Cumulative Incidence Of Grade Research Articles

Bfr (bendamustine, fludarabine, rituximab) Nonmyeloablative Allogeneic Conditioning for Lymphoid Malignancies: 8-Year Results

Background: We previously reported favorable 2-year outcomes of NMA transplantation after BFR conditioning in patients with relapsed lymphoid malignancies. In this report, we evaluated the long-term outcomes of this treatment. Methods: Patients were enrolled on two consecutive clinical trials. Patients received bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, together with 30 mg/m2 IV of fludarabine given on the same days. Rituximab was given at a dose of 375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, and +8. Rituximab was omitted in patients with T-cell diseases. Tacrolimus and mini-methotrexate were used for GvHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant. Results: Sixty- nine consecutive patients were enrolled between April 2009 and February 2013. Histologies included: CLL (n=28) (8 with 17p- and 2 Richter's), follicular (n=13), mantle cell (n=16), diffuse large cell (n=9), peripheral t-cell lymphoma (n=3). Median age was 59 (range, 30-72) years. Median prior treatments was 3 (range, 1-7); 7 (10%) had failed a prior autotransplant. At transplantation, 29 (42%) patients were in CR/CRu, 31 (46%) in PR, and 8 (12%) had refractory disease. Twenty (29%) patients were PET+, and 19 (27.5%) had elevated LDH. Thirty-six (52%) received their transplants from HLA-compatible siblings and 33 (48%) from unrelated donors. Median number of CD34-positive cells infused was 5.58 x 106/kg. Neutrophil counts recovered to > 0.5 x 109/L a median of 0 days after transplantation (range, 0-17 days). Seventeen patients (25%) never experienced an ANC < 0.5 x 109/L. Fifty-eight patients (84%) never experienced a platelet count of < 20 x 109/L. All patients engrafted donor cells. By day 30, median donor myeloid and T-cells were 92% and 97%, respectively. Both increased to 100% by day 90. The cumulative incidence of grade 2-4 GvHD and chronic extensive GvHD were 17% and 31%, respectively. Treatment-related mortality at 1-year was 9%. Nineteen (27.5%) patients died: 9 of progression, 6 of infection and 4 of GvHD complications. With a median follow-up time of 5 years (range, 0.1-8 years), the 5-year OS rate was 74% [82% CLL/Richter's, 85% follicular, 67% diffuse large and t-cell, and 56% in mantle cell (p=0.43)] and the 5-year PFS rate was 60% (Figure). Conclusions: Our mature results confirm the earlier observations that the BFR regimen constitutes a well-tolerated NMA allogeneic conditioning for lymphoid malignancies. It allows engraftment of sibling and unrelated donor cells with minimal myelosuppression. Promising long-term survival results were seen in patients with both indolent and aggressive histologies. [Display omitted] DisclosuresKhouri:Novartis: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Oran:Astex: Research Funding; Celgene: Research Funding; AROG: Research Funding.

Prognostic impact of the dosage of methotrexate combined with tacrolimus for graft-versus-host disease prophylaxis after cord blood transplantation.

The optimal dosage of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after cord blood transplantation (CBT) has not been well elucidated. Therefore, we conducted a retrospective study comparing a mini-MTX group (5mg/m2 on day 1, 3 and 6) to a short-MTX group (10mg/m2 on day 1 and 7mg/m2 on day 3 and 6) after CBT. Sixty-three patients were classified as the mini-MTX group and 20 as the short-MTX group. The median time and cumulative incidence of neutrophil engraftment did not vary between the two groups. The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD was similar in both groups. Overall survival in the mini-MTX group was significantly lower than in the short-MTX group (46.9% vs. 88.7% at 1year, p < 0.01), contributing to higher non-relapse mortality (NRM) in the mini-MTX group (32.0% vs. 5.0% at 1year, p = 0.02). In multivariate analysis, the mini-MTX regimen was the most powerful prognostic factor for OS (hazard ratio 4.11; p = 0.03). Although the reduced dosage of MTX had no effect on neutrophil engraftment, increased NRM due to higher incidence of infection, graft failure, and severe acute GVHD resulted in a lower survival rate in the mini-MTX group after CBT.

Low-dose radiation to cardiac substructures and late-onset cardiac disease: A report from the Childhood Cancer Survivor Study (CCSS).

