scholarly journals Comparison of Outcomes of Donor Lymphocyte Infusions with or without Lenalidomide in Patients with Hematological Malignancies Post Allogeneic Transplant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-29
Author(s):  
Sachin Punatar ◽  
Vinodhini Murugaiyan ◽  
Anant Gokarn ◽  
Akanksha Chichra ◽  
Sumeet Prakash Mirgh ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hematological Malignancies ◽  
Group Versus ◽  
Cell Transplant ◽  
Allogeneic Transplant ◽  
Graft Versus Leukemia ◽  
Grade Ii ◽  
Immunomodulatory Drug ◽  
Donor Lymphocyte Infusions ◽  
Graft Versus Leukemia Effect

Introduction Outcomes of patients (pts) with relapsed hematological malignancies post allogeneic stem cell transplant (ASCT) are dismal. Donor lymphocyte infusion (DLI) is one of the treatment options; however outcomes with DLI are also poor especially in acute leukemias. Addition of immunomodulatory drugs to DLI may augment graft-versus-leukemia effect and may improve outcomes. Lenalidomide (len) is an immunomodulatory drug and has several effects on the immune system. Addition of len to DLI has been variably practiced at our centre. In this study, we retrospectively compare the outcomes of DLI with or without len. Methods All pts who received DLI from January 2010 to January 2020 were included in this retrospective analysis. No immunosuppressant prophylaxis was administered and ongoing immunosuppression (if any) was stopped prior to DLI. DLI was defined as therapeutic if it was given for hematological relapse (with or without cytoreductive chemotherapy); pre-emptive if there was cytogenetic / flow cytometric / molecular relapse or slipping chimerism. DLI was prophylactic if it was given to prevent a relapse in the absence of any of the above features. Len was given on a continuous schedule at a starting dose of 2.5-25 mg/day. Len was started along with 1st or subsequent DLI as per discretion of treating clinician. For the purpose of this study, pts were divided into two groups - those who received DLI alone (no len group) versus those who received DLI with len (len group). In both groups, cytoreductive chemotherapy was given for some pts with hematological relapse at discretion of treating physician. Event free and overall survival were calculated from the date of 1st DLI. Event was defined as hematological relapse / progression or death. Complete response (CR) was defined as attainment of full donor chimerism in those with chimerism slippage; attainment of cytogenetic/ flow/molecular negativity in those with any of these positive at time of DLI; attainment of morphological remission in those with hematologic relapse. The primary objective was to compare the overall survival (OS) in no len group versus len group. Secondary endpoints were event free survival (EFS), CR rates, grade II-IV acute GVHD, len related toxicities and therapy related mortality. Patient and donor age, gender, diagnosis, type of ASCT, disease risk index (DRI), time to relapse (or slipping chimerism), type of DLI, pre-DLI morphological disease status, and HLA-A*24 or B*40 in pts were evaluated as factors affecting outcomes with or without len. (HLA-A*24 and B*40 were selected because of prior data from our institute showing benefit of len in pts with AML who had these alleles.) Statistical analysis was done using standard methods. Survival was assessed by Kaplan Meier method. All p values were 2 sided; p value of <0.05 was considered significant. Results Total 61 pts received DLI. Table 1 shows the baseline characteristics, transplant details, & details of DLI & len. The 2 groups were comparable in all aspects except for younger age in len group. Median OS (Fig 1a) and EFS (Fig 1b) were not different in len vs no len group (11 vs 8 months, p=0.66 and 6 vs 2 months, p=0.42). Len was not associated with improvement in OS in pts with myeloid malignancies (n=47, median OS 8 vs 3 months, p=0.80) or in AML pts (n=25, median OS 9 months vs 2 months, p=0.47). Among pts with HLA-A*24 or B*40 (n=26), there was an improvement in OS (median not reached vs 8 months, 4 year OS 62% vs 32%, p=0.1) (Fig 1c) and EFS (median 9 vs 1 month, 4 year EFS 50% vs 22%, p=0.1) (Fig 1d) with len. In this subgroup, hazard ratio for both OS and EFS was 0.47 (Fig 1e and 1f respectively). 49 pts had measurable disease / slipped chimerism at DLI. Among these, CR rate was not different between the 2 groups (41% vs 40% with len, p=0.9). Median time to CR was similar (31 vs 38 days, p= 0.36). Post DLI acute grade II-IV GVHD developed in 8 (19%) in no len group vs 4 (22%) in len group respectively, p=0.75. Median duration of len was 36 days. In the len group, 17 discontinued len; 8 (44%) due to disease progression, 5 (28%) due to GVHD, 3 (17%) due to cytopenias and 1 due to unrelated cause. Death due to DLI related GVHD was seen in 1 (6%) and 4 (9%) in len and no len group respectively, p=0.6. Conclusions There was no difference in outcomes in patients who received DLI with or without len. However, in subset of patients who had HLA*24 or B*40, an improvement in OS and EFS was seen. The relation of above HLA alleles with len needs further exploration. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: This abstract discusses the use of lenalidomide as an immunomodulatory drug to enhance the graft versus leukemia effect of donor lymphocyte infusions for hematological malignancies post allogeneic transplant.

