Allogeneic stem cell transplantation (alloSCT) provides the only potential long-term curative option for patients affected by myeloid malignancies [acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML)], especially those with high-risk features. A subset of patients, however, fails to achieve durable remissions due to graft failure or disease relapse after autologous stem cell transplantation (autoSCT), alloSCT and umbilical cord blood transplantation (UCBT). Such patients, in theory, can be considered for second alloSCT. The Center for International Blood and Marrow Transplant Research (CIBMTR) reported that during the years from 2000 to 2006, 323 patients received a second alloSCT for AML, the majority within 12 months of the first SCT (W Perez and T Petersen, personal communication). In Europe, the Acute Leukemia Working Party (ALWP) registry of the European Blood and Marrow Transplant (EBMT) in the same period reported 614 alloSCTs for adults with AML, the majority for relapse (V Rocha, personal communication). In this review, we examine the data of using second alloSCT after graft failure or disease relapse after autoSCT, alloSCT and UCBT for patients with myeloid malignancies. We discuss the challenges associated with this procedure and highlight predictors of outcome, allowing for optimization of patient-selection criteria.
Graft failure after first allogeneic stem cell transplantation
Graft failure and rejection after alloSCT, although uncommon except after UCBT, are associated with a high mortality. Several factors such as underlying disease state, donor–recipient graft incompatibility, infusion of low numbers of nucleated or CD34+ cell dose, viral infections, defective marrow microenvironment or incomplete ablation of host immune cells have all been implicated . In the papers we reviewed, the definition of engraftment is an absolute neutrophil count (ANC) greater than 0.5 × 109 cells/l for 3 consecutive days, any time after transplantation that may or may not be defined also in the setting of a mixed or full donor chimerism. Never attaining these threshold blood counts defines primary graft failure. Graft rejection, or secondary graft failure, generally is defined as recurrent neutropenia less than 0.5 × 109 cells/l, after initial count recovery without a reversible cause such as infection or medication-induced myelosuppression; again, this finding may be in the setting of mixed or full donor chimerism. In fact, the literature defining neutrophil recovery and engraftment is changing. Confusion in this definition has arisen after the era of reduced-intensity conditioning regimen (RIC), in which a period of bone marrow aplasia does not necessarily occur, and therefore, the definition of neutrophil recovery, as stated above, cannot be followed. One could argue that to fulfill the definition of engraftment, chimerism data are needed to demonstrate the presence of donor cells. The use of chimerism analysis, especially a mixed chimeric state, as a marker of graft failure, rejection, disease relapse or stable remission, however, has not been clearly delineated and, therefore, cannot be recommended to define disease states or guide therapeutic decisions [2••]. Moreover, the definition of engraftment using chimerism in a registry-based point of view also is difficult due to the heterogeneity of chimerism techniques and different evaluation times after transplantation. For these and other reasons, in this review, we exercise caution when interpreting the results of graft failure or nonengraftment in the field of RIC.
Outcomes after allogeneic second transplants for graft failure or rejection
Several studies examined patient outcomes after a second alloSCT performed for graft failure or rejection (Table 1) [3–9,10•,11]. Unfortunately, however, most reports are from single institutions describing small numbers of patients, varied conditioning regimens and differing donor graft sources, both for first and second transplantation. Graft-versus-host disease (GVHD) prophylaxis also is not standardized between centers.
The largest series reported by Guardiola et al. retrospectively examined 82 patients who underwent second alloSCT, but the authors do not specifically state the numbers of patients with AML within the acute leukemia group. Treatment-related mortality (TRM) at 100 days was 53%, and 3-year overall survival (OS) was 30% for the entire cohort, irrespective of underlying disease. Patients with an intertransplant time of more than 80 days had a better OS; 73% of patients had neutrophil counts greater than 0.5 × 109 cells/l for at least 3 days by day +40. The authors postulated that a high neutrophil recovery rate contributed to improved outcomes. The GVHD prophylaxis regimen also contributed positively to OS, as those patients, more than 80 days from first transplantation, who received cyclosporine alone had a 54% 3-year OS compared with only 8% in the noncyclosporine therapy group. Prednisone use appeared to contribute to early deaths from fungal infections and lower neutrophil recovery rates. The data did not distinguish between use of the same or a different donor.
