scholarly journals A Case Report of the Benefit of Cannabidiol (Cannabidiol (CBD)-Predominant Medical Cannabis Preparation) in the Management of Refractory Skin Graft Vs Host Disease (GVHD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5687-5687
Author(s):  
Tsiporah B. Shore ◽  
Jessy B. Ryan ◽  
Michael B. Samuel
Keyword(s):  
Graft Versus Host Disease ◽  
Oral Solution ◽  
High Dose ◽  
Medical Cannabis ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Graft Vs Host Disease ◽  
Anti Inflammatory

Cannabis sativa contains numerous cannabinoids, with D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) the primary cannabinoids of medical interest. Both THC and CBD possess potent anti-inflammatory and immunosuppressive properties, but THC has significant psychoactive properties. In a phase 2 study of CBD plus standard GVHD prophylaxis,, Yeshrun et al found low rates of grade II - IV acute GVHD, and compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II - IV acute GVHD was .3 (P =.0002)1. Also, Kalytera Therapeutics announced promising results in a Phase 2a study evaluating the safety and efficacy of CBD, for the treatment of acute Grade III-IV GVHD, including 9/ 10 responses, of which 7 were complete remission (CR)2. We report a case of steroid refractory eczematous GVHD successfully treated with a CBD-predominant medical cannabis product. A 35 year old woman with T-cell Acute Lymphoblastic Leukemia (T-ALL) was treated on an MSKCC pediatric -inspired ALL protocol. She developed CNS involvement during induction therapy treated with intrathecal therapy with persistent CNS disease. She then received salvage therapy with HyperCVAD part B with high dose methotrexate, high dose cytarabine, with CR and underwent matched related donor (sister) stem cell transplant conditioned with Etoposide, TBI 1200 cGy. GvHD prophylaxis was Alemtuzumab, Tacrolimus. She developed a rash on day 126 post transplant involving face and scalp which spread to chest and back and within 1 week involved 100% of BSA with itching, facial and orbital swelling, ankle/feet swelling. Skin biopsy revealed an eczematous variant of GvHD which is considered to be very aggressive, difficult to control with immunosuppression3, and carries a poor prognosis. Phototherapy and steroid ointment was initiated with initial benefit and regression of rash but then rash and edema returned within 6 months. Ruxolitinib was given on expanded access protocol with no benefit. Systemic steroids were again initiated at 1 mg/kg/ day with minimal benefit. Insurance denied tociluzumab. Extracorporeal photopheresis was started with only minimal response and eventually ibrutinib was initiated. With steroids, photopheresis and ibrutinib she had marginal response but ongoing severe skin GvHD. She had numerous infectious complications including soft tissue skin infections requiring multiple admissions. At 16 months post transplant, the patient began a medical cannabis product manufactured by VIREO HEALTH, consisting of a high CBD:THC ratio (19:1) oral solution containing CBD 47.5mg/ml and THC 2.5mg/ml. A daily dose of 6 ml provided 285 mg CBD and 15mg THC daily comparable to the 300 mg CBD product in the Kalytera product. Toxicity was sleepiness; thus the patient took the dose in the evening. There was a definite response within 3 months, allowing discontinuation of ibrutinib and photopheresis. By 2 years post transplant, her skin issues had resolved with only mild itching and flakiness. She remains on this product at a dose of 6 ml daily. This case adds to the developing evidence regarding the potential anti- inflammatory and immunosuppressive effects of medical cannabis and its activity for the treatment of active GVHD. Both THC and CBD are anti-inflammatory via CB2 receptors and THC inhibits T-lymphocyte expansion in a murine BMT model.1 The THC component may have contributed therapeutic benefit but also explains the toxicity and was dose limiting. Further studies are warranted to explore the role of medical cannabis, the optimal dose of CBD and THC, in the prevention and management of GVHD. 1 Yeshurun, Moshe, et al. "Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study." Biology of Blood and Marrow Transplantation, vol. 21, no. 10, 2015, pp. 1770-1775., doi:10.1016/j.bbmt.2015.05.018. 2. Kalytera Therapeutics Announces Encouraging Results of a Phase 2a Clinical Study for the Treatment of Acute Graft versus Host Disease. Source: Kalytera Therapeutics, Inc.VANCOUVER, British Columbia, Feb. 22, 2017 (GLOBE NEWSWIRE) 3. Creamer D, Martyn-Simmons CL, Osborne G, et al. Eczematoid Graft-vs-Host Disease: A Novel Form of Chronic Cutaneous Graft-vs-Host Disease and Its Response to Psoralen-UV-A Therapy. Arch Dermatol.2007;143(9):1157-1162. doi:10.1001/archderm.143.9.1157 Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: This is a medical cannabis product manufactured by VIREO HEALTH, consisting of a high CBD:THC ratio (19:1) oral solution containing CBD 47.5mg/ml and THC 2.5mg/ml. The drug was used to treat refractory graft versus host disease.