10027 Background: Thoracic radiotherapy (RT) is a risk factor for cardiac disease among survivors of childhood cancer based on studies considering RT doses to the entire heart. Dose to specific cardiac substructures may provide more precise dose-response associations to guide RT planning. We report associations between RT dose to cardiac substructures and risk of specific cardiac outcomes. Methods: We determined the cumulative incidences of CTCAE grade 3 – 5 coronary artery disease (CAD), heart failure (HF), and valvular disease (VD) among 25,481 5-year childhood cancer survivors diagnosed 1970 – 1999 in the CCSS. Median age at diagnosis was 6.1 years (0 – 20 years) and at last follow-up 29.8 years (5.6 – 65.9 years). For the 12,228 individuals receiving RT, fields were reconstructed on an age scaled computational phantom. Mean doses to the entire heart, cardiac chambers, valves, and left main, anterior descending (LAD), circumflex, and right coronary (RCA) arteries were estimated. Adjusted piecewise exponential models (including cumulative anthracycline dose) evaluated associations between mean RT dose to each structure and outcomes. Results: At 30 years from diagnosis, the cumulative incidences of grades 3 – 5 CAD, HF, and VD were 2.3% (95% CI 2.0 – 2.5), 2.6% (95% CI 2.4 – 2.9), and 0.6% (95% CI 0.5 – 0.8) respectively. Low dose RT (mean 5 – 9.9 Gy) to the RCA (relative rate [RR] = 2.6, 95% CI 1.6 – 4.1, p &lt; 0.001), LAD (RR = 1.9, 95% CI 1.1 – 3.3, p = 0.019), and left ventricle (RR = 2.2, 95% CI 1.3 – 3.7, p = 0.002) was associated with increased risk of CAD relative to those not exposed; mean dose of 5 – 9.9 Gy to the entire heart was not (RR = 1.1, 95% CI = 0.8 – 1.6, p = 0.59). Table shows the associated cumulative incidences of CAD for these structures. Mean RT doses of 5 – 9.9 Gy to the aortic valve (RR = 4.6, 95% CI 1.5 – 14.0, p = 0.008) and tricuspid valve (RR = 5.5, 95% CI 2.0 – 15.1, p = 0.001) were associated with risk of VD compared to those with no RT; mean heart dose 5 – 9.9 Gy was not (RR = 0.6, 95% CI = 0.2 – 1.3, p = 0.16). No cardiac structure was significantly associated with an increased risk of HF at a mean dose of 5 – 9.9 Gy. Mean RT doses below 5 Gy were not associated with increased risks of CAD, HF, or VD; doses ≥10 Gy to nearly all substructures and the entire heart were. Conclusions: Low dose RT to the coronary arteries and cardiac valves (5 – 9.9 Gy) from RT is associated with increased risk of CAD and VD, respectively. Sensitivity to low dose RT may vary across the heart and doses to specific structures may be more predictive of late cardiac disease than whole heart dose. These data can guide RT planning to prioritize substructures for avoidance.[Table: see text]

Adjuvant chemotherapy and radiation therapy with the “sandwich” method for endometrial cancer: an institutional analysis

Introduction. Choice of adjuvant therapy for high risk endometrial cancers is controversial. The so-called “sandwich” regimen of pelvic external beam radiation administered between cycles of Carboplatin/Paclitaxel (CT-RT-CT) is commonly used in clinical practice but has not been evaluated in randomized endometrial cancer trials. There is relatively little published data regarding toxicity, patient tolerance, and efficacy of this regimen. Here, we report our institutional experience of CT-RT-CT for locally advanced endometrial cancer, focusing on toxicity and rates of compliance with study therapy. Material and methods. Medical records of consecutive patients treated for surgically staged endometrial cancer at a tertiary care academic medical center between 2010 and 2017 were reviewed. All patients received adjuvant CT-RT-CT. Progression-free and overall survival were recorded from the date of surgery. Toxicity data was obtained from patient medical records and graded according to Common Terminology for Adverse Events Criteria, version 3.0. Results. Thirty-eight patients with histologically proven stage I–IV endometrial cancer were included. Eighty-four percent of patients were able to complete all 6 planned cycles of chemotherapy and 92% completed at least 4 cycles. Cumulative incidence of grade 3–4 hematologic toxicity was 55%. Locoregional recurrence was the first site of failure in 2 patients (5.1%) while distant failure was the first site of recurrence in 8 patients (21%). Two year overall survival and progression-free survival were 76% and 77% respectively. Conclusion. Our results suggest that adjuvant chemotherapy and radiation therapy with the “sandwich” regimen is associated with acceptable toxicity and satisfactory rates of completion of planned therapy.

