Hematopoietic cell transplantation after reduced-intensity conditioning for older adults with acute myeloid leukemia in complete remission

PURPOSE OF REVIEW: Allogeneic hematopoietic cell transplantation with myeloablative conditioning is a well established therapy for patients with acute myeloid leukemia. Its efficacy depends, in part, on the destruction of recipient acute myeloid leukemia cells by the conditioning regimen and, in part on their removal by donor immune cells contained in the graft (graft-versus-tumor effect). Due to regimen-related toxicities, the use of myeloablative allogeneic hematopoietic cell transplantation has been restricted to younger patients in good condition. More recently, the introduction of allogeneic hematopoietic cell transplantation following reduced-intensity or nonmyeloablative conditioning regimens, which rely mainly on graft-versus-tumor effects for tumor cell eradication, has permitted extending hematopoietic cell transplantation to include older patients and those with medical comorbidities. RECENT FINDINGS: Early results with allogeneic hematopoietic cell transplantation after nonmyeloablative and reduced-intensity conditioning for patients with acute myeloid leukemia in first complete remission are encouraging, with 2-year survivals after hematopoietic cell transplantation ranging from 48 to 79% among studies. Further, retrospective studies have demonstrated similar outcomes in adult patients with acute myeloid leukemia in complete remission given either myeloablative or nonmyeloablative conditioning. SUMMARY: Prospective studies are needed to define the place of allogeneic hematopoietic cell transplantation after nonmyeloablative or reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission, and to determine a role for consolidation chemotherapy before hematopoietic cell transplantation, if any.     

Reduced intensity is preferred over myeloablative conditioning allogeneic HCT in chronic lymphocytic leukemia whenever indicated: A systematic review/meta-analysis

Despite availability of new and more effective therapies for chronic lymphocytic leukemia, presently this disease remains incurable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Recent published clinical practice recommendations on behalf of the American Society for Blood and Marrow Transplantation relegated the role of for allogeneic hematopoietic cell transplantation to later stages of the disease. To our knowledge, no randomized controlled trial has been performed to date comparing myeloablative versus reduced intensity conditioning regimens in chronic lymphocytic leukemia patients eligible for the procedure. We performed a systematic review/meta-analysis to assess the efficacy of allogeneic hematopoietic cell transplantation when using myeloablative or reduced intensity conditioning regimens. We report the results in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Based on lower non-relapse mortality and slightly better overall survival rates, reduced intensity conditioning regimens appear to be the most desirable choice whenever the procedure is indicated for this disease. It appears highly unlikely that a RCT will be ever performed comparing reduced intensity vs. myeloablative allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia. In the absence of such a study, results of this systematic review/meta-analysis represent the best available evidence supporting this recommendation whenever indicated in patients with chronic lymphocytic leukemia.     

Survival for older patients with acute myeloid leukemia: a population-based study

BackgroundAcute myeloid leukemia is the second most common leukemia among United States adults with a median age of 69 years. We investigated recent clinical practices related to treatments and disease outcomes in older patients with acute myeloid leukemia in the United States.ResultsAmong 5,480 patients with acute myeloid leukemia (median age 78 years, range 65-93), 38.6% received leukemia therapy within three months of diagnosis (treated group). Practice changed with 16.3% of treated patients receiving hypomethylating agents after 2004 when those agents became available. Median survival was two months in the untreated group versus six months in the treated group (P<0.01) with the biggest improvements seen in those aged 65-69 years (10 months vs. 4 months; P<0.01) and 70-74 years (8 months vs. 3 months; P<0.01). In 46 patients receiving allogeneic hematopoietic cell transplantation (0.8%), the median survival from diagnosis was 22 months.ConclusionsTherapy for leukemia improves overall survival in older acute myeloid leukemia patients. Based on their comorbidities, most patients up to 80 years of age should be considered for treatment. New therapies including hypomethylating agents and allogeneic hematopoietic cell transplantation are promising and must be compared with other chemotherapy regimens.Key words: acute myeloid leukemia, older patients, treatment, disease outcome, survival     

Full-intensity and reduced-intensity allogeneic stem cell transplantation in AML

Allogeneic stem cell transplantation represents the most active form of anti-leukaemic therapy in acute myeloid leukaemia (AML). Advances in transplant technology and supportive care have resulted in improved outcomes in patients allografted using a myeloablative conditioning regimen. At the same time the use of reduced-intensity conditioning regimens has allowed an immunologically mediated graft-versus-leukaemia effect to be exploited in older patients who were previously ineligible for transplantation on the grounds of age or comorbidity. This coupled with the increased availability of alternative stem cell sources, in the form of either unrelated or cord blood donations, has established allogeneic transplantation as a key therapeutic strategy in the treatment of both younger and older adults with AML.     

