In this month’s Pharmacy SIG Literature Update: Updated results from TRANSCEND with longer follow- up, recommendations for management of invasive candidiasis in transplant recipients, GD2-CART01 for relapsed or refractory high-risk neuroblastoma and more!

Literature summaries are provided as information only. Please refer to the original published articles for complete details on study methodology, results and discussion.

***        Must read. Landmark publication that affects practice

**          Recommend reading. Secondary paper that adds to literature Consider reading.

• Cursory importance to the practice

Autologous Stem Cell Transplantation

** Hashmi H, Atrash S, Jain J, et al. Daratumumab, pomalidomide, and dexamethasone (DPd) followed by high dose chemotherapy-Autologous Stem Cell Transplantation leads to superior outcomes when compared to DPd-alone for patients with Relapsed Refractory Multiple Myeloma. Transplantation and cellular therapy. 2023;29(4):262.e1-262.e6. https://pubmed.ncbi.nlm.nih.gov/36682468/

• Single center retrospective study comparing the efficacy and safety outcomes of 83 patients with relapsed/refractory multiple myeloma (RRMM) who received salvage DPd alone (n=62) vs. salvage DPd followed by auto-SCT (n=21).
• For DPd-alone vs. DPd + auto-SCT groups respectively, VGPR or better was observed in 37 (60%) and 18 (86%) patients, a stringent CR was observed in 10 (16%) vs. 12 (57%) patients, median PFS was 17.5 months vs. 42.2 months (p=0.006) and median OS was 38.1 months vs. not reached (p=0.009). Significant improvement in depth of response with auto-SCT with CR rates improving from 25% pre auto-SCT to 76% post auto-SCT.
• The most common grade 3 or 4 adverse events were neutropenia (79% vs. 100%), anemia (18% vs. 33%), thrombocytopenia (0.6% vs. 17%) and neutropenic fever (6% vs. 52%) in the DPd vs DPd + autoSCT groups respectively. Gastrointestinal toxicities were more commonly seen in the DPd + auto-SCT group.
• Authors conclude that patients who received and responded to DPd followed by auto-SCT had a superior depth and durable response compared to those who received DPd alone.

Allogeneic/Haploidentical Stem Cell Transplantation

**Mehta RS, Marin D, Alousi A, et al. Haploidentical vs matched unrelated donors for patients with ALL: donor age matters more than donor type. Blood Adv. 2023;7(8):1594-1603. https://pubmed.ncbi.nlm.nih.gov/36630564

• This was a review of a CIBMTR dataset from a prior study which sought to test the hypothesis that a younger haploidentical donor may result in improved OS when compared with an older MUD donor.
• Multivariate analysis of the entire study cohort found older donor age, but not donor type, to be a significant predictor of poor OS (HR: 1.29; 95% CI: 1.01-1.66; p=0.043). When age was restricted to compare survival between younger (age <35 years) haplo compared to MUD transplant patients and older (age >35 years) haplo versus MUD transplant patients, outcomes were not significantly different.
• The primary analysis evaluated older MUD group (n=232) against younger haplo subset of patients (n=187). Baseline characteristics were comparable except for age and a significantly higher percentage of patients in the MUD cohort had T-cell ALL, received myeloablative conditioning, and received PBSC grafts.

▪ The 4-year OS was 47.1% (95% CI: 39.9-54) compared to 60.5% (95% CI: 50.6-69.1) in the older MUD and younger haplo cohorts, respectively. Multivariate analyses showed that predictors of significantly lower OS included older MUD patients (HR: 1.77; 95% CI: 1.16-2.71; p=0.008), age

>40 years (HR: 1.65; 95% CI: 1.04-2.61; p=0.03) and disease status of CR2 or >CR3.

• The older MUD cohort experienced significantly higher risks of cGVHD (HR: 1.91, 95% CI: 1.28- 2.85; p=0.002) and NRM (HR: 2.75; 95% CI, 1.51-4.99; p=0.001) compared to younger haplo patients. PFS was similar between the two groups.
• HCT using younger haplo donors with PTCy prophylaxis may result in longer OS as well as lower risks of NRM and cGVHD compared to MUD with conventional GVHD prophylaxis albeit at the expense of a higher risk of relapse.

