Phase 2 study of lenalidomide maintenance for patients with high-risk acute myeloid leukemia in remission.

BACKGROUND: New drug combinations have led to significant improvements in remission rates for patients with acute myeloid leukemia (AML). However, many patients with high-risk AML who respond to their initial treatment and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with poor outcomes. METHODS: In this phase 2 trial, the efficacy of lenalidomide maintenance was evaluated in patients with high-risk AML who had achieved their first or second remission after induction chemotherapy and at least 1 consolidation cycle and who were not candidates for immediate ASCT. Lenalidomide was given orally at 10 to 20 mg daily on days 1 to 28 of a 28-day cycle for up to 24 cycles. RESULTS: A total of 28 patients were enrolled in this study with a median age of 61 years (range, 24-87 years). The median number of cycles was 8 (range, 1-24 cycles). Ten patients (36%) completed 24 months of maintenance treatment. With a median follow-up of 22.5 months (range, 2.6-55 months), 12 patients (43%) relapsed after a median of 3 months (range, 0.7-23 months). The median duration of remission for all patients was 18.7 months (range, 0.7-55.1 months). The 2-year overall survival and relapse-free survival rates from the time of enrollment were 63% and 50%, respectively. Overall, lenalidomide was well tolerated; serious adverse events of grade 3 or 4, including rash (n = 5), thrombocytopenia (n = 4), neutropenia (n = 4), and fatigue (n = 2), were observed in 13 patients (46%). CONCLUSIONS: Lenalidomide is a safe and feasible maintenance strategy in patients with high-risk AML who are not candidates for ASCT, and it has beneficial effects for patients with negative measurable residual disease.

Phase II study of single-agent nivolumab in patients with myelofibrosis.

Dysregulated JAK-STAT signaling in myelofibrosis induces pro-inflammatory cytokines, which suppresses T cell proliferation and differentiation, likely responsible for disease progression. The PD-1 pathway, found to be overexpressed in myeloid malignancies, has gained great interest as a therapeutic target, where a significant unmet need exists for novel therapeutic strategies. Preclinical models showed JAK2 mutant cells had higher expression of PD-L1; furthermore, JAK2 mutant xenografts treated with PD-1 inhibition had prolonged survival and reduction in JAK2 allele burden. We evaluated the efficacy and safety of single-agent nivolumab in 8 adult patients with myelofibrosis. Nivolumab was given at 3 mg/kg every 2 weeks for 8 doses, then every 12 weeks for up to 4 years, or until disease progression or toxicity. The median number of nivolumab doses received was 6 [range, 5-16 doses]. Five patients had stable disease including spleen size, total symptom score, and blood requirements for a median of 3.3 months [range, 2.3-15.2 months]. After a median follow-up of 57 months, two patients were still alive. The median overall survival was 6.1 months [range, 3.2-57.4 months]. Due to failure to meet the predetermined efficacy endpoint, the study was terminated early. Trial registration: Clinical trials.gov NCT: 02,421,354.

Philadelphia chromosome-positive acute lymphoblastic leukemia at first relapse in the era of tyrosine kinase inhibitors.

Despite the advances in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with the introduction of tyrosine kinase inhibitors (TKIs), relapses remain challenging. We reviewed clinical data from adult patients with Ph + ALL who received frontline hyperCVAD chemotherapy with a TKI to determine their outcomes after first relapse. Patients with first morphological relapse after prior complete remission were evaluated for predictors of response and survival. For 57 of 233 (25%) patients, there was morphological relapse after a median of 15.9 months from first remission [range: 5.3-94]. The choice of salvage treatments was at the discretion of the treating physician. So, 43 (75%) patients received a TKI in combination with their salvage treatment. Second remission was achieved in 41 of 49 (84%) evaluable patients. Median relapse free survival (RFS) was 10.5 months [range, 0.2-81]. The 1-year and 2-year overall survival (OS) were 41% and 20% respectively. On multivariate analysis, only elevated LDH (units/L), the use of first-generation or no TKI at the time of first relapse and the achievement of a major molecular response (MMR) had a significant effect on OS (HR: 2.82, 95% CI:1.11-7.16, P = .029; HR = 2.39, 95% CI: 1.07,5.39, P = .034; HR = 0.39, 95% CI: 0.16-0.94, P = .03, respectively). Whereas, only achievement of MMR was significantly prognostic for RFS with a HR of 0.48 (95% CI: 0.23-0.98, P = .04). The OS and RFS were comparable between recipients and non-recipients of allogeneic hematopoietic stem cell transplantation (alloHSCT) at second remission, due to a higher non-relapse mortality (53%) seen in patients who underwent alloHSCT.