Acute toxicity of 4-week versus 5-week hypofractionated radiotherapy in localised prostate cancer

AbstractAim:To compare the acute radiation-induced bowel and bladder toxicities of two hypofractionated radiotherapy (HFRT) regimens in localised prostate cancer (PCa).Materials and methods:This trial consists of patients with histologically confirmed stage T1-T3aN0M0 PCa, a prostate-specific antigen concentration of 40 ng/mL or lower, and Eastern Cooperative Oncology Group performance status of 0–2. Participants were randomly assigned (1:1) to 56 Gy in 16 fractions over 4 weeks (arm A) or 70·2 Gy in 26 fractions over 5 weeks (arm B). Acute bowel and bladder toxicities were assessed using Radiation Therapy Oncology Group criteria.Results:Between June 2018 and December 2019, 40 patients were randomly assigned to treatment with 4-week (n = 20) and 5-week HFRT (n = 20). In the third month after completion of radiotherapy, the cumulative incidence of acute bowel and bladder toxicities of arms A and B was 20 versus 5% and 70 versus 85%, respectively. The cumulative incidence of grade 2 or worse bowel and bladder toxicities of the 5-week regimen was non-inferior to 4-week HFRT [bowel toxicity: 5% (arm A) versus 5% (arm B), bladder toxicity: 50% (arm A) versus 60% (arm B), p = 0·52).Findings:The 5-week regimen of HFRT is non-inferior to 4-week HFRT in terms of acute bowel and bladder toxicities.

Risk factors for radiation pneumonitis in lung cancer patients with subclinical interstitial lung disease after thoracic radiation therapy

BackgroundPrevious studies have found that patients with subclinical interstitial lung disease (ILD) are highly susceptible to developing radiation pneumonitis (RP) after thoracic radiation therapy. In the present study we aimed to evaluate the incidence of and risk factors for RP after thoracic intensity-modulated radiation therapy in lung cancer patients with subclinical ILD.MethodsWe retrospectively analyzed data from lung cancer patients with subclinical ILD who were treated with thoracic intensity-modulated radiation therapy with a prescribed dose of ≥ 50 Gy in our institution between January 2016 and December 2017.ResultsEighty-seven consecutive lung cancer patients with subclinical ILD were selected for the study. The median follow-up period was 14.0 months. The cumulative incidence of grades ≥ 2 and ≥ 3 RP at one year was 51.0% and 20.9%, respectively. In the multivariate analysis, a mean lung dose ≥ 12 Gy was a significant risk factor for grade ≥ 2 RP (p = 0.049). Chemotherapy with gemcitabine in the past, V5 ≥ 50%, and subclinical ILD involving ≥ 25% of the lung volume were significantly associated with grade ≥ 3 RP (p = 0.046, p = 0.040, and p = 0.024, respectively).ConclusionMean lung dose is a significant risk factor for grade ≥ 2 RP. Lung cancer patients who have received chemotherapy with gemcitabine in the past, V5 ≥ 50%, and those with subclinical ILD involving ≥ 25% of lung volume have an increased risk of grade ≥ 3 RP in lung cancer patients with subclinical ILD.

Application of a radiation pneumonitis prediction model in patients with locally advanced lung squamous cell cancer.

The aim of the present study was to establish a new prediction model for radiation pneumonitis (RP) in locally advanced non-small cell lung cancer (LA-NSCLC) patients before and after radiotherapy. The study involved 153 patients. Age, arterial partial oxygen pressure (PO2), forced vital capacity, pulmonary emphysema (PE), subclinical interstitial lung disease (sILD), and dosimetric parameters, such as mean lung dose and percentage of lung volume, and a dose >5/20 Gy (V5/V20), were considered candidate RP predictors. Of the 153 eligible patients, 33 (21.6%) developed RP, 68 had PE (43.8%), and 24 (15.7%) had sILD. Grades 2, 3, and 5 RP were scored in 17 (11.1%), 15 (9.8%), and 1 (0.7%) patient/s, Grade 4 RP was not observed. Grades 1, 2, and 3 PE were scored in 45 (29.4%), 22 (14.4%), and 1 (0.7%) patient/s. Grades 0 and 1 sILD were observed in 129 (84.3%) and 24 (15.7%) patients. Univariate analysis found age, PE, and sILD to be significantly correlated with grade ≥2 RP. Multivariate analysis revealed age >68 years, PE grade >1, and sILD grade ≥1 as independent risk factor for grade ≥2 RP in LA-NSCLC with squamous cell carcinoma (SCC). Finally, a new predictive risk score (PRS) comprised of these factors was developed. The PRS score was 0, 3-5, and 6-11 when the cumulative incidence of grade ≥2 RP was 8.8% (5 patients), 13% (3 patients), and 84.6% (13 patients) (P=<0.001). Age, PE, and sILD could independently and significantly predict RP in LA-NSCLC with SCC.

