning both pre-SCT, allowing reduction of conditioning intensity, and post-SCT, to eliminate MRD.¹³ Rituximab has been used in conjunction with

reduced-dose chemotherapy in lymphoid malignancies, and by us after SCT to target MRD.¹⁴ More recently, radiolabeled immune conjugates are used with SCT. Antibodies such as radiolabeled anti-CD20 monoclonal antibodies may be used with SCT to target lymphoma cells allowing the use of less intensive conditioning.

Radiolabeled antibodies such as Bismuth 213 anti-CD45 antibodies can be used with no additional chemotherapy to ablate the marrow and immune system and not specifically tumor cells as reported in preliminary canine models.¹⁵

NST and Regimen-Related Complications

NST regimens were originally designed to enable treatment of older and medically infirm patients not eligible for standard ablative conditioning and to allow the application of SCT to a much wider patient population. This goal has largely been achieved. Standard ablative regimens are usually limited to patients up to age 55 years. Most NST studies have no upper age limit.

Age per se was not found to be an adverse factor for prediction of outcome^16,17after both related and unrelated donor SCT and is no longer a con- traindication for SCT. Standard SCT in certain high-risk settings such as in heavily pretreated patients, patients failing a prior autologous SCT, and in patients with certain diagnoses such as multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma, was associated with unacceptably high treatment-related mortality (TRM) rates, as high as 50%. TRM in the range of 10%–20% can now be observed in these settings using NST regimens. In particular, NST is becoming a common indication for treatment of patients failing a prior autologous SCT,^18,19 and was able to reduce TRM after unrelated donor SCT.^20,21

Reduction of TRM is largely attributed to reduction in organ toxicity. The Seattle group has shown marked reduction in cardiovascular, gastrointestinal, hepatic, infectious, metabolic, neurologic, and pulmonary toxicity when comparing their low-dose TBI-based nonmyeloablative regimen to ablative regimens.²²Nonrelapse mortality within the first 100 days was 9% and 21%, respectively. The major therapy-related organ dysfunction syndromes are reduced in incidence. In particular, idiopathic pneumonia

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syndrome is less frequent after NST, 2.2% versus 8.4% in one study, despite treatment of older patients.²³Hepatic toxicity may still be substantial, especially after some reduced-intensity regimens.^3,24 However, not all syndromes are reduced. We have shown that thrombotic microangiopathy is a frequent devastating com- plication after NST, more common in second SCTs and in association with acute GVHD.²⁵ Diffuse alveolar hemorrhage is also relatively common in this setting. We have hypothesized based on experimental data that fludarabine- related endothelial and pulmonary epithelial toxicity may be associated with this unexpected observation. It was also shown that other hemolytic complications, associated with ABO donor–recipient incompatibility, might be more common after NST.²⁶Although direct toxicities of high-dose chemotherapy are reduced with NST, toxicities involving immune mechanisms may not be. Organ toxicities are largely associated with patient comorbidity score before SCT.²⁷Further research is required to define the relative organ toxicities in different regimens.

NST is less myelosuppressive than standard conditioning. This results in a shorter duration of neutropenia and less transfusion requirements.²⁸ Some of the nonmyeloablative regimens result in only minimal neutropenia and can be safely administered in the outpatient setting.⁷Reduced-intensity regimens usually result in more profound cytopenias more similar to ablative conditioning. The reduced duration of neutropenia and the limitation of mucosal injury result in reduced risk for severe infections in the immediate post-SCT period.^29,30However, the risk for invasive fungal infections is not reduced.^31,32These infections are usually associated with GVHD and corticosteroid therapy, and represent one of the major causes of TRM after NST. In the Seattle study, invasive fungal infection occurred in 19% of NST recipients, they occurred relatively late in the course, at a median of 107 days, and were the primary cause for 39% of nonrelapse-associated deaths.³¹

NST and GVHD

GVHD is one of the major causes of post-SCT morbidity and mortality. When the nonmyeloablative and reduced-intensity regimens were introduced, it was hoped that GVHD incidence

would reduce. Acute GVHD results at least par- tially from tissue injury and cytokine release secondary to the toxicity of the preparative regimen, amplified by donor immune cells.³³ The use of less toxic conditioning should theoretically limit tissue injury and cytokine release and reduce the incidence and severity of GVHD.