Prognostic significance of baseline FLT3-ITD mutant allele level in acute myeloid leukemia treated with intensive chemotherapy with/without sorafenib.

Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene (FLT3) confer a poor prognosis in adult AML. Studies have reported that a higher mutant allelic burden is associated with a worse prognosis. Adult patients with FLT3-ITD mutated AML treated at our institution were identified. Patients were assigned into 2 groups; patients who received idarubicin and cytarabine (IA, group one) containing induction, and who received sorafenib in addition to IA containing regimens at induction (group two). The optimal FLT3-ITD mutant allele cut-off was defined as the cut-off to divide the whole cohort with the highest statistical significance. A total of 183 patients including 104 (57%) in group one and 79 (43%) in group two were identified. The complete remission (CR)/CR with incomplete hematologic recovery (CRi) for group one and group two were 85% and 99%, respectively (P = .004). The median relapse free survival (RFS) for group one and two were 12 and 45 months, respectively (P = .02). The median overall survival (mOS) was 17 months in group one, and has not been reached in group two (P = .008). The optimal FLT3-ITD mutant allele cut-off for OS was 6.9% in group one, there was no optimal cut-off in group two. On multivariate analysis, poor performance status (PS) (P = .003), sorafenib (P = .01), and presenting white blood cells (WBC) (P < .001) were independent predictors of OS. Higher FLT3-ITD allele burden is associated with a worse outcome in patients treated with IA-based chemotherapy. Addition of sorafenib to chemotherapy not only nullifies the negative prognostic impact of higher allele burden, but also improves outcome of FLT3-ITD mutated AML patients regardless of the allele burden.

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

OPINION STATEMENT: With the introduction of tyrosine kinase inhibitors (TKIs) in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the prognosis of patients has improved dramatically. Currently, the standard of care in the frontline setting for fit patients is TKI in combination with chemotherapy. Age-adjusted chemotherapy or corticosteroids alone have been used with TKIs in elderly patients with comorbidities with modest long-term benefit. The primary goal of treatment is the achievement of early deep molecular remission as the achievement of complete molecular remission (CMR) at 3 months has been demonstrated to be predictive of higher long-term survival. The probability of attaining this goal by a more potent TKIs like dasatinib or ponatinib is higher, thus we recommend the use of second- or third-generation TKIs over imatinib. Clinicians should be aware of possible fatal cardiovascular events mainly related to ponatinib. Allogeneic hematopoietic stem cell transplantation (alloHSCT) should still be considered in first remission, especially for younger patients treated with imatinib combination therapy. A subset of patients achieving CMR at 3 months may be able to continue consolidation and maintenance with chemotherapy and TKI without the need for alloHSCT. Because of higher risk of relapses in the central nervous system, intrathecal chemoprophylaxis is mandatory for all patients. New strategies incorporating novel agents, such as antibody-drug conjugates, bispecific monoclonal antibodies, potent TKIs, and CAR T cells are under investigation.

A Pilot Phase II Study of Erlotinib for the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia.

Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, may have off-target activity inducing acute myeloid leukemia (AML) differentiation, possibly through SYK inhibition. We investigated erlotinib in a pilot phase II study for efficacy in relapsed/refractory AML patients at a dose of 150 mg once daily in 28-day cycles. Twenty-nine patients were treated for a median of 29 days (range 12-142 days). Seven patients (24%) received > 1 cycle of therapy and 12 (41%) discontinued treatment before day 28 due to disease progression. One patient (3%) achieved complete remission and 2 (7%) a > 50% reduction in blasts. The most common toxicities associated with erlotinib were fatigue in 10 patients (34%), diarrhea in 10 (34%), nausea in 8 (28%), and rash in 7 (24%). Only 2 patients (7%) had study drug-related adverse events requiring dose reductions and eventual discontinuation. The main reason for treatment discontinuation was disease progression in 26 patients (90%). All patients had died by the time of the last follow-up. Progression of disease was the primary cause of death in all patients. Median overall survival was 14 weeks (range 2.3-96.9 weeks) and median event-free survival was 5 weeks (range 1.7-21.0 weeks). Erlotinib as a single agent has limited clinical efficacy in patients with relapsed/refractory AML.