Cyclosporine Versus Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis after Matched Related and Unrelated Minimal Intensity Allotransplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5014-5014
Author(s):  
Robert P. Nelson ◽  
Jennifer E. Schwartz ◽  
Menggang Yu ◽  
Michael Robertson ◽  
Paul R. Haut ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mycophenolate Mofetil ◽  
Older Patients ◽  
Hematological Malignancies ◽  
Hematopoietic Cell ◽  
Sinusoidal Obstruction Syndrome ◽  
Cell Transplant ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Grade 3

Abstract The purpose of this study was to examine the efficacy of cyclosporine (CsA) alone versus CsA/mycophenolate mofetil (MMF) as GVHD prophylaxis in older patients who received a minimally-intensive allogeneic hematopoietic cell transplant (MIHCT) for the treatment of hematological malignancies (AML=26, MDS=15, NHL=8, CLL=5, MM=3, HD=4, CML=1, ALL=1). Patients (median age, 55 years; 41 males, 22 females) received HLA-matched related (n=33) or unrelated (n=30) peripheral blood hematopoietic cell infusions following immunosuppressive dosages of cyclophosphamide and fludarabine (Childs R, et al. Blood 94; 1999). The initial 28 consecutive patients received monitored CsA from day −1 through day +180 (if no GVHD). The next 35 subjects received CsA/MMF: CsA, day −1 through day +180 and MMF, 1000 mg twice daily, day +1 through day +60 (if no GVHD, then a taper). Patients were followed until death or at least 7 months. There were no differences between recipients of MRD and MUD transplants with respect to sex, age of the recipient, disease status, ABO matching, recipient CMV status or number of CMV-negative donor/recipient pairs. MUD donors were significantly younger and more likely to be CMV-negative. There was no difference in disease distribution between those who recieved CsA and those who recieved CsA/MMF prophylaxis. Follow-up ranged from 25–2241 days (median, 461 days for the CSA group; 449 days for the CSA/MMF group, 1290 days for survivors). All patients engrafted without growth factor support and no subjects experienced sinusoidal obstruction syndrome, mucositis or post-transplant lymphoproliferative disease. Thirty and 100-day transplant-related mortality for the cohort was 1.6% and 15.9% respectively. The incidence of Grade 2–4 aGVHD (n=63) was 49.2% (CsA, 57.1%, CsA/MMF, 42.9%, p=0.315). Grade 3 or 4 aGVHD occurred in 30% (CsA, 32.1%, CsA/MMF, 28.6%, p=0.788). Chronic extensive GVHD occurred in 53.8% (CsA, 61.5%, CsA/MMF, 46.2%, p=0.404) of at risk (survival greater than 100 days) recipients. The incidence of acute or chronic GVHD was not statistically different for MRD versus MUD recipients for either prophylaxis group (p=0.32 and 0.23, respectively). One-year, two-year and three-year overall Kaplan-Meier survival analyses were estimated to be 60.7%, 42.9% (CsA group) and 42.9%and 60%, 45.2% and 32.8% (CsA/MMF group, 0.708). Twenty-seven (42.9%) of the entire cohort are alive at a median of 1290 days post-transplant [CSA, 12/28, (42.9%); CsA/MMF, 15/35, (42.9%)]. Grade 3 or 4 aGVHD was associated with poor overall survival (p=0.0001) for the cohort. These findings provide evidence that MMF does not seem to provide substantial GVHD preventive or overall survival benefit when added to CsA after matched related/unrelated cyclophosphamide/fludarabine MIHCT in older patients with hematological malignancies.

scholarly journals Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2856-2856
Author(s):  
Sumithira Vasu ◽  
Meghan Kromer ◽  
Qiuhong Zhao ◽  
Hannah Choe ◽  
Karilyn Larkin ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Advisory Committees ◽  
High Incidence ◽  
Grade Ii

Abstract Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning. Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD. Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. Figure 1 Figure 1. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

scholarly journals Ponatinib-Induced Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia without the T315I Mutation Relapsing after Allogeneic Transplant