** Dulery R, Goudet C, Mannina D, et al. Reduced post-transplant cyclophosphamide doses in haploidentical hematopoietic cell transplantation for elderly patients with hematological malignancies. Bone Marrow Transplantation (2023) 58:386–392. https://pubmed.ncbi.nlm.nih.gov/36585459/

• Non-randomized, retrospective, cohort study of recipients of PBSC haploidentical allo-HCT to compare transplant outcomes in elderly patients treated with a standard vs a reduced dose of PTCy.
• Study patients included those treated with non-myeloablative conditioning for any hematologic malignancy who were either age > 65 years or age > 60 years with a history of cardiac event comparing those who received PTCy at a total dose 100mg/kg (n=55) versus 80mg/kg (n=38). The PT-Cy 100 mg/kg cohort (50 mg/kg on Day +3, +4) were treated from 2014 to 2018 and the PT-Cy 80 mg/kg cohort (40 mg/kg on Days +3, +4) were enrolled in 2018-2019. Conditioning regimens included either a fludarabine, cyclophosphamide, low-dose TBI regimen or a thiotepa- based reduced intensity regimen. Low-dose anti-thymocyte globulin (ATG) could be included according to each center policy. GVHD prophylaxis included cyclosporine tapered between day

+60 and +180 and mycophenolate mofetil which continued until day +35.

• Baseline characteristics in the two cohorts were similar except use of concomitant ATG was higher in those receiving PTCy 80mg/kg (27% vs 50%; p 0.04). Overall, the median age was 68 years, 45% had comorbidity score was ≥3, and 67% received TBI-based conditioning.
• When comparing those who received PTCy 100mg/kg vs 80mg/kg, the time to neutrophil and platelet engraftment was 21 vs 18 and 27 vs 29 days, respectively. Cumulative incidence of neutrophil and platelet recovery were improved with PTCy 80mg/kg (p=0.01 and 0.02, respectively).
• At day +90, when comparing those who received PTCy 100mg/kg vs 80mg/kg the incidence of grade 2 or higher hemorrhagic cystitis was 13% vs 3% (p=0.09). No difference existed for CMV reactivation, EBV viremia, bacteremia, fungal infections, or left ventricular systolic dysfunction between the two cohorts.
• No difference existed in cumulative incidence of grade II-IV or III-IV aGVHD at day +180 or in 2- year cGVHD, including moderate to severe grading. Use of ATG was only associated with reduction in incidence of moderate to severe cGVHD.
• When comparing those who received PTCy 100mg/kg vs 80mg/kg, no difference existed in 2- year relapse incidence (20% vs 19%) or non-relapse mortality (31% vs 16%). With a median follow-up of 42 months and 22 months, the GRFS was 36% vs 52%, PFS 49% vs 65%, and OS 56% vs 70%.
• While limited by retrospective nature of sequential treatment cohorts, a limited number of patients in the 80mg/kg cohort, and some heterogeneity in the transplant regimens, the authors concluded PT-Cy dose can safely be reduced to 80mg/kg total for older adults receiving haploidentical allo-HCT.

*Ueda Oshima M, Xie H, Zamora D, et al. Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation. Blood Adv. 2023;7(8):1394-1403. https://pubmed.ncbi.nlm.nih.gov/36595478