Philadelphia-chromosome positive acute lymphoblastic leukemia: ten frequently asked questions.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) constitutes a distinctive cytogenetic entity associated with challenging outcomes, particularly in adult patients. Current upfront chemotherapy-tyrosine kinase inhibitor (TKI)-based therapies include first, second and third-generation TKIs that have revolutionized patient outcomes including molecular remission and overall survival. Chemotherapy-free regimens such as blinatumomab-dasatinib or blinatumomab-ponatinib offer exciting possibilities, yet challenges arise, particularly in preventing central nervous system relapse. Monitoring measurable residual disease is now a cornerstone particularly using next-generation sequencing (NGS)-Clonoseq for accurate assessment. Controversy regarding the ability to omit consolidation with allogeneic stem cell transplantation, specifically for patients achieving early molecular remission, is related to the excellent survival achieved with novel combinations in the upfront setting, however challenged by the lower disease control when transplant is utilized beyond first remission. Post-transplant maintenance introduces new dilemmas: the optimal TKI, dosing, and duration of therapy are open questions. Meanwhile, a myriad of new combinations and cellular therapies are used for relapsed Ph+ ALL, prompting us to unravel the optimal sequencing of these promising regimen. In this review, we delve into the breakthroughs and controversies in Ph+ ALL with ten commonly asked questions.

Bi- and Tri-specific antibodies in non-Hodgkin lymphoma: current data and perspectives.

Bispecific antibodies (BsAbs) are a new group of targeted therapies that are revolutionizing the treatment landscape of B-cell non-Hodgkin's lymphoma (B-NHL). In the relapsed/refractory setting, salvage chemotherapy and autologous stem cell transplantation are capable of curing 50% of patients, whereas the other half will have a dismal outcome with a median overall survival of less than 12 months. This unmet need reinforced the importance of innovative therapies like the BsAbs and CAR-T cell therapies. In this review, we delve into BsAbs in B-NHL from the preclinical development to clinical data in both refractory and frontline settings, and then discuss future perspectives.

Venetoclax: A New Partner in the Novel Treatment Era for Acute Myeloid Leukemia and Myelodysplastic Syndrome.

BACKGROUND: Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are two closely related blood cancers that are more frequent in older adults. AML is the most common type of adult acute leukemia, and MDS is characterized by ineffective blood cell production and abnormalities in the bone marrow and blood. Both can be resistant to treatment, often due to dysfunction in the process of apoptosis, the body's natural mechanism for cell death. Venetoclax, an orally-administered medication that selectively targets the BCL-2 protein, has shown promise in enhancing treatment sensitivity in some hematological malignancies by reducing the apoptotic threshold. This review aims to evaluate the effectiveness of venetoclax in treating AML and MDS, as well as potential mechanisms of resistance to the medication. METHODS: A literature search was conducted utilizing PUBMED to capture all relevant research articles on the use of venetoclax as a therapy for both diseases. The MeSH terms "acute myeloid leukemia", "myelodysplastic syndrome" and "venetoclax" were searched. Furthermore, Clinicaltrials.gov was accessed to ensure the inclusion of all ongoing clinical trials. RESULTS: Although Venetoclax showed modest results as a single-agent therapy in AML, venetoclax-based combination therapies? mainly with hypomethylating agents or low-dose cytarabine? yielded significantly positive results. Preliminary results oN the use of venetoclax-based combination therapy with HMA, mainly azacitidine, in unfit high-risk MDS also yielded optimistic results. Identification of mutations for which various drugs have been approved has spurred active investigation of venetoclax in combination trials. CONCLUSION: Venetoclax-based combination therapies have been shown to induce rapid responses and increase overall survival in AML patients unfit for intensive chemotherapy. These therapies are also yielding positive preliminary results in high-risk MDS patients in phase I trials. Resistance to venetoclax and drug-related toxicity are two main obstacles that need to be overcome to reap the full benefits of this therapy.

Novel strategies to prevent and overcome relapse after allogeneic hematopoietic cell transplantation in acute lymphoblastic leukemia.