Clinical Outcomes of the CHIRP Trial: A Phase II Prospective Randomized Trial of Conventionally Fractionated Versus Moderately Hypofractionated Prostate and Pelvic Nodal Radiation Therapy in Patients With High-Risk Prostate Cancer

PurposeHypofractionated radiation therapy (HFRT) may offer treatment advantages for patients with prostate cancer. However, HFRT may also increase the risk of gastrointestinal (GI) or genitourinary (GU) toxicity compared with conventionally fractionated radiation therapy (CFRT). Several large trials have found that HFRT is well tolerated in mixed risk population studies. Here, we report on a phase II, randomized controlled study conducted to evaluate these endpoints in exclusively high-risk patients with prostate cancer treated with prostate and pelvic nodal radiation. Methods and MaterialsAfter giving informed consent, patients with high-risk prostate cancer were randomly assigned to prostate plus pelvic nodal radiation therapy with either HFRT (68 Gy in 25 fractions) or CFRT (78 Gy in 39 fractions) and 18 months of androgen suppression therapy. Toxicity was scored using the Common Terminology Criteria for Adverse Events (version 4.0). Biochemical failure was determined by the Phoenix definition. Patients were analyzed on an intention-to-treat basis. ResultsFrom 2012 to 2018, 111 patients with high-risk prostate cancer were enrolled and 109 patients were treated. The cumulative incidence of grade 2 or higher acute GI toxicity was not significantly different between the arms (HFRT 18.9% vs CFRT 21.8%; P = .812). Similarly, acute GU (HFRT 30.2% vs CFRT 30.9%; P = 1.00), late GI (HFRT 16.0% vs CFRT 10.0%; P = .554), and late GU (HFRT 16.0% vs CFRT 6.0%; P = .200) were not significantly different between the arms. Median follow-up was 38.0 months (4.8-77.8 months). The 3-year biochemical recurrence-free survival was not significantly different between the 2 arms (97.3% for HFRT vs 91.0% for CFRT; P = .606). The 3-year overall survival was 94.8% in the HFRT arm and 100.0% in the CFRT arm (P = .116). ConclusionsHFRT and CFRT using intensity modulated radiation therapy were both well tolerated for patients with high-risk prostate cancer and resulted in similar 3-year biochemical recurrence-free survival and overall survival.

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia

AbstractWe report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell–depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

Rectal Dose Is the Other Dosimetric Factor in Addition to Small Bowel for Prediction of Acute Diarrhea during Postoperative Whole-Pelvic Intensity-Modulated Radiotherapy in Gynecologic Patients.

Simple SummaryAlthough the small bowel volume effect for acute diarrhea during radiotherapy has been investigated, no study has reported the influence of rectal dose. We analyzed 108 patients undergoing intensity-modulated radiotherapy after hysterectomy. Acute diarrhea was defined as onset during radiotherapy based on Common Terminology Criteria for Adverse Events (CTCAE) version 3. Both small bowel and rectum dosimetric parameters affected Grade 2 to 3 diarrhea. The high-dose volume effects on the small bowel still play an important role in postoperative intensity-modulated radiotherapy. This is the first large cohort study to demonstrate the role of both IMRT dosimetric factors of the rectum and the small bowel in acute diarrhea in gynecological patients with a previous hysterectomy. A small bowel volume of 39.6 Gy < 60 mL and a mean rectal dose of <32.75 Gy are suggested as constraints to treatment planning.We studied the association of rectal dose with acute diarrhea in patients with gynecologic malignancies undergoing whole-pelvic (WP) intensity-modulated radiotherapy (IMRT). From June 2006 to April 2019, 108 patients with previous hysterectomy who underwent WP IMRT were enrolled in this cohort study. WP irradiation of 39.6–45 Gy/22–25 fractions was initially delivered to the patients. Common Terminology Criteria for Adverse Events (CTCAE) version 3 was used to evaluate acute diarrhea during radiotherapy. Small bowel volume at different levels of isodose curves (Vn%) and mean rectal dose (MRD) were measured for statistical analysis. The multivariate analysis showed that the MRD ≥ 32.75 Gy (p = 0.005) and small bowel volume of 100% prescribed (V100%) ≥ 60 mL (p = 0.008) were independent factors of Grade 2 or higher diarrhea. The cumulative incidence of Grade 2 or higher diarrhea at 39.6 Gy were 70.5%, 42.2%, and 15.0% (p < 0.001) in patients with both high (V100% ≥ 60 mL and MRD ≥ 32.75 Gy), either high, and both low volume-dose factors, respectively. Strict constraints for the rectum/small bowel or image-guided radiotherapy to reduce these doses are suggested.