Elevated Serum Interleukin-7 Levels Precede the Development of Acute Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1064-1064
Author(s):  
Robert M. Dean ◽  
Terry Fry ◽  
Crystal Mackall ◽  
Seth M. Steinberg ◽  
Frances T. Hakim ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Multiple Time ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Interleukin 7 ◽  
Gvhd Prophylaxis ◽  
Acute Graft

Abstract BACKGROUND: Despite advances in transplantation immunology, there is no clinically practical tool to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Murine models indicate that aGVHD is promoted by interleukin-7 (IL-7), a homeostatic cytokine for naïve CD4+ and CD8+ T-cells. We hypothesized that serum IL-7 levels might be associated with the development of aGVHD in patients (pts) undergoing allogeneic HSCT, and evaluated this using serum samples obtained for this purpose in a prospective clinical trial. METHODS: Thirty-one pts underwent allogeneic HSCT from HLA-identical siblings. Pts received 1 to 3 pre-transplant chemotherapy cycles to induce profound, uniform host lymphopenia (CD4<100), followed by fludarabine-based reduced-intensity conditioning. GVHD prophylaxis was cyclosporine & methotrexate. Serum IL-7 was measured by ELISA at baseline and multiple time points from the day of transplant through 1 year after allogeneic HSCT. IL-7 levels were evaluated for associations with blood lymphocyte counts, aGVHD, and survival. Other variables examined for association with aGVHD were pt and donor age; CD3+ and CD34+ cell doses; donor gender; donor-recipient gender mismatch; donor or recipient CMV status, prior rituximab therapy; donor lymphoid or myeloid chimerism >95% at day +14; serum IL-15 levels; and levels of soluble tumor necrosis factor-α receptors 1 and 2 (sTNFR1 and sTNFR2). RESULTS: Grades I, II, and III aGVHD occurred in 3%, 23%, and 19%, respectively; none had grade IV. Median (range) IL-7 levels rose from baseline 12.1 (0–46.9) pg/ml to 37 (13.3–79.2) pg/ml on day 0 before allografting, then fell to 12.0 (1.3–74.7) pg/ml by day +14; these changes were inversely correlated with absolute lymphocyte counts, CD3, CD4, and CD8 counts at baseline and day +7. The development of aGVHD was associated with IL-7 levels at day +7 (p=0.01) and day +14 (p=0.000033) post-transplant (Figure), along with the allograft CD34+ cell dose (p=0.012). Higher IL-7 levels at day +14 corresponded to more severe grades of aGVHD (p<0.0001). Figure Figure In logistic regression models, these factors jointly classified pts according to development or avoidance of aGVHD with a maximum sensitivity of 86% and a specificity of 100%. IL-7 levels were more strongly associated with aGVHD than were sTNFR levels or other parameters. CONCLUSIONS: Determination of serum IL-7 levels in the early post-transplant period accurately predicted the risk of developing aGVHD after allogeneic HSCT and holds promise as a simple, reproducible test to select pts for pre-emptive therapy. These data support preclinical observations that demonstrate a critical role for IL-7 in inducing aGVHD and provide a rational basis for novel approaches to GVHD prophylaxis through modulation of the IL-7 homeostatic pathway.