The outcome of B-cell acute lymphoblastic leukemia (B-ALL) has improved over time with the incorporation of multi-agent chemotherapy in the treatment landscape as well as the recent approval of immunotherapeutic agents allowing a larger proportion of patients to undergo allogeneic hematopoietic cell transplantation (allo-HCT) which is still considered a potential curative approach. However, relapse post-transplant is still occurring and constitutes a common cause of treatment failure in B-ALL. The present review aims to discuss the novel strategies and therapies used to prevent and overcome relapse post allo-HCT in patients with ALL, focusing on the role of tyrosine kinase inhibitors in Philadelphia chromosome positive B-ALL, the role of innovative agents such as blinatumomab and inotuzumab ozogamicin, and finally the role of cellular therapy.

Haploidentical stem cell transplantation with post-transplant cyclophosphamide challenges and outcome from a tertiary care center in Lebanon.

This letter describes the experience of the American University of Beirut Medical Center in Lebanon with haploidentical stem cell transplant (haplo-SCT) for hematological malignancies in adult patients. Haplo-SCT made it possible through universal and rapid donor availability for most of the adult patients with leukemia or lymphoma not only in the Middle East but also globally. Moreover, the use of post-transplant cyclophosphamide (PTCy) and reduced intensity conditioning (RIC) regimens when indicated improved the outcome and decreased the toxicity of haploidentical stem cell transplant.RIC regimens also allowed its use in the elderly population. Patients from throughout the Middle East come to our center, the American university of Beirut Medical Center, to receive this transformative type of stem cell transplant. In this paper, we discuss the results of haplo-SCT with PTCy done on adult patients with hematological malignancies in our center from 2015 to 2021. The results are encouraging and show that haplo-SCT should be considered more often in the Middle Eastern countries. The subgroup analysis showed the importance of achieving complete remission of the disease prior to transplant to improve outcomes in our center. There is a paucity of literature on the outcomes of haplo-SCT in the Middle East which may contribute to the limited number of centers that offer this type of SCT. Herein, we aim to fill this gap in the hopes of encouraging the implementation of this potentially curative modality of treatment to a larger extent in the Middle East.

Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47-2.24) p < 0.001 and HR = 1.54 (95% CI: 1.34-1.77), p < 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p < 0.001 and HR = 1.71 (95% CI: 1.51-1.94), p < 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease.

Pharmacologic Strategies for Post-Transplant Maintenance in Acute Myeloid Leukemia: It Is Time to Consider!

Patients with high-risk acute myeloid leukemia are offered allogeneic hematopoietic cell transplantation (allo-HCT) in first remission to reduce risk of relapse. However, disease recurrence remains the major reason of allo-HCT failure, occurring in around 35-45% of patients, and leading to dismal outcomes. Strategies to reduce the risk of relapse are greatly needed, especially in the early post-transplant phase where the graft-versus-leukemia (GVL) effect is not yet activated. Some practices include the use of myeloablative conditioning regimens, close monitoring of measurable residual disease and donor chimerism, rapid tapering of immunosuppression, and implementation of pre-emptive strategies as the use of donor lymphocyte infusion. However, it's time to consider prophylactic pharmacologic interventions post allo-HCT that aim at maintaining leukemic clones under control by both direct cytotoxic activity and by enhancing the GVL effect. In this current review, available data on drugs targeting epigenetic pathways like azacitidine, or actionable mutations like FLT3 and IDH1/2 inhibitors used as maintenance post allo-HCT, will be discussed.

Mantle cell lymphoma negative for t(11,14) involving the kidneys: a case report.