Proton Therapy for Pediatric Ependymoma: Mature Results From a Bicentric Study

To report the long-term efficacy and toxicity of proton therapy for pediatric ependymoma. Between 2000 and 2019, 386 children with nonmetastatic grade 2/3 intracranial ependymoma received proton therapy at 1 of 2 academic institutions. Median age at treatment was 3.8 years (range, 0.7-21.3); 56% were male. Most (72%) tumors were in the posterior fossa and classified as World Health Organization grade 3 (65%). Eighty-five percent had a gross total or near total tumor resection before radiation therapy; 30% received chemotherapy. Median radiation dose was 55.8 Gy relative biologic effectiveness (RBE) (range, 50.4-59.4). Median follow-up was 5.0 years (range, 0.4-16.7). The 7-year local control, progression-free survival, and overall survival rates were 77.0% (95% confidence interval [CI], 71.9%-81.5%), 63.8% (95% CI, 58.0%-68.8%), and 82.2% (95% CI, 77.2%-86.3%), respectively. Subtotal resection was associated with inferior local control (59% vs 80%; P < .005), progression-free survival (48% vs 66%; P < .001), and overall survival (70% vs 84%; P < .05). Male sex was associated with inferior progression-free (60% vs 69%; P < .05) and overall survival (76% vs 89%; P < .05). Posterior fossa tumor site was also associated with inferior progression-free (59% vs 74%; P < .05) and overall survival (79% vs 89%; P < .01). Twenty-one patients (5.4%) required hearing aids; of these, 13 received cisplatin, including the 3 with bilateral hearing loss. Forty-five patients (11.7%) required hormone replacement, typically growth hormone (38/45). The cumulative incidence of grade 2+ brain stem toxicity was 4% and occurred more often in patients who received >54 GyRBE. Two patients (0.5%) died of brain stem necrosis. The second-malignancy rate was 0.8%. Proton therapy offers disease control commensurate with modern photon therapy without unexpected toxicity. The high rate of long-term survival justifies efforts to reduce radiation exposure in this young population. Independent of radiation modality, this large series confirms extent of resection as the most important modifiable factor for survival.

The Combination of Anti-Thymocyte Globulin and Basiliximab for Haploidentical Hematopoietic Stem Cell Transplantation

Objectives: Identical hematopoietic stem cell transplantation (haplo-HSCT) is associated with a higher risk of graft rejection when compared to matched sibling donor transplantations. Methods: The study included 34 patients who were treated with a novel regimen combining basiliximab, Anti-thymocyte globulin (ATG) and conventional immunosuppressive in the recipients of haplo-HSCT. Results: The cumulative incidence of grade II–IV and grade III–IV aGVHD was 38.2% and 11.8%, while the rates of limited and extensive cGVHD were 17.6% and 23.5%, respectively. Laboratory evidence of CMV and EBV reactivation were found in 9 patients (26.5%) and 6 patients (18.8%), respectively. The relapse rate of haplo-HSCT was 14.7% at 1 year; and 1-year OS and DFS were achieved in 58.8% and 55.9% of the patients, respectively. Conclusions: The results suggested that basiliximab combined with low-dose ATG could be a promising treatment strategy in haplo-HSCT.

Effect of Cytomegalovirus Reactivation With or Without Acute Graft-Versus-Host Disease on the Risk of Nonrelapse Mortality.

Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied. We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a preemptive strategy for CMVR between 2008 and 2017. The cumulative incidences of grade 2-4 acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.24-2.05; P < .001) and with G24GVHD (HR, 1.34; 95% CI, 1.06-1.70; P = .014), but the interaction between G24GVHD and CMVR was not significant (P = .326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics. These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.

NCOG-29. O6-METHYLGUANINE DNA METHYLTRANSFERASE (MGMT) PROMOTER METHYLATION STATUS AND THE INCIDENCE OF TEMOZOLOMIDE-INDUCED HEMATOLOGIC TOXICITY: AN ASSOCIATION STUDY