A second, large series from Platzbecker et al.  reported on the outcomes of 70 patients who underwent a second alloSCT using peripheral blood stem cells (PBSC) or bone marrow from the same donor. Fifty-three of the patients had a myeloid malignancy. Primary graft failure was the reason for the second transplant in 34 patients, whereas the remainder had disease relapse. The median OS was 3 months for all patients. Patients who were re-transplanted because of graft failure, however, had a 37% OS at 40 months as compared to the 7% OS at 40 months for those patients re-transplanted for disease relapse (P = 0.02). Patient age less than 50 years also portended a better outcome. Underlying disease did not impact survival.
Jabbour et al.  and Chewning et al.  specifically examined fludarabine-based preparative regimens in 25 patients undergoing second alloSCT for primary or secondary graft failure. Although both groups demonstrated high rates of engraftment (six of nine patients and all 16 patients, respectively) in their prospective study of only patients with myeloid malignancies, Jabbour et al. had high rates of acute GVHD and TRM and a lower OS with the combination of fludarabine and antithymocyte globulin. In a larger series of patients, 11 of whom had myeloid malignancies, Chewning et al.  reported a 3-year OS of 35% and disease-free survival (DFS) of 18%; patients aged 20 years or younger had a statistically significant better OS than older patients (five of eight patients younger than 20 years survived more than 6 months as compared to one of eight patients older than 20 years, P = 0.02).
Unrelated umbilical cord blood transplantation
Unrelated UCBT is associated with delayed neutrophil recovery and a higher incidence (10–30%) of engraftment failure as compared to using bone marrow or PBSC . Explanations include: the low number of hematopoietic progenitor cells present in a UCB unit and lower nucleated and CD34+ cell dose infused; the influence of human leukocyte antigen (HLA) disparities; different biologic properties such as lack of some adhesion molecules for homing; greater immaturity of cord blood hematopoietic cells; and usually more advanced disease status at time of transplantation [13•,14].
The majority of the literature addressing use of UCBT for second alloSCT after graft failure is limited to case reports, making widely applicable statements regarding outcomes difficult [4,5] (see Table 1).
Satoh et al., Nakamura et al.  and Ohwada et al. , in three separate case reports, identify three patients, two 44-years-old and one 16-year-old, with AML. All three underwent myeloablative conditioning and UCBT of one unit, and all mismatched at two HLA loci. Two suffered from primary graft failure (diagnosed on day +31 and day +27), whereas the other had graft rejection on day +28, confirmed by complete loss of donor chimerism, neutropenia and a hypocellular marrow. All three received a different RIC regimen and underwent a second UCBT with one cord unit and were engrafted with the second UCBT less than 30 days after second transplantation. The 16-year-old patient remained in complete remission through 19 months after the second UCBT, whereas one 44-year-old patient was in complete remission for at least 5 months after second UCBT. All three patients had 100% second donor chimerism after repeat transplantation.
The Eurocord group analyzed outcomes of UCBT after second transplants as a salvage therapy in the setting of primary graft failure after one or two units of cord blood for hematologic diseases. From May 1995 to July 2007, the results of 1115 UCBT for hematological diseases were reported to the Eurocord registry. A total of 113 of these transplants were diagnosed as primary graft failures (failure to achieve a neutrophil count >500 × 106 cells/l until 60 days after UCBT or having received a treatment for graft failure in this period). From this group, 34 patients did not received treatment, 25 received an autologous rescue from precryopreserved stem cells and 54 received a second hematopoietic stem cell transplantation (HSCT). Median age of these 54 patients at transplant was 12 (1–51) years, and 17 patients had AML or MDS. Median time between first and second transplants was 56 (33–116) days. Source of stem cells for the second transplant was five mismatched unrelated bone marrow (MMUD), 13 haploidentical-related grafts, 26 single UCB and 10 double UCB grafts. T cell depletion was used in 12 cases. RIC regimens (often fludarabine-based) were used in the majority of cases. Low-dose total body irradiation (TBI) was administered to 33 patients, and serotherapy (antilymphocytic globulin/antithymocyte globulin/other monoclonal antibody) was used in 39 patients (five patients received no preparatory conditioning). Twenty-nine of 54 patients engrafted: five of 26 received a single and eight of 10 received a double UCB unit, whereas 16 of 18 received other alternative donor grafts. Eighteen patients (35%) developed acute GVHD grades II–IV; chronic GVHD was observed in eight of 24 evaluable patients (33%). Two-year OS was 24 ± 6%, which varied according to cell source. At 2 years after transplant: 3/5 patients receiving MMUD, 10/13 receiving haploidentical grafts, 5/10 given double UCB and 2/26 receiving single UCB units were alive and well (Eurocord, unpublished data). Thus, second transplants may be considered as a salvage therapy for primary graft failure after unrelated UCBT. Choice of the best conditioning regimen and best cell source still are open questions. On the basis of these preliminary results, patients can be rescued with double UCBT or haploidentical donors.