Conditioning regimens for allogeneic stem cell transplants

In addition to providing cytoreduction at myeloablative dose intensity, conditioning regimens for allogeneic transplantation are designed to immunosuppress the recipient to permit donor lymphohematopoietic engraftment and thereby establish a graft-versus-malignancy effect. Increased confidence in the potency of this allogeneic graft-versus-malignancy effect, together with the need to reduce dose intensity to make transplantation safer and more widely applicable in older patients, has led to a conceptual revolution in conditioning regimen design. Novel nonmyeloablative transplant conditioning treatments have low regimen-related toxicity and low transplant-related mortality. The transplants confer a graft-versus-malignancy effect in myeloid and lymphoid malignancies and in metastatic renal cell cancer. Future prospects are for low toxicity conditioning regimens combined with specific antileukemia or antitumor intensification with radioconjugated or unmodified antibodies and the application of highly immunosuppressive but low toxicity conditioning regimens for mismatched transplants.     

Umbilical cord blood transplantation for myeloid malignancies

PURPOSE OF REVIEW: To review the available data on the outcomes of pediatric and adult patients with acute myeloid leukemia, myelodysplastic syndrome and chronic myelogenous leukemia after umbilical cord blood transplantation. RECENT FINDINGS: The literature shows that after umbilical cord blood transplantation the relapse rate, disease-free survival and overall survival of patients with myeloid malignancies is similar to other hematopoietic stem cells sources. Disease status at the time of transplantation is found in several studies to be a very important determinant of long-term outcome. Newer strategies such as double umbilical cord blood transplant and utilization of nonmyeloblative conditioning regimens show promising results. SUMMARY: Umbilical cord blood is a valuable alternative source of hematopoietic stem cells for transplantation of patients with myeloid malignancies who need an allogeneic transplant, but lack a suitable sibling donor.     

Allogeneic hematopoietic stem cell transplantation in the elderly

The development of reduced intensity or non-myeloablative conditioning (NST) in preparation for allogeneic stem cell transplantation (SCT) revolutionized the field and led to reconsideration of the dogma of upper age limit that was set up by the transplant centers as an eligibility parameter. Analysis of the literature data showed that NST regimens are associated with decreased transplant related mortality, and graft-versus-host disease, in comparison with standard myeloablative conditioning, in patients above the age of 50-55 years, or in younger patients with significant comorbidities. However we have to mention, that our considerations are based on the retrospective analysis of the literature data, and that well controlled prospective randomized studies are needed in order to definitely assess the role of NST. Comorbidity indices might be proved as the most important parameters for the choice of the most proper regimen for each patient in need and should be included in future trials.     

Hematopoietic stem cell transplantation for acute myeloid leukemia: A review

Increasing numbers of patients are receiving allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). Scientific and clinical advances in supportive care, donor selection, and conditioning regimens have resulted in lower transplant-related mortality, extension of care to a wider population of patients, and improvements in survival. Recent era has witnessed an explosive information about the molecular pathophysiology of AML. By early identification of patients at a high risk of relapse, it is expected that a majority of eligible patients will receive HCT in first complete remission. Novel conditioning regimens have been explored to improve transplant outcomes in AML. Currently, a stem cell source can be found for virtually all patients who have an indication to receive HCT. This area of investigation will likely continue to be of intense interest in terms of optimizing transplant outcomes.     

Busulfan-cyclophosphamide versus total body irradiation-cyclophosphamide as preparative regimen before allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia: what have we learned?

