Background: Current hematopoietic cell transplant (HCT) regimens for patients with relapsed refractory acute leukemia have 3-year overall survival (OS) rates for acute myeloid leukemia (AML) and ...acute lymphoblastic leukemia (ALL) of 19% and 16% respectively. Previous studies demonstrated that intensification of total body irradiation (TBI) is not possible due to excessive regimen-related toxicity. Because image-guided targeted radiation therapy (e.g., total marrow and lymphoid irradiation (TMLI)) allows for the precise delivery of radiation through the sculpting of radiation to areas of high risk and disease burden, intensification of radiation dose to target structures as part of a HCT preparative may be possible without increased radiation-related toxicities or non-relapse mortality. Herein we report the results of a phase I trial that combines TMLI (1200-2000 cGy) with fixed doses of etoposide (VP16) and cyclophosphamide (CY); the primary objective is to determine the maximum tolerated dose/recommended phase II dose of TMLI.
Methods: TMLI together with VP16 and CY before allogeneic HCT was assessed for patients with relapsed/refractory AML and ALL. TMLI was administered on days -10 to -6, VP16 60 mg/kg (adj bw) on day -5, and CY 100 mg/kg (ideal bw) on day -3. The initial radiation dose was 1200 cGy, delivered in 150 cGy fractions twice daily. The radiation dose was escalated in increments of 150 cGy, up to 1500 cGy, by use of a standard 3x3 design. At this point, the dose was raised in 100 cGy increments to a 2000 cGy maximum with a rolling 6 design. Bone marrow (n=3) or peripheral blood stem cells (n=48) were given on day 0. Tacrolimus and sirolimus were administered for graft versus host disease (GVHD) prophylaxis. Dose limiting toxicity (DLT) was defined according to the Bearman and CTCAE 3.0 scales, the latter for hematologic toxicity. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Median normal organs received 16-60% of the dose (oral cavity 28%, lung 44%, esophagus 33%).
Results: From 3/14/2008 to 1/30/2014, 51 patients underwent transplantation on this trial. (See table.)
Our phase I trial/safety studies found the TMLI/CY/VP16 conditioning regimen to be well tolerated at TMLI doses up to 2000 cGy; 1-year estimates of non-relapse mortality and overall survival were 8.3% (95% CI: 2.6-18.4) and 54.4% (95% CI: 39.3-67.3) respectively (median follow-up: 23.5 months).Relapsed, progressed, or persistent disease after transplant occurred in 33 patients (bone marrow, 26; extramedullary disease, 6; concurrent bone marrow/extramedullary, 1). Of the 18 patients who were treated with a dose of 1700 cGy or higher, 17 achieved a complete remission at the day +30 evaluation. No radiological-based maximum tolerated dose (MTD) was defined. We determined that the median organ dose at 2000 cGy would be lower than that seen for total body irradiation (TBI), but a higher dose may result in reaching or exceeding TBI organ dose levels. We therefore stopped at 2000 cGy, above which non-targeted organs may no longer be protected.
Acute GVHD (aGVHD) developed in 28 (55%) of patients; of those 7 (14%) developed grades 3-4. The most common toxicities across the tested dose levels were grade 1 GI toxicity and grade 2 stomatitis. One patient (treated at 1500cGy) developed grade 3 stomatitis. No additional DLTs were experienced across all dose levels.
Conclusion: A dose of 2000 cGy targeted to lymph nodes and marrow in combination with CY and VP16 can be safely administered in the context of related and unrelated HCT, using tacrolimus and sirolimus for GVHD prophylaxis. We did not see increased incidence of aGVHD, and the day +100 NRM rate was <5%. A phase II trial is currently being conducted.
TablePatient characteristicsVariableMedian (range) or NAge at transplant (yrs)34 (16-57)Disease diagnosis AML ALL Ph- ALL Ph+ biphenotypic undifferentiated3313221Disease status at HSCT 1 RL 2 RL IF14334Cytogenetic risk (SWOG criteria) favorable intermediate unfavorable unknown significance122199KPS at HSCT80 (60-100)Donor source sibling HLA matched unrelated mismatched (1 allele) unrelated25521WBC at HSCT1.4 (0.1-14.9)% Blasts in blood at transplant*4 (0-93)% Blasts in marrow at transplant*52 (8-98)Extramedullary disease at time of HSCT11*Excludes patients with solely extramedullary disease, n=4
Stein:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Snyder:Incyte: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang: Research Funding; Amgen: Consultancy.
A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology ...demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.
Highlights • The TMLI/CY/VP16 conditioning regimen is safe up to a dose of 2000 cGy. • Radiation to off-target critical organs is lower than typically delivered by TBI. • There is an acceptable risk ...for GVHD and encouraging results for disease control.
