scholarly journals Treatment of AML Relapse After Allo-HCT

2021 ◽  
Vol 11 ◽  
Author(s):  
Jonathan A. Webster ◽  
Leo Luznik ◽  
Ivana Gojo

With advances in allogeneic hematopoietic stem cell transplant (allo-HCT), disease relapse has replaced transplant-related mortality as the primary cause of treatment failure for patients with acute myeloid leukemia (AML). The efficacy of allo-HCT in AML is a consequence of a graft-versus-leukemia (GVL) effect that is mediated by T lymphocytes, and unique mechanisms of immune evasion underlying post-allo-HCT AML relapses have recently been characterized. Relapsed AML following allo-HCT presents a particularly vexing clinical challenge because transplant-related toxicities, such as graft-versus-host (GVHD) and infections, increase the risk of treatment-related morbidity and mortality. In general, the prognosis of relapsed AML following allo-HCT is poor with most patients failing to achieve a subsequent remission and 2-year survival consistently <15%. The two factors that have been found to predict a better prognosis are a longer duration of post-transplant remission prior to relapse and a lower disease burden at the time of relapse. When considered in combination with a patient’s age; co-morbidities; and performance status, these factors can help to inform the appropriate therapy for the treatment of post-transplant relapse. This review discusses the options for the treatment of post-transplant AML relapse with a focus on the options to achieve a subsequent remission and consolidation with cellular immunotherapy, such as a second transplant or donor lymphocyte infusion (DLI). While intensive reinduction therapy and less intensive approaches with hypomethylating agents have long represented the two primary options for the initial treatment of post-transplant relapse, molecularly targeted therapies and immunotherapy are emerging as potential alternative options to achieve remission. Herein, we highlight response and survival outcomes achieved specifically in the post-transplant setting using each of these approaches and discuss how some therapies may overcome the immunologic mechanisms that have been implicated in post-transplant relapse. As long-term survival in post-transplant relapse necessarily involves consolidation with cellular immunotherapy, we present data on the efficacy and toxicity of both DLI and second allo-HCT including when such therapies are integrated with reinduction. Finally, we provide our general approach to the treatment of post-transplant relapse, integrating both novel therapies and our improved understanding of the mechanisms underlying post-transplant relapse.

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4624-4624
Author(s):  
Sanaz Nicky Soltani ◽  
Ramaprasad Srinivasan ◽  
Theresa Jerussi ◽  
A. John Barrett ◽  
Thomas E Hughes ◽  
...  

Acute SR-GVHD occurs in approximately 15% of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), and is associated with a 70-90% long-term mortality rate. We previously reported that concomitant blockade of TNF-α and IL-2 pathways with infliximab combined with daclizumab have a synergistic therapeutic effect, with a high probability of complete resolution of SR-GVHD. Although various treatment modalities are effective in the treatment of SR-GVHD, minimal long-term follow up data exists for complete responders to second line treatments. Here we report long-term outcomes in a cohort of 23 subjects developing SR-GVHD treated with infliximab/daclizumab. A consecutive series of 141 patients with a variety of hematological and non-hematological malignancies as well as nonmalignant hematological disorders including severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria and pure red cells aplasia, underwent a reduced intensity allogeneic HSCT from an HLA identical or single antigen mismatched relative at a single institution between 2/2001 and 12/2008. Transplant conditioning consisted of cyclophosphamide (60 mg/kg days -7, -6) and fludarabine (25 mg/m2days -5 to -1) with or without equine ATG or 6-12 Gy of total body irradiation. GVHD prophylaxis was with cyclosporine with or without additional MMF or MTX. Twenty three patients (median age 35 years, range 13-65 years) developed SR-GVHD at a median of 28 days post transplant. SR-GVHD was defined as absence of response to at least 6 days of high dose methylprednisolone therapy. Following a diagnosis of SR-GVHD, patients received a combination of daclizumab (1mg/kg given on days 1, 4, 8, 15, 22), infliximab (10mg/kg given on days 1, 8, 15, 22), broad spectrum bacterial and anti-fungal prophylaxis, and had their methylprednisolone tapered to 1mg/kg/day. Combined cytokine blockade was highly active against SR-GVHD, with 21/23 (87.5%) patients achieving a complete response (CR), defined as total resolution of GVHD in all involved organ systems. All complete responders survived to hospital discharge. With a median follow-up of 9 years (range 5-10 years), 9/23 (39%) survive, including 6 patients without chronic GVHD whose immunosuppressive therapy (IST) has been discontinued and 3 patients with chronic GVHD (2 limited and 1 extensive) who continue to be tapered off IST. Fourteen of 21 patients with resolution of SR-GVHD died a median 173 days post transplant (range 67-1039 days), including 1 from complications related to recurrent SR-GVHD, 6 from progression of malignancy (all solid tumors), 2 from bleeding related to peptic ulcer disease and 5 from infectious complications including invasive fungal infection and CMV disease. A subgroup analysis showed 5/6 patients with SAA developing SR-GVHD had a complete response to combined infliximab/daclizimab. Remarkably, at a median 6 years follow up, 67% (4/6) of these SAA patients were long-term survivors. All these survivors have maintained normal blood counts and remained transfusion independent with 100% donor chimerism in myeloid and T-cell lineages. Conclusion Patients with SR-GVHD treated with infliximab combined with daclizumab had a high probability of achieving a complete response with nearly 40% of patients having long-term survival. This is the first report to show that long-term survival can be achieved in a substantial proportion of patients receiving combined IL-2 and TNF blockade for SR-GVHD. Disclosures: Off Label Use: Infliximab is FDA approved for the treatment of psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. Daclizumab gained FDA approval for use in transplant rejection.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1465-1465
Author(s):  
Mohammad S Hossain ◽  
Andrew T Gewirtz ◽  
John Roback ◽  
Edmund Waller