Most of the preparative regimens before allogeneic bone marrow transplantation include cyclophosphamide (Cy) with either busulfan (Bu) or total body irradiation (TBI). The Bu-Cy regimen has shown an advantage in chronic myeloid leukemia and TBI-Cy remains the standard conditioning regimen in acute lymphoblastic leukemia, but results are more conflicting in acute myeloid leukemia (AML). We report here the results of the most important studies comparing these two preparative regimens in AML. Survival is superior in all studies for patients treated with TBI and reached statistical significance in one of four trials. Two of three trials show significantly reduced transplant mortality and leukemia relapse. Higher incidences of veno-occlusive disease and hemorrhagic cystitis are reported with Bu. However, our long-term follow-up is limited, and to date no definitive conclusion can be drawn regarding late side effects. New approaches aiming at minimizing the toxicity without impairing the efficacy, such as targeted Bu plasma levels and nonmyeloablative conditioning regimens, seem promising but need to be evaluated further in future prospective studies.     

Allogeneic hematopoietic stem cell transplantation for myelofibrosis

PURPOSE OF REVIEW: This review summarizes the current status and new developments in allogeneic hemopoietic stem cell transplantation strategies for patients with myelofibrosis with myeloid metaplasia, focusing on novel concepts of allogeneic transplantation with reduced-intensity conditioning. RECENT FINDINGS: No substantial progress has been made in the conventional management of myelofibrosis with myeloid metaplasia. Allogeneic hemopoietic stem cell transplantation represents the only treatment modality with proven curative potential. Standard-dose conditioning regimes followed by allogeneic transplantation are associated with a relatively high transplant-related mortality. Reduced-intensity conditioning regimens have substantially reduced treatment-related mortality. This result is from three studies on myelofibrosis with myeloid metaplasia including more than 60 patients overall. The optimal conditioning regimen for this condition is unknown, in particular the utility of using T-cell depleted stem cells to reduce graft versus host disease is not documented. Emerging concepts include new risk classification for a better provision of the transplant outcome, and splenectomy before transplantation for reducing tumor burden. SUMMARY: The data on hemopoietic stem cell transplantation with reduced-intensity conditioning in myelofibrosis with myeloid metaplasia are encouraging. An accurate risk stratification is a pivotal procedure for selecting patients who will receive the greatest benefit for transplantation. Reduced-intensity conditioning should be further evaluated within clinical trials, in particular for assessing the role of splenectomy and for testing the optimal conditioning regimen.     

Reduced intensity conditioning HLA identical sibling donor allogeneic stem cell transplantation for patients with follicular lymphoma: long-term follow-up from two prospective multicenter trials

Background

Allogeneic hematopoietic stem cell transplantation is an effective treatment for patients with poor risk lymphoma, at least in part because of the graft-versus-lymphoma effect. Over the past decade, reduced intensity conditioning regimens have been shown to offer results similar to those of conventional high-dose conditioning regimens but with lower toxicity early after transplantation, especially in patients with chemosensitive disease at transplant.

Design and Methods

The aim of this study was to analyze the long-term outcome of patients with follicular lymphoma who received an HLA identical sibling allogeneic stem cell transplant with a reduced intensity conditioning regimen within prospective trials. The prospective multicenter studies considered included 37 patients with follicular lymphoma who underwent allogeneic stem cell transplantation between 1998 and 2007 with a fludarabine plus melphalan-based reduced intensity conditioning regimen.

Results

The median age of the patients was 50 years (range, 34–62 years) and the median follow-up was 52 months (range, 0.6 to 113 months). Most patients (77%) had stage III-IV at diagnosis, and patients had received a median of three lines of therapy before the reduced intensity conditioning allogeneic stem cell transplantation. At the time of transplantation, 14 patients were in complete remission, 16 in partial remission and 7 had refractory or progressive disease after salvage chemotherapy. The 4-year overall survival rates for patients in complete remission, partial remission, or with refractory or progressive disease were 71%, 48% and 29%, respectively (P=0.09), whereas the 4-year cumulative incidences of non-relapse mortality were 26% (95% CI, 11–61), 33% (95% CI, 16–68) and 71% (95% CI, 44–100), respectively. The incidence of relapse for the whole group was only 8% (95% CI, 2–23).

Conclusions

We conclude that this strategy of reduced intensity conditioning allogeneic stem cell transplantation may be associated with significant non-relapse mortality in heavily pre-treated patients with follicular lymphoma, but a remarkably low relapse rate. Long-term survival is likely in patients without progressive or refractory disease at the time of transplantation.     

Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation in myeloid diseases

Within the past years, reduced or modified doses of chemotherapy or radiotherapy have been widely studied for conditioning before allogeneic hematopoietic cell transplantation in patients with myeloid leukemia not eligible for conventional transplantation. The main goal was to reduce the substantial treatment-related mortality in this patient population while preserving the potential curative graft-versus-leukemia effect. This review summarizes results of published trials using reduced-intensity conditioning (RIC) in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), and myelofibrosis. In most of the published trials conditioning contained fludarabine (90–180 mg/m²) in combination with busulfan (4×10 mg/kg), melphalan (90–140 mg/m²), or 2–5 Gy total body irradiation (TBI). Peripheral blood hematopoietic stem cells from related or unrelated donors were used as graft source in most of the studies. Post-transplantation immunosuppression consisted of cyclosporine combined with methotrexate or mycophenolate mofetil. Although the majority of the patients were above the age of 50 years, early treatment-related mortality was rather low. Nevertheless, the rate of clinically significant graft-versus-host disease (GVHD) seemed to be comparable to conventional transplants in most of the protocols. The outcome differed between trials, but diagnosis and disease status pre-transplant significantly influenced outcome. In summary, this approach is feasible and provides access to the curative potential of allogeneic stem cell transplantation for patients with higher age or comorbidities. Since the majority of the reports included heterogeneous patient populations, mostly with a short follow-up, more and specifically randomized studies are needed to define the role of RIC before allogeneic hematopoietic cell transplantation.     

Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns

Progress in the last decade has improved the understanding of leukemia biology. Molecular markers in combinations with cytogenetics have improved the risk stratification of acute myeloid leukemia (AML) and informed decision-making. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allogeneic hematopoietic cell transplantation (HCT) for a larger number of patients. In this review, the positioning of HCT in the management of patients with AML is evaluated in view of changing risk/benefit ratios associated with both conventional treatments and transplantation, and some of the controversies are addressed in light of emerging data. Increasing data demonstrate outcomes of alternative donor transplantation approaching HLA-identical sibling donors in high-risk AML supporting the inclusion of alternative donors in trials of prospective studies evaluating post remission strategies for high-risk AML. The use of reduced-intensity conditioning has expanded the eligibility of HCT to older patients with AML, and outcome data are encouraging. Continued study of HCT versus alternative therapies is required to optimize patients' outcomes in AML.     

Effectiveness of allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia

Outcomes with conventional chemotherapy for older patients with acute myeloid leukemia (AML) remain disappointing, with few cures. For younger patients with AML, allogeneic hematopoietic cell transplantation (HCT) offers the best chance for cure, but this strategy is seldomly used for older patients. With recently improved methodologies, transplantation has become increasingly safe, suggesting that its use in older patients be reconsidered. This report will address four issues: the current frequency of transplantation for AML according to patient age; the impact of patient age on transplant outcomes; the comparative outcomes of transplantation versus chemotherapy for older patients with AML; and possible methods to improve the outcome of allogeneic HCT in older patients with AML.     

Allogeneic hematopoietic cell transplantation in acute myeloid leukemia

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment modality for select patients with acute myeloid leukemia (AML), functioning as a restorative agent following intensified chemo- and/or radiotherapy and also engendering the disease-directed immunologic threat of graft-versus-leukemia effect. Advancements in conditioning regimen intensity, donor availability, and supportive care have broadened the eligibility for allogeneic HCT, reduced rates of transplant related mortality, and improved outcomes over time. There are still obstacles to transplant in AML, offering opportunities for ongoing discovery, including poor recipient fitness, insufficient donor availability for certain populations, and limited access to care. Relapse remains the most common cause of treatment failure and a high priority area of investigative efforts. Post-transplant maintenance and novel applications of cellular therapeutics are expected to usher in a new era of promise for successful HCT in AML and will aim to overcome the remaining barriers impeding favorable outcomes for these patients.     

