Martina Di Palma1, Elio Gentilini2, Chiara Masucci1, Alessandra Micozzi1, Ombretta Turriziani3, Antonino Mulè4, Robin Foà1, Maurizio Martelli1, Gabriella D’Ettorre2, Saveria Capria1* and Sabina Chiaretti1*..
1 Department of Translational and Precision Medicine, Sapienza University, Rome.
2 Department of Public Health and Infectious Diseases, Sapienza University, Rome.
3 Department of Molecular Medicine, Sapienza University, Rome.
4 UOC di Oncoematologia, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
* The two authors equally contributed to this work.
Correspondence to:
Sabina Chiaretti, MD, Ph.D. Department of Translational and Precision Medicine, Sapienza University, Rome, Italy. E-mail:
chiaretti@bce.uniroma1.it
Published: May 1, 2022
Received: March 20, 2022
Accepted: April 15, 2022
Mediterr J Hematol Infect Dis 2022, 14(1): e2022043 DOI
10.4084/MJHID.2022.043
This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0),
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
|
Abstract
Management
of patients with concomitant acute lymphoblastic leukemia (ALL) and
COVID-19 infection is challenging. We describe the clinical history of
a 40-year-old male with relapsed B-common ALL who developed Sars-CoV2
prior to treatment initiation with inotuzumab. Since the patient was
asymptomatic for COVID-19, the first dose of inotuzumab was
administered, followed by remdesivir as prophylaxis. However, a
worsening in respiratory findings led to a delay in administering the
following doses of inotuzumab. Interestingly, even if the patient did
not receive the full inotuzumab cycle, he achieved a complete
hematologic remission: furthermore, he spontaneously developed
anti-sars-COV2 antibodies. COVID-19 treatment also included
convalescent plasma, leading to negativization of the viral load. The
patient, after COVID-19 recovery, received a second full cycle of
inotuzumab, underwent allogeneic transplantation, and is currently in
complete hematologic and molecular remission, in good clinical
conditions, five months from allograft.
|
Case Report
Coronavirus
disease 2019 (COVID-19), caused by Sars-CoV2, has impacted the health
system worldwide. Elderly, immunocompromised, frail, and further
onco-hematologic patients with COVID-19 have a higher mortality rate.[1]
Acute
lymphoblastic leukemia (ALL) is a hematological neoplasm characterized
by a clonal lymphoid proliferation in the bone marrow and possible
involvement of extramedullary sites. Currently, front-line treatment of
adult ALL is based on pediatric-like intensive regimens, often
associated with severe and prolonged immunosuppression and a high risk
of developing infectious complications.[2] However, in
the relapsed/refractory setting, immunotherapeutic agents, particularly
blinatumomab and inotuzumab, are promising compounds that have proven
effective in inducing hematological remissions and minimal residual
disease (MRD) negativity, with less myelosuppression than chemotherapy.
Blinatumomab is a bispecific monoclonal antibody that binds to CD3 and CD19 and activates T cells against leukemic B cells;[3]
inotuzumab is a CD22 monoclonal antibody conjugated to calicheamicin,
currently approved for the use of relapsed-refractory CD22-positive
B-lineage ALL.[4] Despite their clinical efficacy, it
is unclear if their use might be detrimental in patients with a
concomitant Sars-CoV2 infection. Given the rarity of ALL in the adult
population, there is no consensus about incidence, management, and
outcome of COVID-19 in patients with hematological malignancies,
particularly in patients with ALL.
We describe a 40-year-old male
patient with relapsed B-common ALL who developed Sars-CoV2 prior to
treatment initiation. In December 2020, the patient with a Klinefelter
syndrome and a previous B-common ALL treated with the
pediatric-inspired trial NILG ALL10/07 in 2015,[5]
off-treatment since 2015, presented pancytopenia, fever, and dyspnea.
At Viterbo hospital, peripheral blood morphological examination showed
the presence of blasts with a lymphoid habitus. After a negative
Sars-CoV2 nasopharyngeal swab, the patient was admitted to our Center
in Rome. Laboratory tests confirmed the pancytopenia (Hb 10.3 g/dL, WBC
0.64 x 109/l, Plts 43 x 109/l)
and fluorocytometric analysis revealed the presence of 77% CD10+,
CD22+, CD45+, CD19+, CD34+, CD123+, CDc79a+, TdT+ blasts, consistent
with a diagnosis of relapsed B-common ALL. The molecular profile was
negative for the major molecular aberrations (i.e., BCR/ABL1, E2A/PBX1, KMT2A-r).