Abstract Abstract 1465 Background: Graft-vs-host disease (GvHD) is a major complication in allogeneic Hematopoietic Stem Cell Transplant (HSCT) recipients. Using flagellin, a bacterial protein that agonistically binds with TLR5, we previously reported that two doses of flagellin (before irradiation and after allogeneic HSCT with 5×106 splenocytes) in H-2K à H-2b model significantly reduced GvHD and had 67% long-term survival by 132 days post-transplant whereas control recipients had severe acute GvHD and 100% early mortality within 15 days post transplant. Here, we report the mechanism by which flagellin reduces GvHD using the same H-2K à H-2b HSCT murine model. Methods: 3×106 splenocytes and 5 ×106 T cell depleted bone marrow (BM) cells harvested from the congeneic H-2K donors were transplanted into lethally irradiated (11Gy) C57BL/6 (H-2b) recipients. 50-μg HPLC purified LPS-free flagellin diluted in ice-cold PBS were administered i.p 3 hours before irradiation and 24 hours after transplant. Control recipients were treated with PBS. Recipients (6/group) were sacrificed on day 4 and 10 after post transplant. Serum was collected to determine cytokines by ELISA and splenocytes were analyzed by FACS to determine immune cells phenotypes. Results: Although both Fla and PBS-treated recipients showed identical weight-loss within day 10 post transplant, surprisingly significantly lower numbers of cells/spleen were determined in the spleens of Fla recipients compared to control recipients [Fla 0.9 ± 0.1 (x106) vs PBS 1.7 ± 0.4(x106), p=0.002] on day 4 post transplant but not on day 10 [Fla 186.1 ± 35.1 (x106) vs PBS 151.2 ± 40.5(x106), p=0.43] post-transplant. We investigated the paradoxical immune response of flagellin on donor T cells on day 4-post transplant. First, we determined the numbers of donor spleen-derived Thy1.2+ T cells per spleen. The numbers of donor spleen-derived T cells per spleen were significantly lower in Fla recipients compared to PBS-treated recipients [Fla 0.005 ± 0.002 (x103) vs PBS 0.04 ± 0.03(x103), p=0.02]. Accordingly, donor spleen-derived both CD4 and CD8 T cells per spleen of Fla recipients were also found significantly lower compared to PBS-treated recipients (CD4, p=0.04; CD8, p= 0.003). The CD62L, a naïve and also markers for allo-reactive T cells that cause GvHD were found significantly lower in both CD4 and CD8 T cells (CD4, p= 0.03; CD8, p=0.003) and the inducible co-stimulatory molecule 1 (ICOS-1), another prominent T cells activation marker were also found significantly lower (CD4, p= 0.04; CD8, p=0.007) in Fla recipients compared to PBS-treated recipients. These lower immune phenotypes of donor T cells in Fla recipients may reduce the initiation of GvHD at the early time points of transplant. However, flagellin-induced reduction of donor T cells activity were not suppressed considerably as the numbers of donor spleen-derived CD4 T cells expressing activation markers such as CD25 {Fla 0.5 ± 0.2 (x103) vs PBS 4.5 ± 0.5 (x103), p=0.07} and CD69 {Fla 0.5 ± 0.2 (x103) vs PBS 6.5 ± 5.0 (x103), p=0.08} per spleen were not found significantly different. On the other hand, the numbers of CD8 T cells those expressed CD25 {Fla 0.2 ± 0.04 (x103) vs PBS 1.3 ± 0.7 (x103), p=0.01} and CD69 {Fla 0.4 ± 0.1 (x103) vs PBS 2.4 ± 1.7 (x103), p=0.03} per spleen were found significantly lower in Fla recipients compared to PBS-treated recipients. Although over 90% of donor spleen CD4 T cells of both Fla and PBS-treated recipients expressed PD-1, 24% and 32% respectively, expressed IFN-γ after vitro PMA stimulation. Similar results were found in case of CD8 T cells. The over expression of PD-1 in HSCT recipients, thus did not make the donor T cells exhausted as they expanded over 100 times within day 10 post transplant with the expression of PD-1. Although similar level of serum IFN-γ was determined between the Fla and PBS-treated recipients on day 10 post-transplant, IFN-γ level was found below detection limit on day 4 post-transplant. The serum levels of IL-1β and IL-10 were undetectable on both days 4 and 10 post-transplant. Serum LPS were found identical in both Fla and PBS-treated groups determined on day 4 and 10 days post transplant. Conclusion: Flagellin protected allogeneic HSCT recipients from lethal GvHD by reducing donor CD62L+ and ICOS-1+ T cells expansion and activation within 4 days post-transplant without compromising their normal immune responses. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
pp. 109352662110016
Author(s):  
Brian Earl ◽  
Zi Fan Yang ◽  
Harini Rao ◽  
Grace Cheng ◽  
Donna Wall ◽  
...  

