In this month’s Pharmacy SIG Literature Update: Preventing measles in immunosuppressed cancer and hematopoietic cell transplantation patients, AlloHCT for HIV patients, the role of HCT in the treatment of ALL and much 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

Allogeneic Transplantation

**Ambinder R, Wu J, Logan B, et al.  Allogeneic hematopoietic cell transplant for HIV patients with hematologic malignancies:  the BMT CTN-0903/AMC-080 trial.  Biol Blood Marrow Transplant. 2019;25(11):2160-2166. https://www.ncbi.nlm.nih.gov/pubmed/31279752

• Phase II multicenter trial of 17 patients with HIV who received an alloHCT with MAC (n=8) or RIC (n=9) for hematologic malignancies from May 2012 – December 2015
• Donors were related or unrelated and 8/8 HLA-matched or 7/8 HLA-matched.  One patient was transplanted with a donor homozygous for the CCR5Δ32 and relapsed precluding evaluation of HIV status
• Patients were evaluated by a committee to establish ART therapy which continued through conditioning and minimized drug interactions.  Pre-transplant HIV plasma levels were below level of quantification in 15 patients (88.2%)
• One-year OS was 58.8% (95% CR, 32.5%-77.8%) with primary cause of death relapse/progression (n=5).  One-year NRM was 18.3% (95% CR, 4.1%-40.7%).        Day 100 aGVHD grade 2-4 was 41.2% (95% CR, 17.8%-63.4%) and 1-year cGVHD was 17.6% (95% CR, 4%-39.2%)
• Patients who achieved complete chimeras (n=8) cell-associated HIV DNA was undetectable
• The authors conclude that HIV infection should not preclude patients from alloHCT

**Granot N, Storer B, Cooper J et al.  Allogeneic hematopoietic cell transplantation in the outpatient setting.  Biol Blood Marrow Transplant. 2019;25(11):2152-2159.  https://www.ncbi.nlm.nih.gov/pubmed/31255743   

• Retrospective review of 1037 with hematologic malignancies who received a non-myeloablative alloHCT as an outpatient at the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance (December 1997 – June 2017)
• All conditioning was administered outpatient and consisted of 2-3 Gy TBI on day 0 with fludarabine 30mg/m2/day on days -4 to -2 (n=839), clofarabine 30-50mg/m2/d x  5 days (n=34), or TBI alone (n=164)
• 489 (47%) patients were never hospitalized (61% related recipients and 36% unrelated recipients). 39% of related and 64% of unrelated recipients had >1 admission with a median hospital stay of 6 days.  66% of all admissions occurred in the first 20 days
• Infections were the most common cause for admission and were more frequent in unrelated recipients (23% vs 15%, p=0.001).  Significant risk factors for admission included high comorbidity index scores, malignancy other than myeloma, unrelated grafts, and HLA-mismatch grafts
• The five-year NRM for day 100 survivors was higher for patients who had at least 1 hospital admission compared to non-admission (26% vs 13%, p<0.001).  NRM risk factors included age > 50 years, unrelated grafts, CMV positive patient or donor, increased comorbidities, and at least 1 hospital admission
•  The authors conclude that outpatient non-myeloablative alloHCT is safe and feasible

*Knop S, Engelhardt M, Liebisch P, et al.  Allogeneic transplantation in multiple myeloma: long-term follow-up and cytogenetic subgroup analysis.  Leukemia. 2019;33(11):2710-2719. https://www.ncbi.nlm.nih.gov/pubmed/31462732

• Phase III trial comparing tandem aHCT versus aHCT followed by RIC alloHCT in patients with newly diagnosed multiple myeloma with deletion of chromosome 13q

• After a median of 91 months, median PFS for the auto/alloHCT versus tandem aHCT was 34.5 versus 21.8 months (P=0.003) with a median OS of 70.2 v. 71.8 months (P=0.856).  Two-year NRM was 14.3% versus 4.1% (P=0.008)
• In patients with the deletion of chromosome 13q and 17p, the median PFS and OS were 37.5 and 61.5 months with auto/alloHCT (n = 19) versus 6.1 and 23.4 months with tandem aHCT (n = 6) (P = 0.0002 and 0.032)
• This trial suggests that auto/alloHCT significantly extends PFS versus tandem aHCT in patients with multiple myeloma with deletion 13q, and indicates some survival benefit for first-line alloHCT in high-risk myeloma