Also, MC that is more common after NST allows bilateral transplantation tolerance with graft acceptance and some protection from GVHD.³⁴ However, host antigen-presenting cells that have a major role in initiation of the GVHD reaction may persist after NST and contribute to GVHD.³⁵ The duration of immunosuppressive therapy is usually shorter after NST, and immune manipulations are often incorpo- rated into NST programs increasing the likeli- hood of GVHD although delayed immune manipulations, once the toxicity of conditioning and cytokine release are already resolved, are less likely to produce severe GVHD.³⁶ The net effect of these differences between NST and ablative SCT on GVHD is still not well established and is controversial. The Seattle group reported that the incidence of acute GVHD grade II–IV after NST was significantly lower than after ablative therapy, reaching 64% and 85%, respectively. However, the incidence of chronic GVHD was approximately 70% in both cohorts. Moreover, the initiation of steroid therapy was delayed from an average of 1 month to 3 months after SCT, corresponding to a “new”

syndrome described as late-onset acute GVHD.³⁷This study suggests that GVHD is not reduced in incidence with NST, but is only delayed. In another study, Couriel et al.³⁸ reported an incidence of grade II–IV acute GVHD of 36% after myeloablative regimens (including the reduced-intensity combination of fludarabine and melphalan), but only 12% after truly nonmyeloablative regimens. They also noted reduced incidence of chronic GVHD after NST.³⁷ Further prospective studies are needed to determine the relative incidence of GVHD. However, Because it is still a major cause of morbidity and mortality after NST, several approaches have been explored to decrease the risk.

Initially, NST regimens called for only a short course of immune suppression and early administration of DLI for disease eradication and conversion to CC. However, these interventions are thought to markedly increase the risk of GVHD. More recently, more careful approaches were introduced. For example, the Seattle group

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extended the duration of immune suppression, especially after unrelated donor transplantation, up to 6 months. With better understanding of chimerism and MRD kinetics, the indications for DLI have been restricted, trying to reserve it only for patients destined to relapse or reject their graft and reducing the risk of GVHD in all other SCT recipients (see below for further dis- cussion).

Another approach is the use of in vivo T cell depletion. Alemtuzumab (Campath 1-H) has emerged as an effective agent in prevention of GVHD. Alemtuzumab administered during pre- SCT conditioning depletes host T cells thus reducing the risk of graft rejection reported with in vitro T cell depletion techniques. Alemtuzumab persists after SCT and also depletes, at least par- tially, T cells of the donor, as well as host antigen- presenting cells and thus has been shown to be very effective in prevention of GVHD after reduced-intensity conditioning from both related and unrelated donors. However, patients given alemtuzumab have a higher risk of opportunistic infections, in particular with cytomegalovirus.

Moreover, alemtuzumab recipients have a higher risk of MC and residual disease, require more DLIs, such that after DLI, the ultimate net risk of GVHD is not reduced and there is no improve- ment in survival or TRM.¹⁰ATG given pre-SCT has the same effects although may be less effective in prevention of GVHD. Studies are being conducted to determine the dose of alemtuzumab or ATG that may result in net effects that would improve survival.