One problem in the daily practice of treating UCBT recipients is when to decide that the patient must undergo a second transplant. Given the small numbers of patients studied, no reliable recommendations can be made regarding the treatment of UCBT-associated graft failure and rejection and use of UCB as a graft source for a second alloSCT; these case reports and the Eurocord preliminary analysis suggest that this option is feasible. Currently, patients live longer in aplasia due to improved supportive care and better control of infections. Neutrophil recovery after UCBT can occur as late as 60 days after transplantation. In fact, among 350 unrelated UCBTs for adults with AML performed between 2000 and 2006 and reported to Eurocord, 265 patients engrafted at a median of 21 days; 5% of patients who engrafted had neutrophil recovery after day 45 (Eurocord, unpublished data). At Hospital Saint-Louis, a bone marrow aspiration and chimerism test is performed at day +30 for those patients without signs of engraftment and no response to hematopoietic growth factors, and a second graft search commences.
Currently, at the University of Minnesota, a patient having a persistent ANC less than 0.5 × 109 cells/l and a day +21 bone marrow with less than 5% cellularity prompts a search for a second graft. If by day +28 there is no change in the ANC or bone marrow cellularity, a second conditioning regimen is started. If there is evidence of early hematopoietic recovery on day +28, growth factors are continued and a repeat bone marrow is performed on day +35.
Multiinstitutional studies, however, are needed to evaluate the cell dose and administration route of cord blood [18•,19], including the utility of double UCBT after graft failure or rejection.
Relapse after autologous stem cell transplantation
Although autoSCT procedures have a low TRM, this modality is associated with high-relapse rates and increased likelihood of second malignancies. Thus, there are a number of studies examining patients (Table 2) who received an alloSCT for relapse after an autoSCT [20–26].
There are no data in the literature reporting outcomes of unrelated UCBT for relapse after autoSCT. In a survey of the Eurocord registry, among 350 UCBTs performed for adult AML patients, autoSCT was performed in 76 patients (23%). Median age was 40 (18–65) years. At UCBT, 67% of the patients were in second complete remission and 33% not in remission. Median time from autoSCT to UCBT was 15 months for those patients given a UCBT in remission and 10 months for those transplanted not in remission. A majority of the transplants used a single UCB unit (70%) with one or two HLA disparities. As a preparative regimen, half the patients received a nonmyeloablative regimen. At a median follow-up of 12 months, 2-year OS was 28 ± 6%, 38% for those transplanted in remission and 10% if not in remission. A risk-factor analysis was not possible due to the short follow-up and limited number of patients, but the data show that UCBT can rescue almost 40% of those who relapsed after autoSCT when remission is obtained before UCBT.
Relapse after allogeneic stem cell transplantation
Historically, alloSCT relied solely on myeloablative conditioning prior to transplantation, precluding many patients with end-organ damage from being offered a second alloSCT. RIC and improved GVHD prophylaxis enable more patients to undergo a second alloSCT (Table 3) [27–34]. Studies examining the outcomes of patients after second alloSCT are summarized in Table 3.
Eapen et al., for the CIBMTR, reported on 279 patients (75% with a myeloid malignancy) who relapsed after alloSCT and underwent a second transplant. Time from first transplant to relapse was the most important prognostic indicator. Specifically, time to relapse more than 6 months after first alloSCT was associated with lower TRM and relapse rates, fewer treatment failures and better OS. Patients who relapsed between 7 and 12 months had similar outcomes to those patients who relapsed more than 1 year after first transplantation. Also, age 20 years or younger portended a lower TRM, treatment failure and overall mortality. Improved disease control at second transplant was associated with a lower relapse treatment failure rate. Patients given a RIC regimen had higher relapse rates. There was no difference between those patients with AML versus acute lymphoblastic leukemia (ALL) versus CML in any outcome.