Chemotherapy ◽  
2017 ◽  
Vol 62 (6) ◽  
pp. 353-356 ◽  
Author(s):  
Annamaria Petrungaro ◽  
Massimo Gentile ◽  
Carla Mazzone ◽  
Rosa Greco ◽  
Giuseppina Uccello ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Graft Versus Host Disease ◽  
Lymphoblastic Leukemia ◽  
Salvage Chemotherapy ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
T315i Mutation ◽  
Graft Versus Leukemia Effect

We describe the case of a patient with Philadelphia-positive acute lymphoblastic leukemia treated with dasatinib plus steroids as first-line therapy, who achieved a major molecular response (MMR) before undergoing matched, unrelated donor allogeneic stem cell transplant. Eleven months after the transplant, she experienced molecular relapse. Mutational screening showed negativity for the T315I mutation, The patient underwent a salvage chemotherapy regimen with clofarabine + cyclophosphamide + steroids and ponatinib (clofarabine 70 mg i.v., days 1-5, cyclophosphamide 700 mg i.v., days 1-5, and ponatinib 45 mg p.o., daily starting at day 15). We observed a rapid decrease in minimal residual disease on molecular assessment with an MMR of P190-BCR-ABL/ABL = 0.01% confirmed by bone marrow revaluations at days +23, +59, +108, and +191 after the first day of salvage chemotherapy. After starting ponatinib, the patient experienced skin graft-versus-host disease, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib treatment was well tolerated and considered safe with easily manageable side effects.

Donor lymphocyte infusions in AML and MDS: Enhancing the graft-versus-leukemia effect

2017 ◽  
Vol 48 ◽  
pp. 1-11 ◽  
Author(s):  
Guillermo Orti ◽  
Pere Barba ◽  
Laura Fox ◽  
Olga Salamero ◽  
Francesc Bosch ◽  
...  
Keyword(s):  
Graft Versus Leukemia ◽  
Donor Lymphocyte Infusions ◽  
Graft Versus Leukemia Effect

scholarly journals ASH evidence-based guidelines: is there a role for second allogeneic transplant after relapse?

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 414-418 ◽  
Author(s):  
Monica S. Thakar ◽  
Stephen J. Forman
Keyword(s):  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Allogeneic Transplant ◽  
Graft Versus Host ◽  
Matched Sibling ◽  
Grade Ii ◽  
Total Body ◽  
Evidence Based Guidelines

Abstract A 35-year-old male with a FLT3+ AML underwent allogeneic peripheral blood stem cell transplant using a myeloablative non-total body irradiation (TBI) conditioning regimen from his HLA-matched sibling donor. Following transplantation, he developed grade II acute graft-versus-host disease (GVHD) that resolved with increasing immunosuppression. The medications were subsequently discontinued, and he did not develop any evidence of chronic GVHD. Eighteen months after transplant, while off all immunosuppression, he developed fatigue and a blood count showed circulating blasts consistent with relapse of his disease. Among the various therapeutic questions is whether there is a role for a second allogeneic transplant to treat his disease and if so, at what time, with what conditioning, and with which type of donor.

Outcome of Allogeneic Stem Cell Transplantation after Hypomethylating Therapy with 2′-Deoxy-5 Azacytidine for Patients with Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1468-1468 ◽  
Author(s):  
Leandro De Padua Silva ◽  
Marcos de Lima ◽  
Hagop Kantarjian ◽  
Richard Champlin ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Cord Blood ◽  
Chronic Gvhd ◽  
International Prognostic Scoring System ◽  
Cell Transplant ◽  
Prior Therapy ◽  
Graft Versus Leukemia ◽  
Graft Versus Leukemia Effect