• Single center, retrospective analysis of CMV reactivation and disease among CMV positive patients who received HLA-matched PBSC transplants and GVHD prophylaxis using a calcineurin inhibitor backbone plus PTCy (n=44), MMF (n=414) or MTX (n=322). The study period spanned July 2007 to September 2018 during which patients were not administered letermovir prophylaxis.
• Patients in the MMF group were older and received predominantly NMA conditioning and grafts from older donors compared to patients in the PTCy or MTX groups. Donor CMV seropositive rates were approximately 50% across all three groups.
• Early CMV reactivation (before day 100): the cumulative incidence of CMV ≥250 IU/mL at day 100 was higher in the PTCy group; PTCy: 50% (95% CI: 35-65), MTX: 32% (95% CI: 27-37), and MMF: 39% (95% CI: 34-43; P = .032). After adjusting for recipient and donor age, donor CMV serostatus, donor relationship and conditioning regimen, the risk of CMV reactivation to ≥250 IU/mL was significantly higher in patients who received PTCy (PTCy vs MTX: HR, 1.64; 95% CI, 1.03-2.61; P = .039; MMF vs MTX: HR 1.50 (95% CI, 0.97-2.32; P = .067).
• Late CMV reactivation (day 100 until one year post transplant): at all time points, the HRs for CMV reactivation were numerically lower in the PTCy group and higher in the MMF group relative to patients who received post-transplant MTX.
• Donor CMV seropositivity significantly decreased the risk for CMV disease by day 100 in a univariate and bivariate model that included CMV donor serostatus and PTCy vs non-PTCy GVHD regimens.
• Among MRD and MUD transplant recipients, use of PTCy as GVHD prophylaxis was associated with a higher risk of early CMV reactivation. However, similar rates of late CMV reactivation and overall viral burden were found in the PTCy and MTX prophylaxis. CMV disease was not significantly different between the three GVHD groups at any time point. There was no significant interaction between GVHD regimens and CMV infection on cGVHD.

*Miklos DB, Abu Zaid M, Cooney JP, et al. Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study. J Clin Oncol. 2023;41(10):1876-1887. https://pubmed.ncbi.nlm.nih.gov/36608310/

• Phase 3 randomized, double-blind, placebo-controlled trial in previously untreated moderate or severe cGVHD, which randomly assigned 95 patients to ibrutinib 420 mg once daily plus prednisone 1 mg/kg and 98 patients placebo plus prednisone.
• The primary endpoint of response rate at 48 weeks according to NIH consensus criteria was 41% in the ibrutinib-prednisone arm and 37% in the place-prednisone arm (P=0.54), and the secondary endpoint of median duration of response was 19 months vs. 10 months (P=0.10).
• No new safety signals were identified, with grade ≥3 treatment-emergent adverse events occurring in 68% of patients in the ibrutinib-placebo arm and 67% in the placebo-prednisone arm. This included opportunistic infections (6% and 2%), hyperglycemia (4% and 7%), hypertension (5% and 5%), major hemorrhage (3% and 4%) and atrial fibrillation (2% and 2%).
• No statistically significant difference was observed in the primary or secondary end points with ibrutinib-prednisone treatment.  The primary endpoint was not met.
• Srour M, Alsuliman T, Lebreuche J, et al. Nilotinib efficacy and safety as salvage treatment following imatinib intolerance and/or inefficacy in steroid refractory chronic graft-versus-host-disease (SR- cGVHD): a prospective, multicenter, phase II study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Bone Marrow Transplantation (2023) 58:401–406. https://pubmed.ncbi.nlm.nih.gov/36624161/
   
• Prospective, open-label, non-randomized, multi-center, two-step, phase II trial evaluating the role of nilotinib (Nilo) for salvage treatment after failure/intolerance of imatinib (IM) in patients with SR-cGVHD. The study was conducted in two phases: an induction phase which included initiation of IM (IM-phase) and a salvage phase (Nilo-phase) for patients who did not respond or were intolerant to IM at 12 weeks. The primary endpoint was defined as the 12-week response rate to nilotinib. A 30 percent response rate was the pre-defined response threshold and the sample size goal for the Nilo-phase was 39 patients.
• Study patients were age 18-74 years, post-allogeneic HCT from any stem cell source for any hematological disorder, with confirmed chronic graft-versus-host disease resistant to ≥1 systemic immunosuppressive therapy (SR-cGVHD).
• Imatinib phase: 62 patients were included with initiation of therapy at a median of 12.4 months post cGVHD diagnosis. Patient characteristics include: median of 2 prior lines of therapy [1-4]; most common cGVHD organ involvement - 81% cutaneous, 54% pulmonary, hepatic 50.5%; cGVHD grade - severe 60%, moderate 33%).   IM therapy was initiated at 100mg/day and titrated every 2 weeks to max tolerated dose 400mg/day. At week 12 the response rate was 33% (21% CR; 13% PR) and 22% (14) discontinued due to progression (10%) or intolerance (12%).
• Nilotinib phase: Of the IM treated patients, 29 (12 initial non-responders and 17 with progression or intolerance to IM) received subsequent Nilo salvage at 200mg/day titrated every two weeks to a max tolerated dose of 800mg/day. Of these 29, cGVHD was primarily cutaneous (90%), pulmonary (55), hepatic (48%) and most graded as severe (75.9%). At week 12 of Nilo, the response rate was 21% with 79% discontinuing for intolerance or cGVHD progression.

o  Primary endpoint of response rate to Nilo at week 12 did not reach the prespecified

≥30% threshold. The study failed to reach the enrollment goal in the Nilo-phase and reached a statistical power of 64%.