scholarly journals Post-Transplant High-Dose Cyclophosphamide for the Prevention of Graft-versus-Host Disease

2015 ◽  
Vol 21 (4) ◽  
pp. 604-611 ◽  
Author(s):  
Ahmad Samer Al-Homsi ◽  
Tara S. Roy ◽  
Kelli Cole ◽  
Yuxin Feng ◽  
Ulrich Duffner
Keyword(s):  
Graft Versus Host Disease ◽  
High Dose ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant

scholarly journals A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-Free Graft-Versus-Host Disease Prophylaxis Regimen with Post-Transplantation Cyclophosphamide and Abatacept to Standard of Care

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1816-1816
Author(s):  
Divya Koura ◽  
Dimitrios Tzachanis ◽  
Edward D. Ball ◽  
Caitlin Costello ◽  
Aaron M Goodman ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Standard Of Care ◽  
Post Transplantation ◽  
Transplant Tolerance ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Background: Graft versus host disease (GVHD) is one the major causes of mortality and morbidity after an allogeneic stem cell transplantation. We hypothesized that we can induce post-transplant tolerance by using the combination of post-transplant cyclophosphamide (PTCy) and abatacept (CTLA4Ig) for GVHD prophylaxis. PTCy when given on Days +3 and +4 can eliminate host-reactive donor T cells. CTLA4Ig blocks the costimulatory signals given through CD28 to naïve donor T cells thus favoring an anergic phenotype that promotes tolerance towards recipient derived antigens. CTLA4Ig gives an activating signal to NK cells and therefore has the ability to preserve the graft-versus-tumor effect. Methods: We have initiated a 50 patient randomized clinical trial. Patients with hematologic malignancies in need of a transplant and with an 8/8 matched donor are randomized 1:1 to tacrolimus and methotrexate for GVHD prophylaxis (standard of care arm) or PTCy on days +3 and +4 followed by CTLA4Ig on days +5, +14,+28, +56, +84, +112, +140 and +168. Patients are stratified by conditioning regimen (myeloablative vs reduced intensity) and by donor type (matched sibling vs matched unrelated donor). The primary endpoint is chronic GVHD at 1 year as a marker of tolerance induction. Secondary endpoints include acute GVHD rate, relapse rate, overall survival, GVHD-relapse-free-survival, transplant related mortality and infection rate. Post-transplantation immune reconstitution studies include measuring T cell and NK cell phenotype, PD-1 expression, and alloreactivity to recipient and third party at predetermined time points. Results: 25 patients have been treated on this study, 10 of which are on the experimental arm. Patients on the experimental arm have been followed for up to 516 days post-transplant. So far no cases of chronic GVHD or grade 3-4 acute GVHD have been observed in the experimental arm. All the patients have engrafted and there have been no treatment related deaths. Conclusions: The combination of PTCy and CTLA4Ig for GVHD prophylaxis is feasible. This ongoing study will examine its ability to induce post-transplant tolerance. Disclosures Tzachanis: Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Partner: Consultancy; Fate Therapeutics: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding; EUSA: Consultancy; Takeda: Consultancy, Speakers Bureau; Magenta: Consultancy; Kyowa Kirin: Consultancy. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Mangan: Elevate Bio: Other: ad board. OffLabel Disclosure: abatacept: using as part of graft versus host disease prophylaxis

A Pilot Study Of Continuous Infusion Mycophenolate Mofetil For Graft Versus Host Disease Prophylaxis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4571-4571
Author(s):  
Randy M. Windreich ◽  
Rujuta Joshi ◽  
Raman Venkataramanan ◽  
Denise Howrie ◽  
Rakesh Goyal
Keyword(s):  
Mycophenolate Mofetil ◽  
Continuous Infusion ◽  
Graft Versus Host Disease ◽  
Half Life ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
One Year