Abstract BACKGROUND Despite the growing body of evidence demonstrating an increased clinical benefit of alkylating agents in glioblastoma patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, little is known regarding the effect of MGMT status on toxicity. The purpose of this investigation is to provide insight into the potential association between MGMT promoter methylation and the development of Grade 3/4 hematologic toxicities in patients receiving temozolomide. METHODS A total of 63 patients with documented glioblastoma or anaplastic astrocytoma diagnoses were evaluated retrospectively. A chi-square test of independence was utilized to evaluate the incidence of hematologic toxicities and patient overall survival was determined by univariate analysis estimated through use of Kaplan-Meier curves. Relative frequencies of treatment discontinuation secondary to myelosuppression were also compared. RESULTS At the time of study completion, 71.4% of patients with MGMT promoter hypermethylation had survived compared with 50% of patients with hypomethylation (HR 0.86; 95% CI 0.71 to 1.05; P&amp;gt;0.05). The percentage of patients who experienced Grade 3/4 hematologic toxicities during concurrent treatment was 20% and 5.1% within the hypermethylated and hypomethylated groups, respectively, and 26.7% and 17.9% throughout standard therapy. While a statistical difference was not found between the cumulative incidences of Grade 3/4 hematologic toxicity events throughout both phases of treatment, a statistical difference was noted in the incidence of Grade 4 occurrences with ten events occurring in the hypermethylated group and zero in those with hypomethylated promoter regions (P&amp;lt; 0.01). Furthermore, use of temozolomide in hypermethylated patients resulted in fewer completed cycles of standard therapy and higher rates of treatment delays and drug discontinuation. CONCLUSIONS This study showed marked differences in the frequency of temozolomide-induced hematologic toxicities and treatment discontinuation based on tumor MGMT promoter methylation status. Further research is warranted in larger patient populations to both validate and determine the clinical significance of these findings.

Severe/Life-Threatening/Fatal Chronic Health Conditions (CHCs) after Allogeneic Blood or Marrow Transplantation (BMT) in Childhood - a Report from the BMT Survivor Study (BMTSS)

Background: Allogeneic BMT is a curative option for children with malignant and non-malignant diseases. Nonetheless, the high intensity of therapeutic exposures at a young age increases the risk of organ compromise and thereby the risk of developing CHCs. Yet, there is limited information regarding CHC risk after allogeneic BMT performed in childhood. We address this gap in patients undergoing allogeneic BMT between 1974 and 2014 at 3 participating transplant centers. Methods: BMT recipients and a sibling comparison group (or the parents of participants &amp;lt;18y) completed a 255-item questionnaire that included sociodemographics and health conditions. A severity score (grades 3 [severe] or 4 [life-threatening]) was assigned to CHCs using CTCAE, v. 5.0. Deceased BMT recipients received a CHC-specific grade 5. Risk of severe/life-threatening CHC in BMT survivors vs. siblings: We calculated the cumulative incidence of CHCs for survivors and siblings as a function of attained age. We used logistic regression for estimating the risk of grade 3-4 conditions in survivors compared to siblings, adjusting for sex, age at study, race/ethnicity, education, household income, and health insurance. Risk of severe/life-threatening/fatal CHC in BMT recipients: We used proportional subdistribution hazards model (Fine-Gray) for competing risks to identify predictors of grade 3-5 CHCs, adjusting for demographics, primary disease, conditioning agents, disease status at BMT and chronic GvHD status. Results: 848 patients had received allogeneic BMT at age ≤22 and survived ≥2y after BMT (563 alive at study; 285 deceased after surviving ≥2y). Primary diagnoses included ALL (29%), AML/MDS (28%), SAA (13%), other (30%); median age at BMT: 11.5y (range: 0.4-22.0); median length of follow-up 10.7y (2.0-41.4). Risk of severe/life-threatening CHC in 563 BMT survivors vs. 515 siblings: Cumulative incidence of grade 3-4 condition by age 30y among BMT recipients was significantly higher than that among siblings (38.5±2.7% vs. 5.4±1.0%, p&amp;lt;0.0001), Figure 1. The adjusted odds of developing grade 3-4 CHCs were 8.9-fold higher in BMT survivors (95%CI 6.4-12.5). Higher odds were observed for developing cataracts (OR=48.2; 95%CI 17.9-129.5), heart disease (OR=11.4, 95%CI, 3.9-33.3), diabetes (OR=11.1; 95%CI 3.5-34.8), thyroid nodules (OR=6.6, 95%CI, 2.6-17.0), joint replacement (OR=4.4, 85%CI, 1.7-10.9), and sensorineural disorders (hearing loss/balance disorder/legally blind); OR=3.2, 95%CI, 1.5-6.8). Risk of severe/life-threatening/fatal CHCs in 848 BMT recipients: cumulative incidence of grades 3-5 CHCs was 60.5±3.0% at 40y (Figure 2). The most prevalent grade 3-5 CHCs were second malignancy (11.8%), cataract (5.9%), cardiovascular disease (5.8%), sensorineural disorder (4.4%), diabetes (3.4%), and joint replacement (2.9%). The risk of grades 3-5 CHCs was higher among females (HR=1.3, 95%CI 1.0-1.6), age &amp;gt;12y at BMT (HR=1.4, 95%CI 1.1-1.8) and among those exposed to TBI (HR=1.7, 95%CI 1.2-2.3). Conclusions: Two-year survivors of allogeneic BMT performed in childhood had an almost 10-fold higher risk of severe/life-threatening CHCs compared to siblings. By age of 30, 39% of the survivors had developed a severe or life-threatening CHC. The results of the present study call for close follow-up, from the time of transplantation continuing throughout life. Disclosures Weisdorf: Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Fate Therapeutics: Consultancy; Syndax: Research Funding; Kadmon: Research Funding; Pharmacyclics: Research Funding.