• With limited subjects evaluated, the authors concluded this study confirmed benefit from imatinib in treatment of SR-cGVHD but failed to demonstrate benefit from salvage nilotinib for those unresponsive/intolerant to imatinib.

CAR-T Therapy

***Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023;141(14):1675- 1684. https://pubmed.ncbi.nlm.nih.gov/36542826

• Phase III, global, multicenter, randomized, open-label trial comparing liso-cel (n=92) to standard second-line therapy (n=92) in adults with relapsed or refractory LBCL.
• Baseline characteristics were similar between the two groups; a numerically higher number of patients in the SOC group were male, age <65 years and had an ECOG PS of zero. Fifty-eight (63%) of patients in the liso-cel cohort received bridging therapy, and eighty-nine received the liso-cel infusion. In the SOC cohort, 43 (47%) received high-dose chemotherapy followed by aHCT and fifty-eight crossed-over to receive liso-cel.
• Superior efficacy was shown in patients treated with second line liso-cel and met the primary endpoint of median EFS not reached (95% CI: 9.5-NR) compared to 2.4 months (95% CI: 2.2-4.9) in the SOC group (HR: 0.356; 95% CI: 0.243-0.522). The 18-month EFS was 52.6% (95%: 42.3- 62.9) and 20.8% (95% CI: 12.2-29.5) for liso-cel and SOC, respectively.
• Patients treated with liso-cel achieved a CR rate of 74% (95%: 63.7-82.5) versus 43% (95% CI: 33.2-54.2) in patients who received SOC therapy (p<0.0001), respectively. The median PFS in the liso-cel arm was NR (95% CI: 12.6-NR) versus 6.2 months (95% CI: 4.3-8.6) in the SOC arm (HR: 0.4; 95% CI: 0.261-0.615; p<0.0001).
• Median OS was NR (95% CI: 29.5-NR) versus 29.9 months (95% CI: 17.9-NR) in the liso-cel and SOC cohorts (HR: 0.724; 95% CI: 0.443-1.183; p=0.0987). After adjustment for the treatment effect of crossing over from the SOC to liso-cel arm, the median OS was NR in both groups. However, the 18-month OS rate favored the liso-cel arm at 73.1% (95% CI:63.9-82.3) compared to 54.1% (95% CI, 43.1-65.2).
• Hematologic TEAE including neutropenia, thrombocytopenia and anemia were the most common grade >3 AEs. Rates of all-grade and grade 3 CRS were 49% and 1%; neurologic events were reported in 11% and 4% of patients, respectively.
• Authors concluded that data showed significant improvements in EFS, CR rate, and PFS for liso- cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL.

**Del Bufalo F, De Angelis B, Caruana I, et al. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Engl J Med. 2023;388(14):1284-1295. https://pubmed.ncbi.nlm.nih.gov/37018492/