Shaw et al.  retrospectively examined the outcomes of 71 patients (half with myeloid malignancies) who underwent RIC prior to a second alloSCT for relapsed disease. Early relapse rate within 11 months of initial transplantation negatively affected TRM and OS during the second transplant. Development of chronic GVHD lowered the probability of relapse at 2 years (44 versus 63% for those with and without chronic GVHD, respectively, P = 0.15) and also improved OS at 2 years, 54% for those with chronic GVHD as compared to 29% for those without chronic GVHD (P = 0.014). Those patients with lymphoproliferative disorders fared significantly better than those with ALL, AML, CML or MDS; this finding may have reflected a less aggressive disease course in these patients. Age, disease status, acute GVHD and use of TBI did not impact patient outcomes. They conclude that second alloSCT may be appropriate for a subset of patients relapsing beyond 11 months after initial transplantation, but warn that this retrospective study has selection bias.
In a survey of the ALWP of the EBMT, 244 patients transplanted in first complete remission, who subsequently relapsed and received a second alloSCT in European centers during the period from 2000 to 2006, were analyzed. The SCT donor used in the first transplantation was an HLA-identical sibling in 172 cases, an unrelated donor in 55 and a syngeneic, haploidentical or unrelated UCB unit in the remainder. Conditioning was myeloablative in 70% of the cases. Interval from first to second transplant was 368 (range 63–2162) days for HLA-identical siblings and 377 (range 578–1895) days for unrelated donors. The stem cell source for the second transplant was PBSC in 94% and bone marrow in 6%. Seventy-eight (32%) patients were transplanted in remission and 166 (68%) were not in remission. Conditioning regimen was nonmyeloablative in 60% of the cases. Median follow-up after second transplant was only 7 months. Neutrophil recovery was observed in 89% of the patients. At 2 years, the probability of survival after HLA-identical sibling and unrelated-donors SCT was 23 ± 4 and 15 ± 6%, respectively. If remission was obtained before the second transplant, 2-year OS was 38 ± 7% compared with 16 ± 4% for those patients not in remission (P = <0.001). Median time from first alloSCT to relapse in this population was 11 months. Two-year OS was 17 ± 5% for patients relapsing after first alloSCT and 26 ± 6% for those transplanted after this time (P = 0.002). Age at second transplantation was not associated with OS.
Successful transplantation/prognostic factors
Although there are no large, randomized, controlled trials to assess the prognostic factors and outcomes associated with second alloSCT after graft failure or disease relapse, examining all studies allows for review of risk factors. Disease in remission at time of transplant, younger recipient age and longer time from first transplant to relapse portend the greatest successful outcomes for second alloSCT (Table 4).
Other options: donor lymphocyte infusion
Although alloSCT is performed for curative intent in hematologic malignancies, disease relapse occurs in approximately 40% of patients after transplantation. Median age of leukemia patients is approximately 70 years, and by that time many may have comorbid conditions that preclude an alloSCT, even in the era of RIC; furthermore, many younger patients who underwent an initial alloSCT may have end-organ damage or transplant-related morbidities prohibiting a second transplant. Options for disease control in these patients include donor lymphocyte infusion (DLI) for graft-versus-leukemia (GVL) effect that avoids the morbidity of further conditioning and immune suppression. Additionally, DLI often is used for patients with a high risk of relapse as a planned procedure after alloSCT, especially in those patients without GVHD.