At
relapse, a chest C.T. scan documented a pulmonary embolism, and a
Doppler ultrasound showed a saphenous thrombosis of the left leg with a
concomitant subcutaneous abscess with cellulitis, extended from the
inguinal region to the femoral-popliteal area, which required
fondaparinux administration and antibiotic treatment
(piperacillin/tazobactam, metronidazole, and daptomycin). In addition,
the patient started methylprednisolone, 60 mg/day, but on 1 January
2021, the Sars-CoV2 nasopharyngeal swab proved positive (later
confirmed also on bronchoalveolar lavage (BAL), and he was therefore
transferred to a COVID-19 ward at our hospital.
The patient did not receive COVID-19 vaccination since no vaccination was available at the time of relapse.
Our ALL strategy contemplated 2 cycles of inotuzumab (0.8 mg/m2 D1, 0.5 mg/m2
D8 and D15) and an allogeneic transplant (allo-SCT), depending on donor
availability. Since the patient was asymptomatic for COVID-19 infection
and the C.T. scan was negative, on 5 January 2021, the first dose of
inotuzumab was administered, followed by the anti-viral drug remdesivir
as prophylaxis for ten days (loading dose 250 mg/day, then 100 mg/day)
starting on day +1 after inotuzumab. However, on day 9, the clinical
conditions worsened, with an acute respiratory syndrome requiring
oxygen support; chest C.T. showed bilateral multilobar ground-glass
opacities (Figure 1A). By day
15, after eight days of neutropenia, an improvement in the radiological
findings and respiratory symptoms was documented. Since a bone marrow
aspirate showed a partial response (30% of blasts), on 22 January (day
17), the second dose of inotuzumab (0.5 mg/m2) was administered. As already observed after the first dose, the respiratory syndrome worsened (Figure 1B)
but again improved with oxygen and steroids support without
non-invasive ventilation; fondaparinux was already ongoing for the
pre-existing thrombosis. This condition lasted until day +50 when it
gradually improved. On day +49, we documented the presence of an
antibody response to Sars-Cov2 (33.6 U/ml, cut-off >1U/ml), but the
Sars-Cov2 nasopharyngeal swab was persistently positive (Figure 2); thus, convalescent plasma (CP, 200 ml/day continuous infusion for three days) was administered, without complications.
![Figure 1](https://www.mjhid.org/mjhid/article/download/4979/version/2082/4185/36213/figure1.jpg) |
Figure
1. Chest T.C. after Inotuzumab. A) Chest T.C. after the 1st dose of Inotuzumab. B) Chest CT after the 2nd dose of Inotuzumab.
|
On
day +67, a bone marrow aspirate revealed a complete hematological
remission with a minimal residual disease of 1% by flow cytometry, and
on day +75, after 20 days from the C.P. infusion, the patient had his
first Sars-CoV2 PCR negative result (Figure 2).
![Figure 2](https://www.mjhid.org/mjhid/article/download/4979/version/2082/4185/36214/figure2.jpg) |
Figure 2. Clinical and laboratory monitoring.
|
On
day +84, the patient was dismissed in hematological remission, with a
1% persistence of leukemic cells by flow cytometry, a negative swab for
Sars-Cov2, and complete recovery of COVID19-related pneumonia.
Meanwhile, there was a slight worsening of the lower left limb
cellulitis, despite the continuous administration of antimicrobic
treatment. In addition, MRI was suggestive of osteomyelitis; thus, the
patient was kept on oral rifampicin and levofloxacin for an additional
month.
He returned to Sicily, where he received the second cycle
of inotuzumab and two doses of I.T. methotrexate, achieving MRD
negativity (by flow and IG/TR). The sars-COv2 vaccine was not
administered to the patient since the patient was going to be
allografted shortly after and also because, as already mentioned, he
did indeed developed antibodies. Therefore, after a conditioning
regimen with TBI and cyclophosphamide, on 9 July 2021, the patient
received a MUD allo-SCT. He presented a mild vein occlusive disease
(VOD), treated with defibrotide. Stem cell engraftment was on day 17.
The patient is currently in good clinical condition, with a normal
blood count and without graft signs.