Post-hematopoietic stem cell transplant secondary solid neoplasms are uncommon and usually host-derived. We describe a 6-year-old female who developed a mixed donor-recipient origin mesenchymal stromal tumor-like lesion in the liver following an unrelated hematopoietic stem cell transplant complicated by severe graft-versus-host disease. This lesion arose early post-transplant in association with hepatic graft-versus-host disease. At 12 years post-transplant, the neoplasm has progressively shrunken in size and the patient remains well with no neoplasm-associated sequelae. This report characterizes a novel lesion of mixed origin post-transplant and offers unique insights into the contribution of bone marrow-derived cells to extra-medullary tissues.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1417-1417
Author(s):  
Michael Boyiadzis ◽  
Jesse Carson ◽  
Kenton Allen ◽  
Sarfraz A. Memon ◽  
Robert A. Dean ◽  
...  

Abstract NK cells express diverse activating and inhibitory receptors, which collectively determine the NK cytotoxic response. Because NK cells can be potent anti-tumor effectors in the post transplant period of minimal residual disease, we investigated the receptor expression on NK cells following non-myeloablative, HLA-matched, allogeneic hematopoietic stem cell transplant (HSCT). We focused on activating receptors, comparing the expression of natural cytotoxicity receptors (NCR) and C-type lectin receptors on circulating NK cells at one, three, six and twelve months following HSCT with that of the donor-derived mobilized stem cell apheresis. During the first post-transplant month, the absolute numbers of NK cells recovered to normal levels in the 14 patients studied, but the subpopulation of CD56++(bright) CD16− NK cells increased disproportionately compared to the more common CD56+(dull) CD16+ NK cells. By six months the proportions of the NK cell subsets normalized to pre-transplant levels. At one month post transplant, the median percentage of NK cells expressing the anti-tumor NCR NKp46 increased from 15 to 64% and that expressing NKp30 increased from 23 to 40% as compared to the donor’s NK cells; expression remained elevated during the first year. Expression of NKG2D, the homodimeric activating C-type lectin receptor, similarly increased post-transplant. CD94 was also upregulated on NK cells, but the activating heterodimeric partner of CD94, NKG2C, did not change significantly. To investigate these shifts in NK populations and receptor expression, we investigated the effect of cytokine milieu post transplant on these shifts in NK populations and receptor expression. We have determined that plasma levels of IL-15, a cytokine critical in NK differentiation and expansion, increase more than 50-fold in these HSCT patients from pretreatment to the day of transplant and decline in the first weeks post transplant, inversely proportional to NK recovery. When NK cells were cultured with rIL-15, we observed a disproportionate expansion of CD56++ NK cells and a rapid up-regulation of the NCR and NKG2D receptors, similar to the changes observed post-transplant. These data suggest that the cytokine milieu of transplant, in particular elevated levels of IL-15, may contribute to anti-tumor efficacy post transplant by affecting the recovery of NK subsets and modulating expression of activating receptors.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4315-4315
Author(s):  
Shoichi Nagakura ◽  
Tetsuyuki Kiyokawa ◽  
Michihiro Hidaka ◽  
Takahiro Yano ◽  
Kazutaka Sunami ◽  
...  