• Phase 1-2 dose-escalation and dose-expansion study of GD2-CART01, a novel CAR-T therapy targeting disialoganglioside GD2 with inducible caspase-9 kill switch and both CD28 and 4-1BB costimulatory domains, in pediatric (age 1-25) patients with relapsed, persistent, or progressive neuroblastoma. In phase 2, patients could be enrolled after first-line treatment even if they had a complete response.
• A total of 27 patients were enrolled and received treatment; 26 patients had resistance to at least two lines of treatment (with 24 patients having stage 4 metastatic disease), while onepatient was in complete remission at the end of 1st-line therapy. Thirteen patients had not received prior GD2-directed therapy.
• All patients received fludarabine + cyclophosphamide lymphodepleting chemotherapy prior to infusion of GD2-CART01. Manufacturing was successful in all patients and multiple doses of cells were generated for each patient. Eleven patients received multiple infusions: 7 with two infusions, 3 with three infusions, and 1 with a maximum 4 infusions.
• No DLTs were reported and the RP2D was determined to be 10x106 CAR-positive T cells/kg. CRS was observed in 74% of patients, with only one grade 3 CRS event. One patient received rimiducid to induce the caspase-9 kill switch due to altered consciousness, although further workup revealed a brain hemorrhage as the causative event. Other toxicities included anemia (100%), neutropenia (100%), thrombocytopenia (89%), elevated transaminases (74%), and hyperbilirubinemia (15%).
• Six weeks after infusion of GD2-CART01, 33% of patients achieved or maintained CR, 30% had PR, 19% had SD, and 19% did not respond, for an ORR of 63%. After a median follow-up of 1.7 years, 5 of the 9 patients with initial CR continued to be in remission. Overall, 3-year OS was 40% and EFS 27% (60% and 36%, respectively, in patients who received the RP2D).
• Authors conclude that treatment GD2-CART01 may result in durable remission for some patients with relapsed or refractory neuroblastoma. Additional studies are under way to assess the role of GD2-CART01 in the multimodal treatment of high-risk neuroblastoma.

Supportive Care

** Neofytos D, Steinbach WJ, Hanson K, Carpenter PA, Papanicolaou GA, Slavin MA. American Society for Transplantation and Cellular Therapy Series, #6: Management of Invasive Candidiasis in Hematopoietic Cell Transplantation Recipients. Transplantation and cellular therapy. 2023;29(4):222-

227. https://pubmed.ncbi.nlm.nih.gov/36649748/
     • Guideline update for management of invasive candidiasis (IC) prepared by the practice guidelines committee of ASTCT and Transplant Infectious Disease Special Interest Group to better serve clinical providers with clinical decisions. Topics covered epidemiology, clinical diagnosis, prophylaxis, treatment of IC as well as special considerations for pediatric, cord blood, haploidentical, and T cell depleted HCT recipients and CAR T cell recipients.
     • Clinical presentation: Candida infections occur primarily post conditioning mucositis or severe GI GVHD and indwelling CVC due to translocation of GI flora or CVC infection. Presenting with persistent fever, diffuse maculopapular rash, and bilateral micronodular and ground-glass patterns on chest computed tomography scan.
     • Diagnosis: blood cultures, b-d-glucan, PCR and T2Candida/ magnetic resonance panel
     • Treatment: preferred agents are monotherapy echinocandin (micafungin and caspofungin) and treatment administered for at least 14 days and after both resolution of neutropenia and relevant clinical signs and symptoms and blood culture sterilization. CVC removal is strongly recommended with candidemia in both neutropenic and non-neutropenic patients.
     • Prophylaxis: primary anti-Candida prophylaxis is recommended for all allogeneic HCT recipients (including cord blood, haploidentical or T cell depleted grafts), starting with either conditioning or stem cell infusion and continuing until 75 to 100 days post-transplantation. For patients receiving ≥ 1mg/kg/daily of steroids, posaconazole for Candida and mold coverage is recommended. Mold-active agents (voriconazole, posaconazole) may be used in patients at high risk for IC. Similar approach is recommended in pediatric patients.

• CAR-T cell recipients: recommended from start of chemotherapy until resolution of neutropenia and mucositis. Mold-active agents recommended for CAR-T patients who previously received an allo-HCT, steroid doses ≥ 1mg/kg/day or IL-6 inhibitor administration.

*Scordo M, Gilbert LJ, Hanley DM, et al. Open-label pilot study of romiplostim for thrombocytopenia after autologous hematopoietic cell transplantation. Blood Adv. 2023;7(8):1536-1544. https://pubmed.ncbi.nlm.nih.gov/36409612