BACKGROUND: Mantle cell lymphoma is the rarest subtype of non-Hodgkin's lymphoma. It can exhibit diverse extranodal manifestations. However, renal involvement is uncommon, and if it occurs, it usually only gets detected postmortem. There are several mechanisms by which mantle cell lymphoma can damage the kidneys. Renal failure is a potential complication, and prompt evaluation and diagnosis are critical steps to prevent long-term complications. CASE PRESENTATION: We present the case of a 75-year-old non-Hispanic White male with past medical history significant for hypertension and dyslipidemia, presenting with fever, weight loss, and night sweats. Work-up showed markedly elevated white blood cells, multiple enlarged lymph nodes, and a kidney mass. The patient was diagnosed with mantle cell lymphoma with kidney involvement confirmed with a kidney biopsy. His disease was positive for cyclin D1 overexpression despite t(11; 14) absence. The patient received six cycles of alternating vincristine, rituximab, cyclophosphamide, doxorubicin, and prednisone then dexamethasone, high-dose cytarabine, and oxaliplatin, after which he was maintained on ibrutinib and rituximab, with resolution of symptoms and disease regression. CONCLUSION: We present a case of a rare presentation of Mantle cell lymphoma while describing the clinical presentation and diagnostic and treatment approaches. This case report can assist physicians in the clinical work-up and treatment of patients with similar diagnosis or presentation.

Safety and Efficacy of Elective Switch from Nilotinib to Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia.

The treatment of newly diagnosed chronic phase chronic myeloid leukemia (CML) with nilotinib has resulted in a higher rate of major molecular (MMR) and complete cytogenetic response (CCyR) at 12 months compared to imatinib but at a higher cumulative cost and increased risk of serious adverse events. To maintain long-term efficacy and minimize both toxicity and costs, we aimed at evaluating in a prospective single-center trial the efficacy and safety of a response-directed switch from nilotinib to imatinib after 12 months in patients newly diagnosed with chronic phase CML. Thirteen adult patients were enrolled. Twelve patients started on nilotinib 300 mg twice daily. Eleven patients completed one year of nilotinib and were switched to imatinib 400 mg daily as per protocol. At 3 months, all patients achieved a complete hematologic response, with 7 (58%) patients had early molecular response. At 12 months, all patients achieved CCyR, of whom 5 (42%) and 4 (33%) patients achieved MMR and MR4.5, respectively. Three (27%) patients switched back to nilotinib after 18, 24, and 51 months respectively: 1 patient because of loss of CCyR after 18 months, and 2 patients because of imatinib intolerance. At last follow-up, all patients (n = 12) were alive and in MMR, 6 (50%) of them in continuous MR4.5. These findings suggest that response directed switch from nilotinib to imatinib at 12 months is capable of maintaining long-term response, with manageable side effects. This approach warrants further exploration with larger prospective trials. Clinical trial registration: Clinicaltrials.gov identifier: NCT01316250, https://clinicaltrials.gov/ct2/results?cond=&term=NCT01316250&cntry=&state=&city=&dist=. .

Relapse after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia: an overview of prevention and treatment.

Despite therapeutic progress in acute myeloid leukemia (AML), relapse post-allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major challenge. Here, we aim to provide an overview of prevention and treatment of relapse in this population, including cell-based and pharmacologic options. Post-transplant maintenance therapy is used in patients who have undetectable measurable residual disease (MRD), while pre-emptive treatment is administered upon detection of MRD. Prompt transfusion of prophylactic donor lymphocyte infusion (DLI) was found to be effective in preventing relapse and overcoming the negative impact of detectable MRD. In addition, patients with persistent targetable mutations can benefit from targeted post-transplant pharmacological interventions. IDH inhibitors have shown promising results in relapsed/refractory AML. Hypomethylating agents, such as decitabine and azacitidine, have been studied in the post-allo-HSCT setting, both as pre-emptive and prophylactic. Venetoclax has been shown effective in combination with hypomethylating agents or low-dose cytarabine in patients with newly diagnosed AML, especially those unfit for intensive chemotherapy. FLT3 inhibitors, the topic of another section in this review series, have significantly improved survival in FLT-3-ITD mutant AML. The role of other cell-based therapies, including CAR-T cells, in AML is currently being investigated.

Plerixafor and granulocyte colony stimulating factor for poor mobilizers in patients undergoing autologous peripheral hematopoietic stem cell transplantation: Single institution study.