Abstract Decitabine is approved for the treatment of patients with intermediate- and high-risk myelodysplastic syndrome (MDS). In vitro studies have demonstrated an increased expression of MHC class I molecules, HLA-DR and beta-2-microglobulin on the surface of MDS cells after decitabine therapy, potentially increasing their susceptibility to immune surveillance mechanisms and a graft-versus-leukemia effect. We analyzed the outcome of 12 patients with MDS with a median age of 58.5 years (range, 37 – 66) who underwent an allogeneic stem cell transplant (5 sibling, 5 unrelated, 2 cord blood) after prior therapy with decitabine. At diagnosis, 2 patients had intermediate-1, 7 intermediate-2 and 3 high risk MDS by the international prognostic scoring system. Nine had a non-myeloablative and 3 an ablative regimen. The source of stem cells was marrow in 2, peripheral blood in 8 and cord blood in 2. The patients had received decitabine for a median of 5.5 cycles (range, 1 – 20) and a median duration of treatment of 7.1 months (range, 1 – 27). Decitabine was well tolerated with reversible gastrointestinal toxicity and neutropenic infections as the main toxicity. Best response to decitabine was CR in 4 patients, PR in 6, and hematological improvement in 2. Eight had disease progression on decitabine. Five patients received additional chemotherapy and achieved a CR before transplant. The median time between completion of decitabine and transplant was 3.4 months (range, 0.2 – 11.7). At the time of transplant, 8 patients were in CR and 4 in PR. The median CD34+ cell number was 4.17 x 106 cells/kg (range, 0.58 – 10.1 x 106 cells/kg). Eleven patients engrafted and one had secondary engraftment failure. Median times to neutrophil and platelet engraftment were 13.7 days (range, 7 – 27) and 17.3 days (range, 7 – 28), respectively. No unusual toxicity was encountered. Nine patients (75%) developed acute GVHD, and 6 chronic GVHD (55% of those alive beyond 100 days). Ten patients were in CR and 1 in PR at day 100 post transplant. With a median follow 11.5 months (range, 3 – 26), 9 patients are alive (8 in CR and 1 with progressive disease) and 3 have died (2 after relapse and 1 from GVHD and sepsis). We conclude that prior therapy with hypomethylating agents may potentially improve the outcome of allogeneic transplant in MDS through enhancement of graft versus leukemia effect and should be examined prospectively.

Lenalidomide Maintenance After Stem-Cell Transplantation For Multiple Myeloma: Follow-Up Analysis Of The IFM 2005-02 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 406-406 ◽  
Author(s):  
Michel Attal ◽  
Valérie Lauwers-Cances ◽  
Gérald Marit ◽  
Denis Caillot ◽  
Thierry Facon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Placebo Group ◽  
Disease Progression ◽  
Group Versus ◽  
Cell Transplant ◽  
Second Line ◽  
First Line

Abstract Methods and Patients This randomized, placebo-controlled, phase 3 trial investigated the efficacy of lenalidomide (LEN) maintenance after transplantation for multiple myeloma. Patients, under 65 years of age, with non-progressive disease after a first-line autologous stem-cell transplant (ASCT) were randomized to receive maintenance with placebo or LEN (10 to 15 mg/d) until disease progression or unacceptable toxic effects. From July 2006 to August 2008, 614 patients were randomized. In January 2011, the DSMB recommended to stop LEN due to the increased incidence of second primary malignancies (SPMs). The median duration of maintenance treatment with LEN was 2 years (IQ range= 1-3). We previously reported this trial with a median follow-up of 45 months (Attal et al, N Engl J Med 2012). Results As of May 2013, median follow-up was 70 months from diagnosis and 60 months from randomization. LEN maintenance improved the 5-year progression-free survival (PFS) post randomization: 42%, versus 18% with placebo (p<0.0001), respectively. Overall, 403 patients had disease progression and 364 have started a second line therapy. The median 2nd PFS for the treated patients (time from progression in first-line to the second progression or last follow-up or death) was 10 months within the LEN arm versus 18 months within the placebo arm (p<0.0001), respectively. The median 2nd PFS in the LEN and placebo groups were 9 and 8 months (NS) for patients treated with a bortezomib-based regimen, 8 months and 18 months (p<0.01) for patients treated with an IMiD-based regimen, 14 months and 28 months (p=0.03) for patients treated with a regimen without new agents or with a second line ASCT, respectively. The 5-year post randomization overall survival (OS) was similar in the 2 groups: 68% in the LEN group versus 67% in the placebo group (HR=1). In the multivariate analysis, the OS was significantly related to age (p=0.001), International Staging System (p=0.03), and poor cytogenetics (t(4;14) or chromosome 17 deletion; p=0.008). The median survival after the first progression was 29 months in the LEN group versus 48 months in the placebo group (p< 0.0001). An increased incidence of SPMs was observed in the LEN group: 44 SPMs (hematologic: 20, non-hematologic: 24) in 35 patients were reported in the LEN group versus 28 SPMs (hematologic: 6, non-hematologic: 22) in 20 patients in the placebo group. The incidence of SPMs (excluding non melanoma skin cancers) was 2.3 per 100 patient-years in the LEN group versus 1.3 in the placebo group (p=0.03). Conclusion This new analysis confirms that lenalidomide is an effective treatment to prolong PFS after transplantation for multiple myeloma patients. However, this impressive benefit is not currently associated with an improved overall survival, due to a shorter survival after the first progression. Disclosures: Attal: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Off Label Use: FRONTLINE THERAPY WITH CARFILZOMIB IN MULTIPLE MYELOMA. Facon:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Hulin:JANSSEN: Honoraria; CELGENE: Honoraria. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Roussel:JANSSEN: Honoraria; CELGENE: Honoraria. Avet-Loiseau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau.

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