Abstract To determine the long-term outcome of patients undergoing unrelated donor transplantation (URD) after a reduced intensity conditioning (RIC) regimen, we performed a retrospective analysis of ...the transplant outcomes of the first 5 years of RIC experience as reported to the National Marrow Donor Program (NMDP). Patients were included if they were older than 18 years and had undergone a URD transplant procured through the NMDP from January 1, 1996 until May 31, 2001, with an RIC regimen for a hematologic malignancy. The number of URDs performed using an RIC increased from 59 during 1996 to 1999, to 149 in the year 2000. RIC recipients were older (53 vs. 33 years) and had a higher likelihood of having advanced disease (81% vs. 51%) when compared to patients undergoing a myeloablative conditioning regimen during the same time period. The 5-year survival rate is 23% (95% confidence interval CI; 18, 28), whereas the 5 year incidence of progression/relapse is 43.4% (95% CI; 37,49). Prognostic factors for better overall survival on multivariate analysis were earlier disease stage, longer time to transplant from diagnosis, better HLA match, ≥90% performance score, and use of peripheral blood stem cells. This analysis demonstrates that long-term survival and disease control can be obtained with URD progenitor cell transplantation after RIC conditioning. However, only prospective trials will define the optimal role of this therapy in patients with hematologic malignancies. Therefore, URD transplantation with RIC should continue to be explored in the context of clinical trials.
The combination of tacrolimus/sirolimus (Tacro/Siro) has been evaluated as a promising graft-versus-host disease (GVHD) prophylaxis regimen with reduced acute GVHD rates and decreased non-relapse ...mortality (NRM) by several groups. However, the Tacro/Siro combination has been associated with increased risks of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA), which often requires cessation of Tacro, Siro, or both drugs early after HCT. Mycophenolate mofetil (MMF) is one of the standard alternatives to Tacro/Siro in these situations. In this study, we evaluated a cohort of patients who had to switch their planned prophylaxis of Tacro/Siro to an MMF-based alternative to determine their transplant characteristics and outcomes.
Between January 2009 and September 2011, a total of 411 consecutive patients with hematologic disorders underwent allogeneic hematopoietic cell transplantation (HCT) using Tacro/Siro-based GVHD prophylaxis at our institution. Under the IRB-approved protocol, we reviewed their medical records and identified 57 patients (13.9%) who had to discontinue Tacro (n=24), Siro (n=8), or both drugs (n=25) and started MMF within 30 days of transplant. These 57 cases excluded patients who required MMF after having developed GVHD since the study objective was to evaluate the use of MMF as GVHD prophylaxis, not as a treatment for GVHD. In addition to MMF, steroids were used within 30 days of transplant in 77% of these patients (n=44). The patients (median age 57: range 28-73, 21 females and 36 males) received reduced-intensity conditioning (fludarabine/melphalan: n=50) or fully ablative conditioning (FTBI/Cyclophosphamide: n=7) followed by allogeneic HCT from related (n=13) or unrelated (n=44) donors. All patients but two received peripheral blood hematopoietic stem cells. The planned GVHD prophylaxis was Tacro/Siro only (n=45) or Tacro/Siro plus mini-methotrexate (n=9) or r-ATG (n=3). Patient diagnoses included AML (n=11), MDS (n=15), NHL (n=12), ALL (n=6), MPD (n=4), CML (n=3), Hodgkin lymphoma (n=2), or CMMoL (n=1), PLL (n=1). Thirty-seven patients (65%) had clinically significant co-existing disease/organ impairment with a median comorbidity index of 1 (range: 0-6).
The patients required MMF at a median of 10 days post-HCT (range: day -2 to day +30) due to renal dysfunction (n=25), TMA (n=13), confusion (n=8), VOD (n=4), hypertriglycemia (n=2), or other Tacro/Siro-related toxicities (n=5). Serum creatinine level at the time of MMF start was significantly higher at 1.3mg/dl (median range: 0.4-3.0) than at baseline of 0.88 mg/dl (range: 0.5-1.7) (<0.0001). Some of these patients were able to resume Tacro (n=22) and/or Siro (n=13) at later time.
Among these 57 patients, 28 (49%) subsequently developed grade II-IV acute GVHD (grade II: n=14, grade III-IV: N=14). After a median follow up of 15.2 months for surviving patients, the 1-year overall survival probability was 75.8% (66.6-82.8) while 100-day and 1-year non-relapse mortality (NRM) rates were 19.4% (11.7-32.2) and 30.0% (20.3-44.3), respectively (Figure). The causes of deaths include relapse/disease progression in 7, GVHD in 8, infection in 3, graft failure in 2, alveolar hemorrhage in 2 and others in 5.