Allogeneic Hematopoietic Cell Transplantation (allo-HCT) in T-Cell Prolymphocytic Leukemia (T-PLL): An Analysis from the CIBMTR

Introduction T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive malignancy with limited treatment options, frequent relapse, and poor long-term survival. Allogeneic hematopoietic cell transplantation (allo-HCT) is reported to be effective in T-PLL yielding durable remissions and improved survival. Rates of survival and non-relapse mortality vary; data is scant and limited to small retrospective series. Whether regimen intensity - a modifiable factor- is associated with outcomes is unknown. Here, we report an analysis of patients with T-PLL undergoing allo-HCT in 87 centers using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods A retrospective multicenter study was conducted utilizing the CIBMTR dataset, which captures all consecutive patients transplanted in participating centers. The study population included patients aged 18 or older with T-PLL who underwent allo-HCT between 2008 and 2018. All donor types, graft sources, and conditioning intensities are summarized (Table 1). Cox regression analysis was used to assess overall mortality, treatment-related mortality (TRM), relapse or progression, disease-free survival (DFS) and acute and chronic graft-versus-host disease (GVHD). Due to the strong correlation between regimen intensity and patients' age, a combined variable was constructed, and in all models, interactions between age/regimen and significant covariates were examined. Results A total of 266 pts were identified and included in this analysis (Table 1). Median follow up of survivors was 49 months (range 3-117); the completeness of survival data out to four years was 95%. In univariate analysis, the 4-year overall survival (OS) rate was 30% (95% confidence interval [CI]: 23.8-36.5%). The 4-year DFS, relapse, TRM rates were 25.72% (95%CI: 20-32%), 41.9% (95%CI: 35.5-48.4%), and 32.4% (95%CI: 26.4-38.6%), respectively. Cumulative incidences of grade 2-4 acute GVHD at day +180 and chronic GVHD at 1-year were 22.5%% (95%CI: 16.8- 28.9%) and 38.3% (95%CI: 32.9-44.9%), respectively. Multivariate analyses was performed using age (Age &amp;gt;60 vs Age ≤60) and conditioning intensity (myeloablative [MAC] vs. reduced intensity/non-myeloablative [RIC/NMA]) as main effect (Table 2). Poor performance status was associated with inferior TRM, DFS and OS. Compared to MAC/Age ≤ 60, RIC/NMA/Age≤ 60 correlated significantly with less TRM (hazard ratio [HR] 0.28, 95% CI 0.14-0.55, p= 0.0022, superior DFS [HR 0.53, 95% CI 0.35-0.81, p= 0.0029; (Figure 3) and OS HR 0.49, 95% CI 0.32-0.75, p= 0.0009; (Figure 2). Similar trend was observed for RIC/NMA/ Age&amp;gt; 60 for all 3 outcomes but did not reach statistical significance. Remission status at time of allo-HCT (stable disease or progression vs. complete remission) correlated with relapse (hazard ratio [HR] of relapse=2.13, 95%CI 1.23-3.71, p=0.0072), however degree of response (partial response vs. complete remission did not significantly correlate with relapse (HR of relapse=1.41, 95%CI 0.91-2.17, p=0.1257). In vivo T cell depletion with ATG (N=47) or alemtuzumab (N=2) was associated with worse TRM [HR 1.82, 95% CI 1.08-3.08, p= 0.0255] and inferior DFS [HR of death or progression=HR 1.50, 95% CI 1.05-2.15, p= 0.0276]. The most common cause of death was disease relapse (52%) followed by infection (15%) and GVHD (13%). Conclusion This CIBMTR study, with the largest cohort of allo-HCT in T-PLL to date, demonstrates allo-HCT is effective in providing durable remissions. MAC and poor performance status were predictive of inferior TRM and OS. Disease relapse was most common cause of death, and pre-allo-HCT remission inversely correlated with relapse rate. The data suggest that reduced intensity conditioning and avoidance of post-transplant ATG/alemtuzumab may be beneficial. Novel strategies are needed both pre and post-allo-HCT to further improve outcomes. Disclosures Dholaria: J&amp;J: Research Funding; bms: Research Funding; Takeda: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding. Jagadeesh:Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Regeneron: Research Funding. Oran:Celgene: Consultancy; ASTEX: Research Funding; Arog Pharmaceuticals: Research Funding. Nakamura:Viracor: Consultancy; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; NapaJen Pharma: Consultancy; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Kadmon Corporation: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation. Sauter:Spectrum Pharamaceuticals: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Gamida Cell: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Celgene: Consultancy, Research Funding; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy, Research Funding. kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