Abstract BACKGROUND: Despite recent increase of reduced intensity conditioning (RIC) transplantation, mortality rates after RIC and myeloabrative conditioning (MAC) HSCT remain high and hepatic veno-occlusive disease (VOD) cannot accurately predicted. OBJECTIVE: To determine the value of risk factors associated with the development of VOD after allergenic HSCT with RIC and MAC. Estimating VOD based on clinical factors may further improve results of allogenic HSCT. PATIENTS AND METHODS: A retrospective review of 415 consecutive allogenic HSCT was performed with attention to VOD, pre-transplant factors and laboratory data in five hematopoietic cell transplantation centers between 2000 and 2005. Patients underwent transplantation with MAC (n=247) or RIC (n=168). Main outcomes and risk factors were analyzed in multivariable analyses (a logistic regression model) with RIC and MAC. Three kind of laboratory data set, pre-transplant (day −10), post-transplant (day 20) and differences from pre-transplant to post-transplantation were analyzed. RESULTS: VOD occurred in 65 of 415(15.7%) transplant recipients; 40 of 247(16.1%) with MAC and 25 of 168(14.9%) with RIC. Multivariate analyses identified risk factors with the development of VOD with MAC (albumin level, creatinine level) and with RIC (HCT-CI, number of prior chemotherapy regimen, ALT) in pre-transplant laboratory data set. The risk factors of VOD were identified in post-transplant and differences (Table). The Akaike’s information criterion (AIC) of risk factors with differences was better than with the post-transplant. CONCLUSION: Our results provided risk factors of VOD with MAC and RIC. The estimation of VOD before transplantation may be useful for the selection of conditioning regimens. Differences of laboratory data with the time course of transplant may be useful for the early diagnosis of VOD. MAC Pre-transpant data Post-transplant data Differences data OR P-Value OR P-Value OR P-Value Age - - 0.945 0.0090 - - Alb 0.290 0.0125 - - - - Cr 10.204 0.0307 1.786 0.0039 1.984 0.0139 TPro - - 0 358 0.0019 - - TBi I - - 1.385 0.0027 1.314 0.0037 Ara-C - - 5.000 0.0139 goodness of fit AIC 106.727 126.499 86.931 RIC Pre-transpant data Post-transplant data Differences data OR P-Value OR P-Value OR P-Value Sex - - 3.401 0.0446 - - HCTCI 3.922 0.0050 2.000 0.0123 - - ImpScore 2.000 0.0314 - - - - TPro - - 0.366 0.0091 - - TBi I - - 1.675 0.0042 2.273 0.0004 ALT 0.969 0.0432 - - - - CY - - - - 5.682 0.0447 goodness of fit AIC 61.552 91.09 52.808


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3149-3149
Author(s):  
Susan E. Prockop ◽  
Nancy A. Kernan ◽  
Elizabeth G Klein ◽  
Rachel Kobos ◽  
Andromachi Scaradavou ◽  
...  