DLI for CML relapse has been shown to be effective; however, the data for DLI in AML are less convincing, especially for patients in frank leukemic relapse. Tomblyn and Lazarus  recently reviewed the use of DLI in a variety of conditions including relapsed CML. In a collective cohort of over 500 patients, there were variations in cell dose and escalation schedule among the studies; 77% of patients achieved a molecular complete remission, with an OS ranging from 53 to 95% over 3 years. In the only large-scale review restricted to patients with AML, Schmid et al. reported on 399 patients from EBMT centers who received DLI (n = 171) or other treatment (n = 228) for relapsed AML after alloSCT. Patients who received DLI had a better 2-year OS, 21 versus 9%, than those who did not. Factors associated with a better survival were relapse time more than 5 months from initial alloSCT, age less than 37 years and the use of DLI. In the cohort of patients who received DLI, patients in remission or with favorable cytogenetics had a 56% 2-year OS as compared to 21% for women not in remission, but with a lower tumor burden. All other patients had only a 9% 2-year OS after DLI. Those patients with acute GVHD had a lower OS due to early mortality; however, patients with chronic GVHD had a better OS in those patients who had DLI. The authors suggest that DLI for relapsed disease be used in conjunction with chemotherapy to attempt remission and should be considered in a subset of patients. The lack of large, randomized controlled trials makes further recommendations difficult.
Factors important to a successful outcome with DLI are similar to the good prognostic indicators for a second alloSCT. The ideal indication, cell dose, dosing schedule and necessity of chemotherapy prior to infusion of DLI cannot be established with the data currently available for those myeloid malignancy patients. Moreover, some other strategies to consolidate the remission obtained after DLI are not reported, and more questions than answers remain.
Both autoSCT and alloSCT can be a curative procedure for a majority of patients with myeloid malignancies; however, graft failure and disease relapse occur, necessitating further therapy. The ideal salvage treatment is unknown, but second alloSCT deserves consideration, given the availability of less toxic preparative regimens and better supportive care (antibiotics and acute GVHD prophylaxis) during the transplantation period. The published data are limited due to small sample size, as many of the studies are single-institution, retrospective reviews. These data indicate that second alloSCT is not feasible in all patients, and it is difficult to make recommendations regarding patient and disease selection for a procedure still associated with high TRM. Benefits and risks of second transplants must be discussed with patients and their families. Variables such as underlying disease, patient age, comorbid conditions, disease status at the time of transplantation, conditioning and GVHD regimens, and donor type as well as graft source introduce uncertainty and make application to a wide patient population challenging. There are no well designed, retrospective studies that include large numbers of homogenous groups of patients, and importantly, there is no prospective study addressing the question of the feasibility of second transplants for graft failure or relapse after SCT. For patients in relapse, the best candidates for the procedure are younger, have late-relapsed disease and are in remission at time of consideration of second alloSCT, but larger, multicenter trials are needed. On the contrary, for SCT recipients who experience graft failure and rejection, it is unclear how to optimally treat these patients. As UCBT is increasing in recent years, the role of second transplants for graft failure after this procedure will need to be investigated.
Second transplants for graft failure, mainly after unrelated UCBT and for relapse after SCT, have shown disappointing results. Importantly, only a selected group of patients without important comorbidities or those obtaining remission should be considered for second transplants. More experimental data, including animal models, may be helpful and trigger new approaches to improve the dismal results of second transplants. To improve the results of second transplants, the development of strategies that decrease the toxicity of the procedure, increase the engraftment rate and the GVL effect as well as decrease acute GVHD after second transplants are needed. Among those strategies, one could speculate: use of new immunosuppressive drugs with low toxicity to be used in the conditioning regimen; use of monoclonal antibodies that target leukemia cells and avoid the host-versus-graft reaction; better understanding of homing and tolerance with an intelligent modification of the composition of the graft such as the increase of specific natural killer, veto [37•] or T regulatory cells; modification of the route of administration of hematopoietic cells; new immunosuppressive drug combinations to avoid GVHD after second transplants such as mycophenolate mofetil, sirolimus or even use of cyclophosphamide early after transplant ; and use of posttransplant therapy with new molecular drugs to reinforce the molecular and hematologic remission of some AML subtypes. All these approaches can only become realistic in improving results of second transplants by undertaking well designed, multicenter, prospective clinical trials.
Disclaimer regarding the data provided by the CIBMTR: The data presented here are preliminary and were obtained from the Statistical Center of the CIBMTR. The analysis has not been reviewed or approved by the Advisory or Scientific Committee of the CIBMTR. The data may not be published without the approval of the Advisory Committees.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 152).
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
disease relapse; graft failure; myeloid malignancy; second allogeneic stem cell transplantation; umbilical cord blood transplantation