Immune-Therapeutic Intervention after NST

Relapse of the underlying malignancy remains the major cause of treatment failure after ablative SCT and even more so after NST. Most of the data on the safety and efficacy of DLI comes from myeloablative SCT. DLI has been administered after NST in a variety of indications, mostly for conversion of MC to CC and for the treatment of relapse or residual disease.³⁹DLI is associated with significant morbidity and mortality, mostly because of complications related to GVHD and marrow aplasia. Marks et al.³⁹ reported in a large series of DLI after NST that the rate of severe GVHD was 15%, and TRM was 9%; marrow aplasia was rare, suggesting that

DLI after NST was safer than what is reported after standard myeloablative SCT. The Seattle group reported similar results.⁴⁰This may represent advances in DLI administration, such as administration in incremental dosing, and at MRD where DLI may also be more effective, and may be given at a lower starting dose. There is also experimental data suggesting that DLI may even be more potent in mixed chimeras because of persistence of host antigen-presenting cells.⁴⁰ DLI administered late after SCT has a lower risk of complications³⁶; however, the window of opportunities for administration of DLI for prevention of relapse may be short and missed while waiting for a safer time point. Even in programs planning early DLI, on days 60–100 post- SCT, DLI is only administered after cyclosporine withdrawal and many patients are ineligible for prophylactic DLI because of GVHD or rapid progression already occurring before DLI.

As discussed above, initially DLI was incorpo- rated into NST protocols early in the course for conversion of MC to CC.⁵MC may be associated with increased risk for relapse, especially in aggressive malignancies, and may also be associated with MRD. However, as experience with NST was gained, the role of DLI in this setting became more controversial. High-level MC (more than 50%–60% donor chimerism) usually converts to CC spontaneously, whereas patients with low-level donor chimerism (less than 20%–40%) often reject the graft despite DLI. DLI is now administered more carefully for this indication, and patients are followed closely with DLI reserved for impeding graft rejection as evidenced by declining chimerism. In patients with aggressive malignancies, DLI may still be administered early trying to convert to CC and induce GVL rapidly.

The second indication for DLI has been for persistent or progressive disease, with an overall response rate of 25%–45%, depending on the underlying disease.^39,40 DLI has also been explored as prophylactic therapy after NST.

Although this approach may reduce relapse risk, responses are often associated with GVHD.

Because DLI is still associated with substantial risk, a more rational approach is to try to limit DLI only to those destined to relapse, avoiding unnecessary toxicity from those destined to remain in remission based on determination of MRD after NST.⁴²

Significant progress has been achieved in technologies for MRD assessment.⁴²Quantitative

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polymerase chain reaction tests are very sensitive in detecting tumor-associated transcripts, allowing serial monitoring. Threshold levels have been established for some malignancies above which relapse is imminent. Persistent negative tests, low level or decreasing MRD level are consistent with continuous remission, whereas, high-level MRD or increasing levels predict incipient relapse. Patients at high risk for relapse are candidates for additional cellular or targeted therapy.

The optimal time point and cell dose of DLI have not been established. The decision to administer DLI can be based on several factors:

The aggressiveness of the underlying malignancy and the risk for rapid progression, the sensitivity of the test used to determine MRD, the expected kinetics of MRD and the trend of MRD in serial quantitative testing, the level of MRD, as well as the SCT regimen used.

In indolent malignancies such as chronic myeloid leukemia (CML), chronic lymphocytic leukemia, follicular lymphoma, and to a lesser extent multiple myeloma, MRD is often detected after SCT, both after ablative conditioning, and even more so after reduced-intensity conditioning. MRD can be followed and no intervention is indicated unless progression or a plateau in response is observed or quantitative MRD is ris- ing. In aggressive malignancies such as acute leukemia and CML in blast crisis, and especially when not in remission at SCT, timing is more crucial. There may not be sufficient time to follow quantitative MRD because the doubling time of MRD may be short and relapse may occur within weeks, whereas effective DLI response may take 2–3 months. Thus, the sensitivity of the test is important. When using very sensitive tests, such as quantitative polymerase chain reaction, when applicable, one can follow MRD very closely, every 1–2 weeks and if MRD is declining, no intervention is needed. The kinetics of MRD in this setting after NST is not well established as after ablative conditioning.⁴² The same level of MRD may not necessarily have the same significance. MRD surviving high-dose chemotherapy, and to a lesser extent reduced- intensity conditioning, represent highly resistant malignancy, whereas MRD is expected after NST. MRD remaining after T cell-depletion SCT or the use of alemtuzumab in NST is also highly predictive of relapse.