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA) has been used successfully for graft-versus-host disease (GVHD) prophylaxis. Most MMF dosing regimens and pharmacokinetic (PK) parameters have been established in solid organ transplant recipients. Empiric fixed-dose-escalation strategies have failed to achieve target MPA exposure, especially in the early period following conditioning therapy. We hypothesized that a PK-based dosing approach using a novel continuous infusion (CI) method of MMF will be able to achieve and maintain target MPA exposure. The objective of this study was to evaluate the safety and feasibility of this MMF dosing approach in pediatric BMT recipients. Fifteen patients were enrolled in the study. The median age at transplant was 8.4 years (0.9 – 21.5); eight were female and seven were male. Thirteen patients were transplanted for hematologic malignancies and two patients for nonmalignant diseases. Stem cell sources included matched-sibling bone marrow in seven, 10/10 allele matched donor bone marrow in four, and unrelated cord blood in four cases. All patients received a myeloablative conditioning regimen with either cyclophosphamide-TBI (n=8) or busulfan-cyclophosphamide (n=7). In addition, of eight unrelated donor transplants, six patients received equine ATG and two received fludarabine. All patients received cyclosporine A and MMF for GVHD prophylaxis. Intravenous (IV) cyclosporine was initiated on day -2 as a continuous infusion (target blood level: 160 to 250 ng/mL). IV MMF was started on day “0” in a dose of 15 mg/kg every 8 hours. After a minimum of five doses, serial blood samples were collected within one dosing interval for the 1st PK analysis. Using these results, MMF was converted from intermittent IV to CI administration to target total MPA AUC0-24 of 40-80 mcg/mL/hr. MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7-3.3 mcg/mL. CI MMF was converted to every-8-hour oral dosing when patients were tolerating oral medications. A 2nd PK study was performed after a minimum of five oral doses, and dose adjustments were made to maintain a total MPA trough concentration (Ctrough) of 1-3.5 mcg/mL. MMF was continued until day 42, and in the absence of acute GVHD, tapered off over 8 weeks. On the initial 15 mg/kg q8 IV MMF dose schedule, MPA half-life was 1.3±1.3 hrs and AUC0-24 was 44.3±60.3 mg* hr/L. During the CI schedule, MMF dose was 44±16 mg/kg/day and MPA AUC0-24 38.4±20.7 mg* hr/L, and thirteen of fifteen (87%) patients achieved MPA Css within target of 1.7–3.3 mcg/mL. On conversion to oral route, median MMF dose was 45±19mg/kg/day, MPA half-life 1.95±2.3 hrs and AUC0-24 38.3±16.0 mg* hr/L. MPA clearance was 17±14 ml/min/kg. Higher steady state MPA concentrations were achieved with CI method (Css 1.6 ±0.9 mcg/mL) compared with intermittent IV or oral dosing (Ctrough 0.7±0.9 mcg/mL). All patients achieved neutrophil engraftment at 13 ± 11 days post-transplant, and platelet engraftment at 45 ± 72 days post-transplant. Seven out of 15 patients (47%) developed stage I-IV acute GVHD. Three patients had stage III-IV aGVHD (20%); they were steroid-refractory but went into remission with additional therapy. For 11 patients with a minimum of one year follow-up post-transplant, one (9%) developed “overlap” chronic GVHD. MMF was discontinued without weaning in four patients: in three of them due to concern of delay in blood count recovery and all of them achieved hematopoietic engraftment, and in one patient with severe aGVHD due to potential concern for MMF gut toxicity. One patient with severe congenital neutropenia developed autologous hematopoietic recovery by day 52. One patient with ALL died of relapse 150 days after transplant. With a median follow-up of 23 months (range 100 days to 3.6 y), 14 out of 15 patients are alive, and one-year event-free survival and overall survival are 83% and 92% respectively. In conclusion, we show that continuous infusion of MMF is feasible and well-tolerated. In this pilot PK study, we observed no toxic deaths, excellent engraftment, and low rates of grade III-IV aGVHD and cGVHD. The PK studies showed significantly lower half-life and higher drug clearance in pediatric BMT recipients compared to stable pediatric renal transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation. Disclosures: Off Label Use: Use of Mycophenolate Mofetil for Graft versus Host Disease Prophylaxis.