Role of reduced intensity conditioning in allogeneic hematopoietic cell transplantation for patients with multiple myeloma

High-dose chemotherapy followed by autologous hematopoietic cell transplantation continues to play an integral role in the treatment strategy in patients with newly diagnosed multiple myeloma. Incorporation of newer potent anti-myeloma agents has further improved outcomes. However, disease relapse or progression remains a challenge after autologous transplantation. Allogeneic hematopoietic cell transplantation remains the only potentially curative modality for some patients due in part to graft-versus-myeloma effect. High transplant-related mortality, in the range of 30% to 40%, previously seen with myeloablative conditioning regimens, including total body irradiation plus cyclophosphamide has been significantly reduced by introducing less ablative preparative regimens, so called reduced-intensity conditioning. Cumulative evidence suggests encouraging prospects for allogeneic transplantation through improved outcomes of myeloma patients (overall survival exceeding 70% at 2 years in some studies); however, which patient population would benefit most from this treatment remains to be defined. newer strategies to augment graft-versus-myeloma effect and minimize post transplant toxicities are in need of further improvement in patients with myeloma.     

Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: definitions and current practice in Europe

The Accreditation Subcommittee of the EBMT regularly publishes special reports on current practice of haemopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders in Europe. Major changes have occurred since the first report was published in 1996. Haemopoietic stem cell transplantation today includes grafting with allogeneic and autologous stem cells derived from bone marrow, peripheral blood and cord blood. With reduced intensity conditioning regimens in allogeneic transplantation, the age limit has increased, permitting the inclusion of older patients. New indications have emerged such as autoimmune disorders and AL amyloidosis for autologous, and solid tumours for allogeneic transplants. The introduction of alternative therapies has challenged well-established indications such as imatinib for chronic myeloid leukaemia. An updated report with revised tables and operating definitions is presented here.     

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??Abstract??Umbilical cord blood (CB) has now become a commonly used source of hematopoietic stem cells (HSCs) for allogeneic transplantation.Many studies have shown a decreased relapse rate and an increased transplantation-related mortality rate with similar overall survival rates after allogeneic hematopoietic stem cell transplantation with CB as compared with other donor sources.Substantial advances have been made resulting in better outcomes for our patients.The transplantation of double CB units has overcome the dose limitation and thus has markedly extended the use of CB to larger children and adults.Similarly??the use of reduced intensity conditioning in the CB transplantation setting has allowed the treatment of older patients who would be unable to tolerate the myeloablative regimens used in the original CB transplantation protocols.     

Reduced-intensity allogeneic hematopoietic stem cell transplantation for acute leukemias: 'what is the best recipe?'

Reduced-intensity stem cell transplantation (RIST) has been shown to be a safe and useful alternative transplant method for patients including elderly and medically unfit patients. RIST conditioning regimens vary widely in the intensity of myeloablation, immunoablation, and antileukemia effects, and thus optimal regimen for each disease entity is yet to be determined. Most reports on RIST to date are small, single-institution experiences or retrospective studies with heterogeneous patient populations and primary diseases, complicating any direct comparison between studies. In acute myeloid leukemia (AML), moderate-intensity regimens may be effective, achieving 30-70% 1-year disease-free survival in various series, but minimal-intensity regimens are associated with high relapse rates. In acute lymphoblastic leukemia (ALL), not even moderate-intensity regimens are effective and most patients with advanced ALL relapse post transplant. Thus, the risk/benefit ratios of graft-versus-host disease/graft-versus-leukemia effect differ among diseases. Larger, prospective, multi-center clinical trials are needed to determine the best use of RIST in hematologic malignancies.     

Allogeneic transplantation for myelodysplastic syndrome (MDS)

Haematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). Developing conditioning regimens with low toxicity, at the same time as preserving an effective graft versus tumour response, is pivotal to expanding the scope for allogeneic transplantation in older patients with MDS. With the introduction of reduced intensity conditioned regimens, transplant centres worldwide are able to offer allogeneic HSCT to a much larger cohort of patients. Graft versus host disease (GvHD) remains a significant cause of morbidity and mortality, however with the use of T-cell depletion, centres have been able to utilise volunteer unrelated donors with an increasing degree of HLA disparity. The graft versus dysplasia effect resulting from allogeneic HSCT and the infusion of donor leukocytes has led to a greater understanding of the immunological mechanisms that govern outcome following transplantation in MDS.