To date, few cases are
reporting the management of ALL during COVID-19 infection. Treating ALL
patients with a concomitant COVID 19 infection is a challenge,[6],
since a therapeutic delay might negatively impact prognosis. Different
reasons drove our therapeutic choice: the presence of a novel and
poorly known viral disease, the initial patient’s management in a
non-hematology department, and his wish to continue treatment in
Sicily. Considering these aspects, we deemed that inotuzumab ozogamicin
was the most appropriate choice since it is more manageable than
blinatumomab. Indeed, inotuzumab administration does not require a
continuous infusion, which may interfere with remdevisir infusion.
Furthermore, at variance from blinatumomab, whose most frequent side effect is represented by the cytokine release syndrome,[7]
which can confound and worsen the clinical picture of COVID-19,
inotuzumab is in this respect is more manageable; lastly, inozutumab is
a more potent compound in treating ALL with a high burden of disease.
Finally, inotuzumab is more myelosuppressive than blinatumomab but less
than systemic chemotherapy. This effect may have led to an exacerbation
of the respiratory symptoms related to COVID19 pneumonia after each
dose.
The optimal COVID-19 pneumonia treatment remains unclear and
particularly delicate in onco-hematologic patients. Remdesivir is a
nucleotide analog prodrug that inhibits viral RNA replication. Recent
guidelines recommend remdesivir in the presence of a severe infection.
A multicenter randomized trial of remdesivir versus placebo for
COVID-19+ patients demonstrated that patients treated with remdesivir
have a shorter median time to recovery than the placebo group (10 vs.
15 days) and a lower mortality rate (6.7% vs. 11.9%).[8]
However, the optimal duration of treatment with remdesivir is not
well-established. In our COVID19 center, remdesivir is used for five
days in immunocompetent patients. Supported by other studies,[8] we
opted to use remdesivir for ten days in our patient - given the primary
hematologic neoplasm - as a bridge between the first and second dose of
inotuzumab. This choice appeared appropriate since its use improved the
respiratory distress that occurred after the administration of
inotuzumab.
Nevertheless, the patient remained persistently
positive in the nasopharyngeal swab for Sars Cov2. A turning point was
the use of C.P., a passive immunization method previously applied to
other viral infections.[9] The neutral antibodies
(NAbs) against Sars-Cov2 inhibit the entry and viral amplification and
activate different pathways (complement activation, antibody-dependent
cellular cytotoxicity, and phagocytosis).[10]
It was reported that C.P. might reduce mortality and improve symptoms in the elderly with COVID-19,[11] though with disappointing results in the non-onco-hematologic population.[12]
Data on the use of C.P. in COVID-19 patients are increasing, but the
experience in immunocompromised patients is very limited.
Immunocompromised patients are unable to develop an appropriate humoral
immune response to SARS-CoV-2 and are ideal candidates for passive
immunization. Tremblay and colleagues[13] studied 24
patients treated with C.P. with cancer, including 14 with hematological
malignancies: of the latter, eight were discharged, one was
mechanically ventilated, and five died. Heuso et al.[14]
treated 17 patients with CP (15 with hematological diseases). All but
one patient showed a clinical improvement, and 9/17 documented a virus
clearance. Britains and collaborators[15] studied
five onco-hematologic patients with COVID-19 treated with C.P. All
patients developed NAbs, and all but one witnessed a clinical
improvement. However, there is not yet a consensus[16] regarding the dose and timing; results of studies with a larger number of patients are awaited (NCT04393727).
Unexpectedly,
our patient developed antibodies against Sars-Cov2 before C.P.
administration: despite the administration of inotuzumab weakening the
patient’s immune system, he possibly presented a subset of lymphocytes
capable of producing antibodies.
Our experience demonstrates the
complexity in the care of ALL patients and Sars-Cov2 infection. At
present, the patient has recovered from COVID-19 and is at five months
from allogeneic transplant in complete molecular remission and good
clinical conditions, clearly showing that treatment must be continued,
if feasible, and that a multidisciplinary approach is required for the
optimal management of these cases.
Acknowledgments
Work
partly supported by the Associazione Italiana per la Ricerca sul Cancro
(AIRC), Metastases Special Program, N° 21198, Milan, Italy (RF);
Progetti di Rilevante Interesse Nazionale (PRIN) Italia, 2017PPS2X4
project (SC).
References
- Passamonti F, Cattaneo C, Arcaini L, Bruna R, Cavo
M, Merli F. Clinical characteristics and risk factors associated with
COVID-19 severity in patients with haematological malignancies in
Italy: a retrospective, multicentre, cohort study. Lancet Haematol.