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In summary, we identified a significant proportion of patients (13%) requiring to discontinue Tacro, Siro, or both drugs early post-HCT when the combination of Tacro/Siro was used as GVHD prophylaxis. MMF-based salvage prophylaxis was associated with a relatively good control of GVHD. The NRM and OS rates were also in an acceptable range given the high-risk nature of these patients who experienced significant early toxicities. Further analyses of the current cohort regarding the risk factors for early Tacro/Siro failures will be important in order to optimize patient selection and/or dosing of the combination of Tacro/Siro, both of which have a narrow therapeutic index.
Non-Relapse Mortality (n=57)
Off Label Use: mycophenolate mofitil, sirolimus, and tacrolimus for GVHD prophylaxis.
Background: MM patients with enhanced immune responses following AHSCT are known to have better long-term disease control. While it has been shown that early responses are mediated by NK cells and ...alternate inhibitory/stimulatory pathways, including costimulatory molecules, the characterization of these costimulatory molecule profiles in MM patients post AHSCT is not well established. To address this issue, we conducted a pilot study designed to characterize NK cells and function after AHSCT in MM patients through the expression of a cytolytic receptor (CD16), an antibody-dependent cell mediated cytotoxic (ADCC) receptor, and through NK cells functional status based on interferon gamma (IFN-γ) expression as well as the expression of stimulatory (4-1BB) and inhibitory (PD-1 and CTLA-4) molecules. The aims are to characterize the inhibitory and activating costimulatory pathways involved in immune reconstitution after autologous transplantation and to describe changes in the immune signature profile post transplant in response to maintenance therapy and disease status.
Methods: A prospective consecutive case-series of 37 MM patients who underwent AHSCT, median age 59.6 years (36-71.4), were enrolled. Peripheral blood samples were collected pre-AHSCT and again on days 14, 30, 60, 90, 180 and 360 post-AHSCT. IMWG criteria were used for response assessment. NK cells and NK costimulatory molecules were evaluated by flowcytometry using two, six color panels of antibodies. Kruskal-Wallis (KW) test using Graphpad Software was used to plot data/assess differences. The specific time trend for each molecule was modeled using a repeated measures model with unstructured covariance using SAS v9.3. Models were evaluated graphically by taking a scatter plot of data for each molecule and then fit using categorical time, d60-90 response and their interaction as covariates. Since NK expression values were positively skewed, the log-transformed expression + 0.1 (to account for 0) were used as model outcomes. Model outcomes were assessed as absolute number of NK/uL, percent of NK cells, and MFI (mean fluorescence intensity) of NK cell receptor expression. Statistical significance was set at α=0.05 for all analyses.
Results:TableDisease Statusd60-90d180*d360*PR or worse (≤ PR)181417Very Good Partial Response or better (≥VGPR)192219
* One patient - in evaluable
The patients were grouped into ≤ PR (PR + SD+PD: n=18) and ≥VGPR (VGPR +CR: n=19) based on their d60-90 disease status.
· Median percent NK cell was highest (20% of total lymphocytes) at d14 (KW p=0.0001) but returned at d60 to baseline value (11.6% of total lymphocytes).
· The median percent of NK cells post-AHSCT was significantly higher in ≥VGPR group than the ≤ PR group at D 90, 180 and 360 (p= 0.01, <0.01 & 0.02 respectively).
· The total number of NK cells expressing CD16 was not significantly different by group at d14 through d180. However, at d360, CD16 expression that was 13 times higher in ≥VGPR patients than the ≤PR group (p=.0053) (Figure 1).
· The differences in the percentage of NK expressing IFN-γ, were significant between the two groups at d30 (p=.007) and d60 (p=.006). At both time points, ≥VGPR had on average 74% fewer NK IFN-γ cells than ≤PR group.
· There were no significant difference between ≥VGPR and ≤PR groups at different time points, the average expression of PD1 by MFI in ≥VGPR group was 55 % higher than ≤PR group (p=.0126). The average expression of MFI for PD1 + NK cells in all patients were higher at d180 (2.9 fold, p=0.003) and d360 (3.0 fold, p=0.0006) when compared to d14.
· The percent NK/ 4-1BB+ cells were on average 26% lower in ≥VGPR patients than ≤ PR patients (p=0.0156) and the average expression in all patients was significantly higher at d360 (84%, p=0.0115) when compared to d14.
Conclusion: After AHSCT, NK cell recovery was reached at day 60 and was higher overall in the ≥VGPR compared to the ≤PR group. The better disease response group ≥VGPR had higher CD16 expression at d360 but lower IFN-γ at d30 and 60 than the ≤ PR group. Higher CD16 expression (responsible for ADCC killing) and higher NK cells number seem to predict better disease response as well as a low level of IFN-g and 4-1BB expression showing a lower stress response by NK cells.
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No relevant conflicts of interest to declare.
•Ruxolitinib use was associated with a reduction in prednisone dose.•The rate of infectious/bacterial infections was high and contributed to the overall mortality.•Ruxolitinib as salvage therapy is ...promising for chronic graft-versus-host disease refractory to steroids.
Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval, .388 to .673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost.
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