**Shimoni A, Labopin M, Savani B, et al.  Comparable long-term outcome after allogeneic stem cell transplantation from sibling and matched unrelated donors in patients with acute myeloid leukemia older than 50 years: a report on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.  Biol Blood Marrow Transplant.  2019;25(11):2251-2260.  https://www.ncbi.nlm.nih.gov/pubmed/31271887

• Retrospective review comparing outcomes for AML patients age >50 years who received a MSD (n=848) or MUD (n=286) alloHCT between 2000-2007 and were alive and leukemia-free after 2 years
• 10-year LFS was 72% for MSD alloHCT and 62% for MUD (p=0.3) and 10-year GRFS was 65% for MSD and 57% for MUD (p=0.47). Factors identified with inferior LFS and GRFS included active disease at time of transplant, CR2 compared to CR1, adverse cytogenetics, female patients, and prior cGVHD
• 10-year NRM was 13% for MSD and 21% for MUD (p=0.15) while 10-year relapse cumulative incidence was 15% for MSD and 17% for MUD (p=0.97). Neither conditioning intensity nor donor type were found to impact NRM or relapse
• Subgroup analysis of donor type, conditioning intensity, and prior cGVHD showed that patients who received RIC and had prior cGVHD resulted in lower LFS for MUD compared to MSD (47% vs 70%, p=0.007) with a higher NRM (33% vs 17%, p=0.006)
• The authors conclude that long-term outcomes are similar for older AML patients regardless of donor type, although MUD may have increased NRM from GVHD

 **Wang Y, Liu QF, Wu DP, et al. Improved survival after offspring donor transplant compared with older aged-matched siblings for older leukaemia patients. Br J Haematol. 2019 Nov. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31696939

• Multicenter retrospective study of patients 50 years or older with intermediate- or adverse risk AML or high-risk ALL in CR1 who received a HCT from offspring or MSD
• Offspring HCT resulted in lower three-year transplant-related mortality (9% vs. 26%; P = 0.023) and relapse incidence (6% vs. 17%; P = 0.066), which led to higher OS (85% vs. 58%; P = 0.003) and LFS (85% vs. 56%; P = 0.001)
• Cumulative incidence of grade II-IV aGVHD and cGVHD was comparable between groups
• The current analyses support that non-HLA donor characteristics, such as kinship and donor age, rather than HLA disparity, predominantly influence survival in older acute leukaemia patients

 

Graft Versus Host Disease

*Finazzi MC, Boschini C, Craddock C, et al. Characteristics of graft-versus-host disease occurring after alemtuzumab-containing allogeneic stem cell transplants: incidence, organ involvement, risk factors and survival. Br J Haematol. 2019 Nov. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31713861

• Study of 201 consecutive adult patients who received an alemtuzumab-based RIC allograft
• After a median follow-up of 24 months, the cumulative incidence of classic acute and late aGVHD grades II–IV was 34% and 20% respectively and the cumulative incidence of classic acute and late aGVHD grades III–IV was 13% and 8% respectively
• The cumulative incidence of classic cGVHD and overlap syndrome were 4% and 7% respectively
• A previous diagnosis of classic aGVHD is a risk factor for cGVHD (HR 10.91, 95% CI 2.35–50.63), while unrelated donor transplant is a risk factor for the development of classic aGVHD (HR 2.28, 95% CI 1.34–3.87)
• This study describes a distinctive pattern of GVHD following alemtuzumab-RIC allografts and identifies the risk factors for GVHD development

 

Haploidentical Transplantation

*Solomon S, Solh M, Zhang X, et al.  Fludarabine and total-body irradiation conditioning before ablative haploidentical transplantation:  long-term safety and efficacy.  Biol Blood Marrow Transplant. 2019;25(11):2211-2216. https://www.ncbi.nlm.nih.gov/pubmed/31247313