Background: Autologous hematopoietic stem cell transplantation (ASCT) has become the mainstay treatment for many hematological malignancies and solid tumors. An adequate number of stem cells must be collected for better ASCT outcomes, which is challenging in 5%-30% of patients. To improve mobilization, plerixafor is used along with granulocyte colony-stimulating factor (G-CSF). Patients and methods: We conducted a retrospective single center study involving patients who received plerixafor pre-ASCTs between January 2013 and December 2020 at a tertiary care center in Lebanon. We identified a total of 84 consecutive adult patients. All patients identified were poor mobilizers and have eventually received plerixafor either as pre-emptive use before first apheresis in those with peripheral CD34 + of less than 20 cells/ul, or after failure of first apheresis in those with peripheral stem cells (PSC) >2.0 × 106 cells/Kg. Results: The median age at ASCT was 52.7 years (22-74) with 61% male predominance. Multiple myeloma was the most prevalent disease 64% followed by Lymphoma 32%. The majority of patients were in complete remission 64% at the time of ASCT. Most patients received proteasome inhibitor-based induction therapy 67% and Melphalan-based conditioning therapy 68%. The median follow-up from ASCT was 9 months (1-59). It was noted that greater body mass index (BMI) is a significant factor for better PSC collection whether premobilization (P = 0.003), or post plerixafor mobilization (P = 0.024). Moreover, Multiple Myeloma patients showed better mobilization using Plerixafor (P = 0.049). Using Plerixafor along with G-CSF in poor mobilizers post G-CSF alone showed a statistically significant increase in the collected PSC mean from 0.67 × 106 cells/Kg to 4.90 × 106 cells/Kg (P < 0.001) with a failure rate only for 12 patients (15%). The infusion of PSC > 2.5 × 106 cells/Kg has shown 3 days decrease in time to platelet engraftment (P = 0.021) and a 36% decrease in progression/relapse rate (P = 0.025). Conclusion: Plerixafor is effective in increasing the PSC yield in poor mobilizers. Low BMI and hematologic malignancies other than Multiple Myeloma are risk factors for poor mobilization. More studies should be performed to establish more risk factors, helping us to identify poor mobilizers more accurately and initiate plerixafor mobilization early on.

20-Year Steady Increase in Survival of Adult Patients with Relapsed Philadelphia-Positive Acute Lymphoblastic Leukemia Post Allogeneic Hematopoietic Cell Transplantation.

PURPOSE: Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains the first cause of transplant failure in patients with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). In other hematologic malignancies, therapeutic advances resulted in significant improvement over time in survival of patients relapsing after transplant. EXPERIMENTAL DESIGN: We compared outcomes at European Society for Blood and Marrow Transplantation (EBMT) participating centers of 899 adult patients with Ph+ ALL who relapsed between 2000 and 2019 after allo-HCT performed in first complete remission. Median follow-up for alive patients was 56 months. RESULTS: Overall, 116 patients relapsed between 2000 and 2004, 225 between 2005 and 2009, 294 between 2010 and 2014, and 264 between 2015 and 2019. Patient and transplant characteristics were similar over the four time periods except for a progressive increase in unrelated donors, peripheral blood stem cells, reduced intensity conditioning, and in vivo T-cell depletion and a progressive decrease in total body irradiation. The 2-year overall survival (OS) after relapse increased from 27.8% for patients relapsing between 2000 and 2004 to 54.8% for 2015 and 2019 (P = 0.001). A second allo-HCT within 2 years after relapse was performed in 13.9% of patients resulting in a 2-year OS of 35.9%. In multivariate analysis, OS from relapse was positively affected by a longer time from transplant to relapse and the year of relapse. CONCLUSIONS: We observed a major progressive improvement in OS from posttransplant relapse for patients with Ph+ ALL over the years, likely multifactorial including transplant-related factors, posttransplant salvage, and improvement in supportive care. These large-scale real-world data can serve as a benchmark for future studies in this setting. See related commentary by Gale, p. 813.

The Elephant in The Room: AML Relapse Post Allogeneic Hematopoietic Cell Transplantation.

Relapsed acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (allo-HCT) is an unfavorable event associated with a poor prognosis, particularly for patients with early relapses. It usually arises from resistant leukemic blasts that escaped both preparative chemotherapy regimen and the graft-versus-leukemia (GVL) effect. Independent from the choice of salvage treatment, only minority of patients can achieve durable remissions. In recent years, better understanding of the disease relapse biology post allo-HCT allowed the application of newer strategies that could induce higher rates of remission, and potential longer survival. Those strategies aim at optimizing drugs that have a direct anti-leukemia activity by targeting different oncogenic mutations, metabolism pathways or surface antigens, and concurrently enhancing the immune microenvironment to promote GVL effect. This review discusses the current treatment landscape of AML relapse post allo-HCT.