Abstract Abstract 3149 Young children in need of allogeneic hematopoietic stem cell transplant (HSCT) are at increased risk of unacceptable side effects from total body irradiation (TBI) and have historically been considered candidates for non-TBI containing regimens. However, disease free survival (DFS) has been poorer in cohorts of very young patients transplanted without TBI and novel chemotherapy based regimens are needed. We report results in a cohort of 14 children all under three years of age at the time of transplant (6 – 32 months; median 19.8 months) using a clofarabine-based ablative regimen. Fourteen patients in this age group have undergone transplant with a regimen consisting of clofarabine 20 mg/m2/day × 5, thiotepa 10 mg/Kg/day × 1 and melphalan 70 mg/m2/day × 2. All patients had high risk disease. Seven (7) pts were transplanted for ALL, 6 for AML and 1 for JMML. Patients with ALL or AML in first remission (CR1) or CR2, were categorized as patients with good risk disease while all other pts were considered as poor risk irrespective of all other factors. Transplant risk was good for 6/7 with ALL, and 3/6 with AML. The patient with JMML had stable disease. Stem cell grafts consisted of unmodified bone marrow (BMT) (N=6), double cord blood (dCBT) (N=7) and T cell depleted PBSCT (N=1). Donors were matched unrelated (N=5) or mismatched unrelated (N=9) including 7 double umbilical cord blood grafts, and one T cell depleted graft. Graft versus host disease (GvHD) prophylaxis was with tacrolimus and methotrexate for unmodified BMT, tacrolimus and mycophenolate for dCBT or T cell depleted HSCT. Two patients died early post transplant of infection (1) and acute GvHD (1). Neutrophil engraftment for the 13 evaluable patients was at a median of 13 days (10 –29 days) for PBSC and BM grafts and 17.5 days (12 –23 days) for recipients of CB grafts. Platelet engraftment for the 12 evaluable patients was at a median of 23 days (16 – 36 days) for recipients of PBSC and BM grafts and 43.5 days (36 –66 days) for recipients of CB grafts. In all five patients developed grade II-IV GvHD, and two patients chronic GvHD. Seven patients developed transaminitis which resolved in all cases. No patients developed Grade IV mucositis. One patient (AML) died after relapsing 5.5 months post transplant. Two patients are alive after relapsing at 1.3 months (AML) and 10.8 months (JMML) post-transplant. Nine of the 14 patients are alive in continuous complete remission seven of whom are greater than 36 months from transplant (40.2 – 71 months). The seven patients without chronic GvHD have had robust immune reconstitution, have responded to vaccination, and continue to meet growth and developmental milestones. Only one patient (transplanted at 14 months of age) has mild neurocognitive deficits. This novel chemotherapy based regimen is associated with durable engraftment of unmodified and cord blood HSCT grafts and promising disease free survival in very young children with leukemia. Based on the low toxicity profile in this cohort of patients higher dosing of clofarabine will be explored as a possible way to improve leukemia remission in the highest risk patients. Disclosures: Off Label Use: Clofarabine.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6552-6552
Author(s):  
Sunita Nathan ◽  
John Joseph Maciejewski ◽  
Elizabeth Shima Rich ◽  
Parameswaran Venugopal ◽  
Kent W. Christopherson ◽  
...  

6552 Background: Plerixafor for mobilization of autologous stem cells (ASC) has increased the yield of transplanted ASC and is evolving as an important option for mobilization. A prior study reported a 10% incidence of SN after AHSCT (BMT 2009 Aug; 44(3): 175-83). Incidence and outcome of SN in the setting of Plerixafor/G-CSF (P/G), is unknown. We report the incidence and possible etiology for the development of SN in pts undergoing AHSCT for lymphoma at our institution. Methods: Data from 80 consecutive AHSCT pts over a 2 year period were reviewed. All pts were mobilized using P/G. Demographics, AHSCT indication, prior therapies (Rx), conditioning regimen (CR), engraftment and post-transplant complications were identified and collected. SN was defined as ANC <1000 after initial engraftment. Results: 80 pts underwent an AHSCT for lymphoma from 2009-11. 70 pts had evaluable data. 37 (52.86%) pts (average age 55.4 yrs) were male and 33 (47.14%) pts (average age 48.3 yrs) female. 25 (35.7%) pts had ≥2 comorbidities. Indications included relapsed/ refractory B-NHL, T-NHL and HL. 47 (67%) pts had Stage IV ds, 48.9% with BM involvement. 17 (24.3%) pts had >2 Rx, 18 (25.7%) with loco-regional XRT and 3 (4.3%) with RIT. CR included BEAM, BEC and Benda-EAM +/- Rituxan. # of CD34+ cells given ranged; 1.77-19.99 x 10^6/kg. Neutrophil engraftment occurred at a median of 11 days. 26 (37.14%) pts developed SN possibly from PCP prophylactic antibiotics and infections. Prior BM involvement, Rx or XRT had no role. 5 (45.4%) pts with Benda-EAM CR had SN. Associated morbidity/mortality were not noted. Conclusions: We conclude that secondary neutropenia is common after autologous stem cell transplant using the Plerixafor/GCSF combination for mobilization and is higher than reported in the literature (37% vs 10%). Patients who received this combination for mobilization should be followed up closely in the post-transplant period for secondary neutropenia. About half the patients who received the Benda-EAM conditioning regimen developed secondary neutropenia warranting its use with caution outside of a clinical trial.


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