In the future, tumor-specific lymphocytes, or DLI generated against hematopoietic-specific

minor histocompatibility antigens, such as HA- 1 and HA-2,⁴³may be used to harness antitumor responses without the risk of GVHD, and may follow SCT with T cell-depleted grafts.

Targeted therapy is another option for treatment or control of MRD. Imatinib mesylate is an effective therapy for CML. There is emerging data that imatinib may be effective in salvaging patients with relapse or persistent disease after SCT, either front line, or as second-line therapy after failure of DLI. Imatinib may also have a synergistic effect with DLI.¹³ Rituximab is another example. We have used rituximab after SCT in patients with aggressive lymphoma.¹⁴ The reduced risk of relapse in very high-risk patients suggested that rituximab may have eliminated MRD. It may have synergized with the donor immune system providing effectors for antibody-dependent cytotoxicity. The MD Anderson group showed similar effects of rituximab administered for residual chronic lymphocytic leukemia after NST.⁴⁴ Future studies may identify other methods to target MRD, trying to reduce relapse risk after SCT.

Selection of Conditioning Regimen

As a general role, myeloablative conditioning is the standard conditioning before SCT, and NST is still considered an experimental therapy, in which the long-term results have not yet been well defined. As a result, NST should be administered in carefully designed clinical studies.

NST regimens should be reserved mainly for patients not eligible for standard ablative conditioning on the basis of the criteria discussed above. However, some groups have also explored NST regimens as a means to reduce toxicity even in younger and medically fit patients in some settings.

The selection of the appropriate regimen for a patient depends on several factors including age, general medical condition, immune compe- tence of the recipient, genetic disparity between the patient and donor, and center experience.² Perhaps the most important determining factor is the aggressiveness and chemosensitivity of the underlying malignancy and its known susceptibility to the GVL effect.

There is now a spectrum of nonmyeloablative and reduced-intensity regimens with different immunosuppressive and cytoreductive intensity.

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The reduced-intensity regimens are a more appropriate approach for aggressive malignancies such as acute leukemia, and especially when not in remission. In this setting, rapid achieve- ment of CC and transient disease control is needed to induce GVL. However, in indolent malignancies, GVM may occur slowly, even in mixed chimeras, and toxicity may be reduced further using nonmyeloablative regimens. More intensive immune suppression is required for engraftment of allografts from unrelated donors and in patients not previously treated with chemotherapy. Less intensive immune suppression is needed in heavily pretreated patients and in particular those with a recent prior autologous SCT.²

There is no prospective study comparing the outcomes after different NSTs and reduced- intensity regimens that can show an advantage of one over the others. One analysis showed that reduced-intensity regimens might give better results in disease control than nonmyeloablative conditioning in patients with active or refractory leukemia whereas results were equivalent when the leukemia was in remission at the time of SCT.⁴⁵ Among reduced-intensity regimens, we have shown that the use of intravenous busulfan is associated with less regimen-related toxicity that other regimens, after both related and unrelated SCT, similar to what we have shown in ablative conditioning.^17,46Thus, differences between regimens may be significant and studies comparing them, and then comparing the best regimen to standard ablative regimen, are urgently needed.

CML is the malignancy most sensitive to GVL as evidenced by the high response rates to DLI.

There were some concerns of relatively high incidence of graft rejection in patients conditioned with truly nonmyeloablative regimens who had chronic-phase CML and had not been previously treated with intensive chemotherapy.⁷However, consistent engraftment has been achieved with reduced-intensity conditioning. The Hadassah group reported excellent outcomes in CML in the first chronic phase with 85% of patients surviving disease-free.⁴⁷Results in advanced-phase CML are much less favorable. We currently recommend reduced-intensity conditioning even for younger patients with chronic-phase CML; however, it should be appreciated that there are no long-term studies prospectively comparing the two approaches. For advanced-phase CML, we would recommend reduced-intensity conditioning only

for those not eligible for ablative conditioning and usually after a trial of remission induction.