• Single center retrospective review of 82 patients with hematologic disease who received MAC for a haploHCT
• Patients received fludarabine 30mg/m²/d on days -7 to -5 and TBI 150 cGy BID on days -4 to -1 followed by a CD34 T-cell replete allograft.  Immunosuppression consisted of PTCy 50mg/kg/d on days +3-+4, tacrolimus/MMF beginning d+5
• With a median follow-up of 47 months (16-95) estimated 4-year OS was 67%, DFS 60%, and cumulative incidence of relapse 27%.  NRM at 4 years was 13%.  Patients with high/very high disease risk index had statistically significant decreased DFS (50% vs 77%, p=0.001) with higher incidence of relapse (38% vs 20%, p=0.32) compared to patients with standard risk disease
• The cumulative incidence of grade 2-4 aGVHD was 52% by d+180 with 17% grade 3-4.  cGVHD cumulative incidence at 4 years was 37% with 12% severe.  GRFS at 4 years post haploHCT was 37%
• There were no cases of graft failure.  Fever occurred in all but one patient in the first 4 days post-transplant but without > grade 2 CRS.  Significant infectious complications included CMV disease (2%) and severe BK cystitis (2%)
• The authors conclude that MAC with fludarabine/TBI is a reasonable alternative for patients who do not have a matched related/unrelated donor

*Xue Y, Suo P, Huang X, et al. Superior survival of unmanipulated haploidentical haematopoietic stem cell transplantation compared with intensive chemotherapy as post-remission treatment for children with very high-risk philadelphia chromosome negative B-cell acute lymphoblastic leukaemia in first complete remission. Br J Haematol. 2019. [ePub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31725190

• Retrospective analysis of 104 pediatric patients with VHR Ph-negative B-ALL in CR1 receiving either unmanipulated haploHCT (Group A) or ongoing chemotherapy (Group B)
• Estimated 3-year probability of OS was 80.6% in Group A and 62.4% in Group B (P = 0.078) and estimated 3-year probability of DFS was 81% in Group A and 52% in Group B (P = 0.005)
• Estimated 3-year probability of NRM in Group A was 9.4% vs. 0% in Group B (P < 0.001)
• In multivariate analysis, persistently positive MRD or conversion from negative to positive MRD and ongoing chemotherapy were independent risk factors associated with worse OS and DFS
• This study indicates haploHCT may be an option for children with VHR Ph-negative B-ALL in CR1, especially for patients with persistent positive or negative-to-positive MRD

 

Infectious Disease

* Chemaly RF, Dadwal SS, Bergeron A, et al. A phase 2, randomized, double-blind, placebo-controlled trial of presatovir for the treatment of respiratory syncytial virus upper respiratory tract infection in hematopoietic-cell transplant recipients. Clin Infect Dis. 2019 Dec. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31793991

• Phase 2, randomized, double-blind, placebo-controlled study of adult alloHCT or aHCT recipients with positive RSV tests
• 189 patients from 43 centers (9 countries) were randomized 1:1 to receive presatovir (200 mg days 1,5,9,13,17) or matching placebo and were stratified by lymphopenia (<200/uL) and ribavirin use
• Presatovir did not significantly affect time-weighted average decline in RSV viral load from day 1 to 9 (-0.33 log₁₀ copies/mL vs -0/02 log₁₀ copies/mL; p=0.040) or progression to lower respiratory tract complications (11.2% vs 19.5%; p=0.11)
• A post-hoc analysis of patients with lymphopenia showed that presatovir decreased lower respiratory tract complications development by day 28 (13.3% vs 64.3%; p=0.008)
• The authors concluded that presatovir was safe but did not improve viral or clinical outcomes in HCT patients with RSV upper respiratory tract infections but some subsets of patients may benefit

** Rogers WS, Westblade LF, Soave R, et al. Impact of a multiplexed PCR panel on identifying diarrheal pathogens in hematopoietic cell transplant recipients. Clin Infect Dis. 2019 Nov. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/31687767