2020;7:e737-45. https://doi.org/10.1016/S2352-3026(20)30251-9
- Hoelzer
D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C. Acute
lymphoblastic leukaemia in adult patients: ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up. Ann. Oncol.
2016;27:v69-82. https://doi.org/10.1093/annonc/mdw025 PMid:27056999
- Kantarjian
H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A,
Dombret H, Foà R, Bassan R, Arslan O, Sanz MA, Bergeron J, Demirkan F,
Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Bruggemann M, Klapper
W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS.
Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic
Leukemia. N Engl J Med. 2017;376: 836-47. https://doi.org/10.1056/NEJMoa1609783 PMid:28249141 PMCid:PMC5881572
- Kantarjian
H M , DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W,
Gokbuget N, O'Brien S, Wang K, Wam T, Paccagnella M L, Sleight B,
Vandendries E, Advani AS. Inotuzumab Ozogamicin versus Standard Therapy
for Acute Lymphoblastic Leukemia. N Engl J Med. 2016; 375: 740-53. https://doi.org/10.1056/NEJMoa1509277 PMid:27292104 PMCid:PMC5594743
- Bassan
R, Pavoni C, Intermesoli T, Spinelli O, Tosi M, Audisio E, Marmont F,
Cattaneo C, Borlenghi E, Cortelazzo S, Cavattoni I, Fumagalli M, Mattei
D, Romani C, Cortelezzi A, Fracchiolla N, Ciceri F, Bernardi M,
Scattolin AM, Depaoli L, Masciulli A, Oldani E, Rambaldi A. Updated
risk-oriented strategy for acute lymphoblastic leukemia in adult
patients 18-65 years: NILG ALL 10/07. Blood Cancer J. 2020;10:119. https://doi.org/10.1038/s41408-020-00383-2 PMid:33188164 PMCid:PMC7666128
- Zeidan
AM, Boddu PC, Patnaik MM, Bewersdorf JP, Stahl M, Rampal RK, Shallis R,
Steensma DP, Savona MR, Sekeres MA, Roboz GJ, DeAngelo DJ, Schuh AC,
Padron E, Zeidner JF, Walter RB, Onida F, Fathi A, DeZern A, Hobbs G,
Stein EM, Vyas P, Wei AH, Bowen DT, Montesinos P, Griffiths EA, Verma
AK, Keyzner A, Bar-Natan M, Navada SC, Kremyanskaya M, Goldberg Adm
Al.Kali A., Heaney ML, Mazha A, Salman H, Luger S, Pratz KW, Konig H,
Komrokji R, Deininger M, Xicoy Cirici B, Raj Bhatt V, Silvermann LR,
Erba HP, Fenaux P, Platzbecker U, Santini V, Wang ES, Tallman MS, Stone
RM, Mascarenhas J. Special considerations in the management of adult
patients with acute leukaemias and myeloid neoplasms in the COVID-19
era: recommendations from a panel of international experts. Lancet
Haematol. 2020;7:601-12. https://doi.org/10.1016/S2352-3026(20)30205-2
- Pasrija
R, Naime M. The deregulated immune reaction and cytokines release storm
(CRS) in COVID-19 disease. Int Immunopharmacol. 2021;90:107225. https://doi.org/10.1016/j.intimp.2020.107225 PMid:33302033 PMCid:PMC7691139
- Beigel
JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E,
Chu HY, Leutkemeyer A, Kline S, Lopez de Castilla D, Finberg RW,
Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA,
Short WR, Touloumi G, Chien Lye D, Ohmagari N, Oh MD, Ruiz-Placios GM,
Benfield T, Fatkenkeuer G, Kortepeter MG, Atmar RL, Creech CB,
Lundtgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T,
green M, Makowski M, Osinusi A, Nayak S, Lane HC Remdesivir for the
Treatment of Covid-19 - Final Report. N Engl J Med. 2020;383:1813-26. https://doi.org/10.1056/NEJMoa2007764 PMid:32445440 PMCid:PMC7262788
- Marano
G, Vaglio S, Pupella S, Facco G, Catalano L, Liumbruno GM, Grazzini G.
Convalescent plasma: new evidence for an old therapeutic tool? Blood
Transfusion. 2016:14:152-7.