Acute leukemia is a more aggressive malignancy, which is less susceptible to DLI.

Responses can be achieved; however, they are most often transient. Although there are no randomized trials, emerging data suggest that NST may be equivalent or inferior to ablative therapy.^48,49 However, these comparisons may be biased by the criteria for patient allocation.

Reduced-intensity conditioning may have favorable results in patients in remission; however, results have been disappointing in patients with active and refractory leukemia. In these patients, leukemia often recurs shortly after NST outpacing the developing of the GVL response.

Acute lymphatic leukemia (ALL) is considered the least responsive disease to immune effects.

This is not because ALL is not susceptible to GVL, rather because ALL is a very rapidly growing malignancy outpacing GVL. Thus, NST may be successful in high-risk ALL in remission, but has a limited role in active disease.

Hodgkin’s and non-Hodgkin’s lymphoma, and multiple myeloma are often treated with autologous SCT. These diseases show moderate susceptibility to GVM effect. When these patients are candidates for allogeneic SCT, they are often heavily pretreated and standard conditioning is associated with unacceptably high TRM rates. NST is becoming the preferred approach in these patients. It is feasible with favorable results in chemosensitive diseases.⁵⁰ Multiple myeloma is an incurable disease with standard chemotherapy as well as with autologous SCT. NST is being explored as an approach that may achieve cure. It is now established that relapse rates are very high when NST is given after relapse to prior therapy, but may be lower when NST is given upfront. The auto/allo approach in which autologous SCT is given for cytoreduction and is followed by NST to induce GVM seems promising in this setting.¹²

Chronic lymphatic leukemia and follicular lymphoma have been shown to be very sensitive to immune effects, similar to CML. These are indolent diseases for which standard ablative conditioning have very high TRM rates. Thus, these diseases are reasonable targets for NST, and we currently prefer this approach, especially in patients with chemosensitive disease.^8,44 As discussed above, SCT can also be supplemented with targeted therapy, such as rituximab, both before and after NST in these diseases.

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Conclusions

Nonmyeloablative and reduced-intensity conditioning are increasingly being used before allogeneic SCT, in a growing number of indications.

It is now well established that the first goal of allowing SCT for elderly and medically infirm patients has been achieved. NST regimens result in consistent engraftment of allografts from related and unrelated donors. TRM rates have been markedly reduced such that SCT can be administered relatively safely with no upper age limit, and after prior autologous SCT, as well as in certain malignancies, such as lymphomas and myeloma where historically TRM rates were exceedingly high. However, toxicity may still be substantial with some regimens and in patients with a high comorbidity score. GVHD continues to be a major cause of morbidity and mortality after NST, and its incidence may not be lower than after ablative SCT. Invasive fungal infections are a second common cause of TRM, which is closely associated with GVHD, and did not reduce in incidence. Novel approaches to further reduce these two complications are required to further improve outcome. In vivo T cell depletion reduces initial rates of GVHD, but because DLI is required more often for increased risk of disease persistence and MC, the ultimate rate of GVHD remains unchanged.

With gained experience, DLI is used more carefully after NST, limiting its use to patients with persistent MRD after SCT, or imminent graft rejection, and delaying administration in others, trying to reduce the risk for GVHD. Methods to deliver cellular immune therapy without GVHD would be a major step forward. The develop- ment of tumor or minor histocompatibility antigen restricted DLI, and the combination with targeted therapy and tumor vaccines are promising. Currently, despite initial data, there is no firm evidence for advantage of any of the regimens over the others. Although TRM may reduce with NST, theoretically, relapse rates may increase compared with ablative SCT, such that the net effects on disease-free survival are yet to be determined. Prospective comparative studies to determine the best NST regimen and then randomized studies comparing NST and ablative SCT, are urgently required before NST can be accepted as standard therapy, and to better define its role.

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