• Single-center, retrospective study at New York Presbyterian Hospital/Weill Cornell Medical Center which replaced conventional stool testing methods (pre-PCR cohort n=163; June 2014-May 2015) with a multiplex PCR panel (PCR cohort n=182; June 2016-May 2017) for inpatients receiving HCT who experienced diarrheal episodes within 1 year of transplant
• Proportion of patients with >1 identified infectious diarrheal pathogen increased from 25% to 37% for the PCR cohort (P = 0.01) while the number of non-CDiff pathogens identified increased from 5% to 27% (P < 0.001)
• The most common non-CDiff pathogens were enteropathogenic Escherichia coli (n=14, 8%), norovirus (n=14, 8%), and Yersinia enterocolitica (n=7, 4%)
• The number of diarrheal episodes with an identified infectious etiology increased from 14% to 23% (P=0.001) while median total costs of stool testing per patent did not increase (pre-PCR: $473; PCR: $425; P=0.025)
• The authors concluded that infectious etiologies of diarrhea were identified in a higher proportion of HCT recipients after replacing conventional stool testing with a multiplexed PCR assay without increasing testing cost

Other

*Bezerra ED, Flowers ED, Onstad LE.  A phase 2 study of alpha interferon for molecularly measurable residual disease in chronic myeloid leukemia after allogeneic hematopoietic cell transplantation.  Leuk Lymphoma. 2019:60(11):2754-2761. https://www.ncbi.nlm.nih.gov/pubmed/31014151

• Post-alloHCT, patients received IFN for disease relapse
• A projected cytogenic relapse at 4.5 years was 12.6% compared to historical trials, and at a median follow-up of 15.6 years, long-term survival was 75%
• This trial was conducted prior to use of tyrosine kinase inhibitors (TKIs); however, IFN showed effectiveness in this patient population and could potentially be used in patients intolerant or resistant to TKI therapy

*Claiborne J, Bandyopathyay D, Roberts C, et al. Managing post allograft relapse of myeloid neoplasms: azacitidine and donor lymphocyte infusions as salvage therapy.  Leuk Lymphoma.  2019;60(11):2733-2743. https://www.ncbi.nlm.nih.gov/pubmed/31046498

• Prospective single-arm multicenter phase-II trial
• Patients (n = 28) with relapsed AML or MDS post-alloHCT received azacitidine and DLI
• One-year OS was 44%, 2-year OS was 35%.  Azacitidine + DLI was associated with remission
• Authors concluded azacitidine + DLI is effective post-alloHCT

***DeFilipp Z, Advani A, Bachanova V, et al.  Hematopoietic cell transplantation in the treatment of adult acute lymphoblastic leukemia:  Updated 2019 evidence-based review from the American Society for Transplantation and Cellular Therapy.  Biol Blood Marrow Transplant. 2019;25(11):2113-2123.  https://www.ncbi.nlm.nih.gov/pubmed/31446198

• Updated review and consensus recommendations by a panel of experts on the role of HCT in the treatment of ALL
• Indications for AlloHCT
  • Ph-negative ALL:   standard- or high-risk ALL in CR1 or MRD-positive CR1, > CR2 but MRD-negative preferred, refractory disease consider novel therapies
  • Ph-positive ALL:  CR1 with HLA-matched donor, aHCT may be utilized for consolidation if alloHCT not an option
  • AYA Ph-negative ALL:  high-risk, CR2, or persistent MRD post-induction, standard-risk CR1 treated with pediatric regimens recommended to continue chemotherapy
• Disease and transplant:
  • Prior CNS positive disease:  CNS prophylaxis not supported
  • TBI-based conditioning is standard of care for MAC
• Post-transplant maintenance with TKI for Ph-positive ALL recommended
• Research needed on MRD assessment, alternative donor sources, and incorporation of targeted and immune therapies

*Modi D, Kim S, Singh V, et al.  Pre-transplant hypomethylating agents do not influence post-transplant survival in myelodysplastic syndrome.  Leuk Lymphoma. 2019;60(11):2762-2770.  https://www.ncbi.nlm.nih.gov/pubmed/31010370