scholarly journals Transplant Outcomes of 9/10 HLA Matched Unrelated Donors (MUD) Treated with Post-Transplant Cyclophosphamide for Prevention of Graft Versus Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2486-2486 ◽  
Author(s):  
Sai Ravi Pingali ◽  
Denai Milton ◽  
Uday R. Popat ◽  
Chitra M. Hosing ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Post Transplantation ◽  
Modest Improvement ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Background: Graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (ASCT). The incidence of GVHD with conventional GVHD prevention is higher with HLA mismatched compared to matched donors, with 69% of patients (pts) developing grade 2-4 and 16% grade 3-4 acute (aGVHD) and more than half the pts developing chronic (cGVHD), as previously reported by us(Ciurea SO abstract ASH 2010). Here we report preliminary results of 9/10 MUD transplant pts receiving GVHD prophylaxis with post-transplantation cyclophosphamide (PTCY), in addition to tacrolimus and mycophanolate mofetil (MMF). Methods: Patients were treated prospectively using a 9/10 MUD on a separate arm of a phase II clinical trial (2009-0266). Conditioning regimen consisted of Melphalan 140 mg/m2 on day −8 (100mg/m2 for pts ≥55 years or with comorbidities), Thiotepa 5-10 mg/kg on day −7 and Fludarabine 40 mg/m2/day on days −6, −5, −4, and −3. All patients received T-cell replete bone marrow graft. GVHD prophylaxis included PTCY 50mg/kg on days +3 and +4, MMF was given until day 100 and Tacrolimus until day 180 if no GVHD. Primary objectives were to determine the incidence of acute and chronic GVHD and non-relapse mortality (NRM), while secondary objectives included progression free survival (PFS) and overall survival (OS). Results: 39 patients with median age of 50 years (range 20-64) received a 9/10 MUD with PTCY GVHD prophylaxis. 20 patients (51%) were women and AML/MDS was the most common indication for transplantation in 13(33%), NHL 8(21%), ALL 7(18%), AA in 4(10%) and CLL, CML/MPD, HL and MM constituted rest of the patients. Poor, intermediate and low risk cytogenetics were seen in 6, 8 and 4 patients with leukemia, respectively. 22 patients (56%) were not in complete remission at the time of transplantation. Median follow-up time for survivors was 35.9 months (range: 2.6–123.5). All patients engrafted the donor cells. Day 100 NRM for all pts was 18%.The cumulative incidence (CI) of grade II-IV aGVHD and gr III-IV aGVHD was 42% and 17%, respectively. CI of all cGVHD was only 20% and extensive only cGVHD was 13%. NRM for all pts was 36% at 1 year and 40% at 3 years. OS for all pts at 1 and 3 yr was 57% and 44%, while PFS at 1 and 3 yr was 43% and 39%, respectively. Conclusions: Post-transplant cyclophosphamide for prevention of GVHD which has been successfully used in haploidentical transplantation, resulted in a modest improvement in the rates of grade 2-3 and 3-4 acute GVHD compared to reports of standard GVHD prophylaxis for 9/10 MUD transplants. However, a promising low rate of chronic GVHD was observed. This approach can produce durable remissions for patients with hematologic malignancies who lack an HLA matched donor. Figure 1 Figure 1. Disclosures Andersson: Otsuka Pharmeceuticals: Research Funding, Research funding from Otsuka Pharmeceuticals Other.

scholarly journals A Novel Secondary Neoplasm Following Allogeneic Hematopoietic Stem Cell Transplant: Mixed Donor-Recipient Primitive Mesenchymal Proliferation of the Liver

2021 ◽  
pp. 109352662110016
Author(s):  
Brian Earl ◽  
Zi Fan Yang ◽  
Harini Rao ◽  
Grace Cheng ◽  
Donna Wall ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant

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.

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