• Single-center, single-arm, open-label, pilot study of weekly romiplostim starting day +1 after aHCT until self-sustained platelet count >50 × 109/L in adults with MM, Non-Hodgkin Lymphoma (NHL), or Hodgkin Lymphoma (HL).
• Fifty-nine patients were included in the study population; the median age was 63 years with 58% being male and approximately two-thirds of patients with the diagnosis of MM. Analyses were performed against a retrospective cohort of aHCT patients who did not receive romiplostim (n=853) and a subset matched 1:2 on age, sex, conditioning regimen, CD34+ stem cell dose and number of prior lines of therapy (n=108).
• Patients in the romiplostim-treated group had a median time to platelet engraftment was 19 days (95% CI: 17-20). When compared to romiplostim-naïve patients, the romiplostim cohort experienced similar depth and duration of platelet engraftment, median number of days of grade 4 thrombocytopenia or days necessitating transfusions and number of platelet transfusions during aHCT. The romiplostim group demonstrated delayed enhanced platelet recovery beginning between day +15 and day +21.
• Multivariate analyses using the matched cohorts demonstrated significantly higher platelet count recovery at day +21 and day +30 by an average of 40 × 109/L (95% CI: 14-67; p=0.003) and 118 × 109/L (95% CI: 84-152; p<0.001), respectively.
• At least one adverse event was documented for all patients treated with romiplostim. Seven patients experienced platelet overshoots; while most patients were asymptomatic, one patient developed right posterior pleuritic chest pain and a low-risk pulmonary embolism.
• Romiplostim did not shorten the depth and duration of the platelet nadir post aHCT, it was associated with a promising safety profile and patients achieved significantly improved platelet counts by day +21.

*Mohty M, Blaise D, de Latour RP, et al. Real-world use of defibrotide for veno-occlusive disease / sinusoidal obstruction syndrome: the DEFIFrance Registry Study. Bone Marrow Transplantation 2023; 58:367-376. https://doi.org/10.1038/s41409-022-01900-6.

• Multi-center, post-marketing registry study of retrospective and prospective real-world data on patients receiving defibrotide at 53 French HCT centers conducted from July 2014 to March 2020.
• All patients who received defibrotide for any reason were eligible for the study. Indications included treatment and prophylaxis of for veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with a minority of patients receiving defibrotide for other indications. Diagnosis of VOD/SOS was at the investigator’s discretion using standard criteria and disease severity was graded using EBMT criteria.
• The primary study population was patients who received defibrotide for severe/very severe VOD/SOS post-HCT. The primary endpoints in the primary study population were survival and complete response (CR) at day 100 post-HCT. Key secondary endpoints included treatment- emergent serious adverse events (TESAEs), overall mortality, and VOD/SOS-related mortality.
• Of 798 patients included in the study analysis, 381 received defibrotide for VOD/SOS prophylaxis and 336 received it for VOD/SOS treatment (all severity grades). Of those receiving defibrotide for treatment, 251 had severe/very severe disease, which constituted the primary study population. The median age of the primary study population was 45 years (range: 0, 74) and 23% were pediatric. Myeloablative conditioning was received by 54% of patients (42% in adults and 93% in pediatric) and the most common risk factor for VOD/SOS was prior treatment with hepatotoxic drugs (60%). At diagnosis 22% of patients had anicteric VOD/SOS (bilirubin < 2 mg/dl) and 34% had multi-organ failure.
• At day 100, the Kaplan-Meier (KM) estimated CR (bilirubin ≤ 2 mg/dL, resolution of multiorgan failure) was 74% (95% CI 66%, 81%) in patients with severe/very severe VOD/SOS with a higher CR in patients with severe (84%) vs very severe (63%). The KM estimated day 100 post-HCT survival was 61% (95% CI: 55%, 67%) which was higher for severe (75%) compared to very severe disease (49%). Day 100 CR and survival rates were higher among pediatric patients (CR 93%, survival 88%) than in adult patients (CR 67%, survival 53%). TEAEs of interest occurred in 29% of patients with the most common being infection (17%) and hemorrhage (16%). The VOD/SOS-related mortality at 12 months was 15%.
• In high-risk patients (> 90% had > 2 risk factors) receiving defibrotide for prophylaxis, 20% developed VOD/SOS (34% severe, 34% very severe) by day 30 post-HCT.
• The authors report that this study is the largest collection of real-world data on the post- registration use of defibrotide and that the results demonstrate favorable efficacy and safety in the treatment of severe/very severe VOD/SOS. Outcomes were more favorable in patients with less severe disease highlighting the importance of prompt diagnosis and treatment. Limitations of the study include the absence of a control group and heterogeneity in the use of diagnostic criteria.