Impact of Donor Search Strategy for Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical or Matched Unrelated Donor for Patients Older Than 55 Years with Hematological Malignancies: Randomized Prospective Phase III Study

Impact of Donor Search Strategy for Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical or Matched Unrelated Donor for Patients Older Than 55 Years with Hematological Malignancies: Randomized Prospective Phase III Study

Allogeneic Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Post-Transplantation Cyclophosphamide: Assessing the Importance of Conditioning Regimen, Donor Choice, and Tyrosine Kinase Inhibitor Use

Allogeneic Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Post-Transplantation Cyclophosphamide: Assessing the Importance of Conditioning Regimen, Donor Choice, and Tyrosine Kinase Inhibitor Use

Chemotherapy Relative Dose Intensity, Overall Survival, and Hematologic Toxicity in Solid-Tumor Cancer Patients: A Literature Review and Meta-Analysis

Background: Reduction in chemotherapy relative dose intensity (RDI) is a common outcome of hematologic toxicity during cancer chemotherapy and can affect treatment efficacy and, consequently, survival time. Several published studies have reported associations between RDI and overall survival, as well as the cumulative incidence of hematologic toxicities. A systematic literature review and meta-analysis of these results can elucidate opportunities to improve overall survival by managing hematologic toxicity. Methods: PubMed, Embase, and Web of Science databases were searched from 2013 through 2019 to identify studies reporting the associations of chemotherapy RDI with survival in adult solid-tumor cancer patients. Titles and abstracts of articles were reviewed and after excluding irrelevant studies, two independent reviewers assessed the de-duplicated, full-text articles and abstracted relevant studies into an extraction database. Endpoints included overall and progression-free survival by RDI and the cumulative incidence of grade 3 or higher hematologic adverse events. Eligible publications included observational studies and clinical trials published in English from peer-reviewed journals and conference abstracts. Random-effects meta-analyses were conducted to quantify the association between RDI levels and overall survival using studies reporting a hazard ratio (HR) for overall survival by tumor type, chemotherapy regimen, and RDI threshold of 80% or 85%. The results of included outcomes were summarized across available studies, weighting studies by the inverse of their variance. Study heterogeneity was evaluated using Cochran's Q and I2 statistical tests. Summary HR and 95% confidence intervals (CI) were represented using forest plots. Results: After reviewing 914 articles resulting from the literature searches, a total of 41 studies were included in the extraction database. Overall, two major categories of studies were identified: platinum-based regimens for breast, non-small cell lung cancer, or ovarian cancer; and 5-fluorouracil-based regimens (e.g. FOLFOX, FOLFIRI) for colorectal or pancreatic cancer. Meta-analysis of the five platinum-based studies (HR 1.17; 95% CI: 1.07-1.27) and four 5-fluorouracil-based studies (HR 1.39; 95% CI: 1.03-1.89) demonstrated significantly shorter survival time at RDI levels &amp;lt;80/85% vs. RDI levels ≥80/85% (Figure 1). Grade 3 or higher hematologic toxicities were reported by nine studies (two with age stratification). The cumulative incidence estimates of grade 3+ hematologic adverse events were higher for platinum-based regimens (14-22% for thrombocytopenia; 15-19% for anemia; and 24-58% for neutropenia) than 5-fluorouracil regimens (1-4% for thrombocytopenia; 5-19% for anemia; and 19-47% for neutropenia). In each study, neutropenia incidence was higher (0-58% across studies) than anemia (5-28%) and thrombocytopenia (1-22%) (Figure 2). Thrombocytopenia and anemia incidence were higher with paclitaxel in pancreas and ovarian cancers than other therapies. Hematologic toxicities were not reported separately by RDI in these studies. Conclusions: Recent publications demonstrated longer survival with RDI ≥80/85% than with lower RDI for solid tumor cancer patients on platinum-based and 5-fluorouracil-based chemotherapy regimens. Grade 3+ hematologic toxicities commonly occurred in studies of platinum-based regimens and some 5-fluorouracil studies. Managing such toxicities may contribute to maintenance of higher RDI and ultimately benefit overall survival. Disclosures Bylsma: EpidStrategies: Current Employment. Nielson:Amgen Inc: Current Employment. Fryzek:EpidStrategies: Current Employment. Saad:Amgen Inc: Current Employment.

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)-Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)-Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)