- Du L, He Y,
Zhou Y, Zheng BJ, Jiang S. The spike protein of SARS-CoV--a target for
vaccine and therapeutic development. Nat Rev Microbiol. 2009;7:226-36. https://doi.org/10.1038/nrmicro2090 PMid:19198616 PMCid:PMC2750777
- Libster
R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, Esteban I,
Caballero MT, Wood C, Berrueta M, Rondan A, Lescano G, Cruz P, Ritou Y,
Fernzandez Vina V, Alvarez Paggi D, Esperante S, Ferreti A, Ofman G,
Ciganda A, Rodriguez R, Lantos J, Valentini R, Itcovici N, Hintze, A,
Oyarvide ML, Etchegaray C, Neira A, Name I, Alfonso J, Lopez Castelo R,
Caruso G, Rapelius S, Alvez F, Etchenique F, Dimase F, Alvarez D,
Aranda SS, Sanchez yanotti C, De Luca J, Jares Baglivo S, Laudanno S,
Nowogrodzki F, Larrea R, Silveyra M, Leberzstein G, Debonis A, Molinos
J, Gonzales M, Perez E, Kreplak N, Pastor Arguello S, Gibbons L,
Althabe F, Bergel E, Polack FP. Early high-titer plasma therapy to
prevent severe Covid-19 in older adults. N. Engl. J. Med.2021;
384:610-8. https://doi.org/10.1056/NEJMoa2033700 PMid:33406353 PMCid:PMC7793608
- Bégin
P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, Zeller MP,
Beaudoin-Bussieres G, Amorim L, Bazin R, Cadogan Loftsgard K, Carl R,
Chasse m, Cushing MM, Daneman N, Devine DV, Dumaresq J, Fergusson DA,
Gabe C, Glesby MJ, Li N, Liu Y, McGeer A, Robtaille N, Sachais BS,
Scales DC, Schwartz L, Shehata N, Turgeon AF, Wook Heidi, Zarychanski
R, Finzi A. Convalescent plasma for hospitalized patients with
COVID-19: an open-label, randomized controlled trial. Nat Med.
2021;27:2012-24. https://doi.org/10.1038/s41591-021-01488-2 PMid:34504336 PMCid:PMC8604729
- Tremblay
D, Seah C, Schneider T, Bhalla S, Feld J, Naymagon L, Wang B, Patel V,
Jun T, Jandl T, Rahman F, Liu STH, Aberg JA, Bouvier N. Convalescent
Plasma for the Treatment of Severe COVID-19 Infection in Cancer
Patients. Cancer Med. 2020;9: 8571-78. https://doi.org/10.1002/cam4.3457 PMid:32945149 PMCid:PMC7537286
- Hueso
T, Pouderoux C, Péré H, Beaumont AL, Raillon LA, Ader F, Chatenoud L,
Eshagh D, Szwebel TA, Martinot M, Camou F, Crickx E, Michel M, Mahevas
M, Boutboul D, Azoulay E, Joseph A, Hermine O, Rouzaud C, Faguer S.
Petua P, Pommeret F, Clerc S, Planquette B, Merabet F, London J, Zeller
V, Ghez D, Veyer D, Ouedran A, Gallian P, pacanowski J, mekinian A,
Granier M, Pirenne F, Tiberghien P, Lacombe K. Convalescent plasma
therapy for B-cell-depleted patients with protracted COVID-19. Blood.
2020;136: 2290-5. https://doi.org/10.1182/blood.2020008423 PMid:32959052 PMCid:PMC7702482
- Betrains
A, Godinas L, Woei-A-Jin FJSH, Rosseels W, Van Herck Y, Lorent N,
Dierickx D, Compernolle V, Meyfroidt G, Vanderbeke L, Vergote V, Lagrou
K, Verhamme P, Wauters J, Vermeersch P, Devos T, Maes P, Vanderschueren
S. Convalescent plasma treatment of persistent severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma
with impaired humoral immunity and lack of neutralising antibodies. Br
J Haematol. 2020; 192: 1100-05. https://doi.org/10.1111/bjh.17266 PMid:33314018
- Fung
M, Nambiar A, Pandey S, Aldrich JM, Teraoka J, Freise C, Roberts J,
Chandran S, Hays SR, Bainbridge E, DeVoe C, Rosque Gardner A, Yokoe D,
Henrich T, Babik JM, Chin-Hong P. Treatment of immunocompromised
COVID-19 patients with convalescent plasma. Transpl Infect Dis. 2021;
23: e13477. https://doi.org/10.1111/tid.13477 PMCid:PMC7537112
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