• Retrospective analysis of 172 patients receiving HMAs as pre-transplant cytoreduction for MDS
• Patients were divided into three groups based on blast count prior to alloHCT(group 1:  pre-alloHCT blasts <5 + HMA (n=42), group 2:  pre-alloHCT blasts ≥ 5% with HMA (n=38), group 3:  no HMA (n=92)]
• At a median follow-up of 4.08 years, one-year survival and relapse rates were 75%, 40.2%, and 60.71%, respectively; and 17.6%, 26.6%, and 9.8%, respectively, with no differences in OS
• Authors concluded that a higher relapse rate was observed in the non-responding patients, indicating possible chemotherapy resistant disease

*Murphy J, McKenna M, Abdelazim S, et al.  A practical guide to gynecologic and reproductive health in women undergoing hematopoietic stem cell transplant.  Biol Blood Marrow Transplant. 2019;25(11):e331-e343. https://www.ncbi.nlm.nih.gov/pubmed/31394266

• Comprehensive review on gynecologic care for women prior, during, and after HCT
• Pre-transplant patients should be assessed and counseled on fertility preservation, predisposing gynecologic complications such as HPV disease, management of menses, and sexual health
• Post-transplant patients should be evaluated for genital GVHD, HPV vaccination when appropriate, assessment of ovarian function, hormonal therapy considerations, sexual health, and fertility

**Pergam S, Englund J, Kamboj M, et al.  Preventing measles in immunosuppressed cancer and hematopoietic cell transplantation patients:  A position statement by the American Society for Transplantation and Cellular Therapy.  Biol Blood Marrow Transplant. 2019;25(11):e321-e330. https://www.ncbi.nlm.nih.gov/pubmed/31394271

• Frequently asked questions addressed by specialists in infectious diseases and HCT/cellular therapy on measles in immunocompromised patients including diagnosis, outcomes, treatment, and vaccination.  Due to lack of published data, recommendations are based predominantly on expert opinion per the authors
• Treatment of measles consists of supportive care.  Use of IVIG for post-exposure prophylaxis is not recommended.  Vitamin A in children is low risk and recommended by the WHO
• Revaccination with MMR is recommended 24 months post HCT and off immunosuppression and certain maintenance therapies
• Early revaccination during outbreaks of measles are delineated for aHCT, alloHCT, and CAR T-Cell patients based on patient characteristics

Abbreviations:

AE: adverse event

aGVHD: acute graft-versus-host disease

aHCT: autologous hematopoietic cell transplantation

alloHCT: allogeneic hematopoietic cell transplantation

ALL: acute lymphoblastic leukemia

AML: acute myeloid leukemia

ART: antiretroviral therapy

AYA: adolescent and young adult

CAR T-cell: chimeric antigen receptor T-cell

cGVHD: chronic graft-versus-host disease

CDI: Clostridioides difficile infection                                 

CMV: cytomegalovirus

CR: complete response

CRS: cytokine release syndrome

DFS: disease-free survival

DLI: donor lymphocyte infusion

GRFS: graft-versus-host disease, relapse-free survival

GVHD: graft-versus-host disease

haploHCT: haploidentical hematopoietic cell transplantation

HCT: hematopoietic cell transplantation

HIV: human immunodeficiency virus

HLA:  human leukocyte antigen

HMA: hypomethylating agent

HPV: human papilloma virus

IFN: alpha-interferon

IVIG: intravenous immunoglobulin

LFS: leukemia-free survival

MAC: myeloablative conditioning

MDS: myelodysplastic syndrome

MMF: mycophenolate mofetil

MMR: measles, mumps, and rubella

MRD: minimal residual disease

MSD: matched sibling donor

MUD: matched unrelated donor

NRM: non-relapse mortality

OS: overall survival

PFS: progression-free survival

PTCy: post-transplant cyclophosphamide

RIC: reduced-intensity conditioning

RSV: respiratory syncytial virus

TBI: total-body-irradiation

TKI: tyrosine kinase inhibitor

VHR: very high-risk

WHO: World Health Organization

 

ASTCT Pharmacy SIG Communications Working Committee:

Brandi Anders, Telyssa Anderson, Tiene Bauters, Eileen Chen, Jason Jared, Kathryn Maples, Amanda Peffer, Ryan Shaw, Meg Taylor, Jamie Ziggas

Tags: Pharmacy SIG, literature update, HIV, AlloHCT